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DOI： 10.2967/jnumed.122.263838

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BACKGROUND: Connecting individuals in need of psychiatric treatment with adequate medical services has been a major strategy for suicide prevention in Japan. By investigating serious suicide attempters admitted to our Critical Care Medical Center (CCM), we aimed to examine longitudinal changes in the psychiatric treatment status of high-risk suicidal individuals, and to explore the association between any improvement in psychiatric treatment status and suicide decline. METHODS: Subjects from two periods, 2006-2011 and 2012-2017, were enrolled. We collected the data of 32,252 suicides in Tokyo from police reports and the data of 942 suicide attempters admitted to CCM from medical records. Data were annually collected by both age and gender for the number of suicide completers, the number of suicide attempters, and the psychiatric treatment rates, respectively. ANOVA and t-test were used to examine whether there were differences in the number of suicides and attempers between the two periods. The difference in psychiatric treatment rate between the two periods was examined by chi-square test. Additionally, we used Pearson's correlation coefficient to analyze any correlation between annual treatment rate and the number of suicide completers in subgroups with altered psychiatric treatment rates. RESULTS: The number of suicide attempters in the 20-39-year age group of decreased together with the number of suicides. Psychiatric treatment rates of male attempters aged 20-59 years improved significantly from 48.7 to 70.6% and this improvement correlated with a decrease in suicides. However, psychiatric treatment rates in the elderly, which have the highest number of suicides in both genders, did not improve and remain low. CONCLUSIONS: The number of suicide attempters, as well as that of suicides, decreased in Tokyo. Improvement of psychiatric treatment status in high-risk suicidal male adults may have contributed to the reduction of suicides in Tokyo. However, the continuing low rate of psychiatric treatment in the elderly is a pressing issue for future suicide prevention.

DOI： 10.1186/s12888-022-03866-7

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DOI： 10.1186/s13550-022-00882-2

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DOI： 10.1021/acschemneuro.1c00730

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BACKGROUND: The number of suicides in Japan decreased during the period from 2012 through 2019. Because data on factors associated with this decline are limited, we conducted a retrospective longitudinal study of psychiatric diagnoses of serious suicide attempters before 2012 and after 2019. METHODS: Serious suicide attempters admitted to the critical care medicine (CCM) department of Nippon Medical School Hospital between 2006 and 2017 were included and classified as those before and after the suicide decline in 2012. Chi-square test and residual analysis were used to analyze changes in the proportion of suicide attempters among all patients admitted to CCM and to examine differences in the proportion of psychiatric diagnoses. RESULTS: The proportion of suicide attempters among CCM hospitalized patients decreased overall (χ2 (1) =18.29, p<.01). The proportion of psychiatric diagnoses changed significantly (χ2 (8) =62.21, p<0.001); specifically, it decreased for schizophrenia (residual: -2.28), depressive disorders (residual: -5.39), persistent mood disorders (residual: -3.58), and reaction to stress disorders (residual: -2.73). Depressive disorders decreased and had a large contribution ratio in both sexes. CONCLUSIONS: The decrease in the proportion of attempted suicides among patients admitted to CCM was consistent with the decline in suicides in Japan. Analysis by psychiatric diagnosis confirmed a significant decrease in the proportion of suicide attempts associated with depressive disorders, schizophrenia, and reaction to stress disorders, which were the most common disorders associated with attempted suicide. Depressive disorders made the greatest contribution to the reduction in suicide attempts.

DOI： 10.1272/jnms.JNMS.2022_89-405

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Rationale

Since ephedrine has a dopamine transporter (DAT) inhibitory effect similar to amphetamine, dl-methylephedrine, a derivative of ephedrine, is considered to have the characteristics of a central nervous system stimulant due to the DAT inhibitory effect. For example, the World Anti-Doping Agency categorizes dl-methylephedrine as a stimulant in the prohibited list for competitions. Assuming to have the same effect as ephedrine, the urinary concentration of dl-methylephedrine is regulated below 10 μg/mL, as is ephedrine. However, the extent to which dl-methylephedrine affects brain function is not yet fully understood.

Objectives

The purpose of this study was to evaluate DAT occupancy by a single oral administration of a daily dose of dl-methylephedrine using positron emission tomography (PET) with [¹⁸F]FE-PE2I to characterize its stimulatory effect on the central nervous system.

Methods

Nine healthy male volunteers were enrolled in the study. The experiments were designed as a placebo-controlled randomized double-blind crossover comparative study. After the first PET scan in a drug-free state, the second and third PET scans were performed with randomized dosing at 60 mg of dl-methylephedrine or placebo. The plasma and urine concentrations of dl-methylephedrine were measured just before and after the PET scans, respectively.

Results

Mean urine and plasma concentrations of dl-methylephedrine were 13.9 μg/mL and 215.2 ng/mL, respectively. Mean DAT occupancy in the caudate was 4.4% for dl-methylephedrine and 1.2% for placebo. Mean DAT occupancy in the putamen was 3.6% for dl-methylephedrine and 0.5% for placebo. There was no significant difference of DAT occupancies between the groups.

Conclusion

In this study, the urinary concentration of dl-methylephedrine (13.9 μg/mL) was higher than the prohibited reference value (10.0 μg/mL), and there was no significant difference in DAT occupancy between dl-methylephedrine and placebo. These findings suggest that a clinical daily dose of dl-methylephedrine may exceed the doping regulation value according to urine concentration; however, it was considered that at least the central excitatory effect mediated by DAT inhibition was not observed at the daily dose of dl-methylephedrine.

DOI： 10.3389/fpsyt.2022.799319

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Electroconvulsive therapy (ECT) is an effective treatment for depressive disorders, although its molecular mechanism of action is unknown. The serotonin 1B (5-HT) receptor is a potential target for treatment of depression and low 5-HT receptor binding in limbic regions has been reported in previous positron emission tomography (PET) studies of depression.The objective of this longitudinal PET study was to examine the effect of ECT for depression on 5-HT receptor binding. Fifteen hospitalized patients with major depressive episodes were examined with PET and the 5-HT receptor selective radioligand [C]AZ10419369, before and after ECT. Fifteen controls matched for age and sex were examined. Limbic regions with previously reported low 5-HT receptor binding in depression and a dorsal brain stem region were selected.Thirteen patients completed the study according to protocol. Eleven out of thirteen patients responded to ECT. 5-HT receptor binding in hippocampus increased with 30 % after ECT (p=0.021). Using linear mixed effects modelling, we observed increases in 5-HT receptor binding following ECT with a moderate to large effect size, which did not differ significantly between regions.

DOI： 10.1016/j.jad.2021.07.060

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Anodal transcranial Direct Current Stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) is known as one of the useful applications for improving depressive symptoms or cognitive performance. Antidepressive effects by anodal tDCS over the left DLPFC are expected, but the neural mechanisms of these effects are still unclear. Further, in depression, reduced performance and left prefrontal hypofunction during verbal fluency task (VFT) are generally known. However, few studies have examined the effect of tDCS on the language-related cerebral network. We aimed to investigate whether anodal tDCS at the left DLPFC affects cognitive performance and the neural basis of verbal fluency.Nineteen healthy volunteers participated in this study. The effects of tDCS on cognitive behavior and cerebral function were evaluated by 1) performance and accuracy of implicit/explicit motor learning task (serial reaction time task: SRTT/sequential finger-tapping task: SFTT), and 2) cerebral activation while the subjects were performing VFT by using a functional MRI protocol of a randomized sham-controlled, within-subjects cross-over design.Reaction times of implicit motor learning task were

DOI： 10.1111/pcn.13208

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DOI： 10.1007/s00213-020-05698-3

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DOI： 10.1158/1078-0432.CCR-19-1871

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DOI： 10.1016/j.bja.2020.08.052

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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AIM: Dysfunction of dopaminergic neurons in the central nervous system is considered to be related to major depressive disorder (MDD). Especially, MDD in geriatric patients is characterized by anhedonia, which is assumed to be associated with reduced dopamine neurotransmission in the reward system. Dopamine transporter (DAT) is considered to reflect the function of the dopamine nerve system. However, previous DAT imaging studies using single photon emission computed tomography or positron emission tomography (PET) have shown inconsistent results. The radioligand [18 F]FE-PE2I for PET enables more precise evaluation of DAT availability. Hence, we aimed to evaluate the DAT availability in geriatric patients with MDD using [18 F]FE-PE2I. METHODS: Eleven geriatric patients with severe MDD and 27 healthy controls underwent PET with [18 F]FE-PE2I, which has high affinity and selectivity for DAT. Binding potentials (BPND ) in the striatum (caudate and putamen), nucleus accumbens (NAc), and substantia nigra were calculated. BPND values were compared between MDD patients and healthy controls. RESULTS: MDD patients showed significantly lower DAT BPND in the NAc (P = 0.009), and there was a trend of lower BPND in the putamen (P = 0.032) compared to controls. CONCLUSION: We found low DAT in the NAc and putamen in geriatric patients with severe MDD, which could be related to dysregulation of the reward system.

DOI： 10.1111/pcn.13020

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DOI： 10.1021/acschemneuro.0c00161

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The metabotropic glutamate receptor subtype mGluR5 has been proposed as a potential drug target for CNS disorders such as anxiety, depression, Parkinson's disease and epilepsy. The AstraZeneca compound AZD9272 has previously been labeled with carbon-11 and used as a PET radioligand for mGluR5 receptor binding. The molecular structure of AZD9272 allows to label the molecule with fluorine-18 without altering the structure. The aim of this study was to develop fluorine-18 analogue of AZD9272 and to examine its binding distribution in the non-human primate brain in vivo as well as to obtain whole body radiation dosimetry. [18F]AZD9272 was successfully synthesized from nitro precursor. The radioligand was stable, with a radiochemical purity of >99% at 2h after formulation in a sterile phosphate buffered solution (pH = 7.4). After injection of [18F]AZD9272 in two cynomolgus monkeys the maximum whole brain radioactivity concentration was 4.9-6.7 % of injected dose (n=2) and PET images showed a pattern of regional radioactivity consistent with that previously obtained for [11C]AZD9272. The percentage of parent radioligand in plasma was 59 and 64% (n=2) at 120 min after injection of [18F]AZ

DOI： 10.1021/acschemneuro.9b00680

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DOI： 10.1007/s00259-020-04739-5

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Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT receptors. The 5-HT receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand. It is of interest to know whether the intrinsic activity of a PET radioligand for the 5-HT receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity C-labeled 5-HT PET radioligands with differing intrinsic activity were applied to PET measurements in cynomolgus monkey to evaluate their sensitivity to be displaced within the brain by endogenous 5-HT. For these experiments, fenfluramine was pre-administered at two different doses (1.0 and 5.0 mg/kg, i.v.) to induce synaptic 5-HT release.A dose-dependent response to fenfluramine was detected for all three radioligands. At the highest dose of fenfluramine (5.0 mg/kg, i.v.), reductions in specific binding in the occipital cortex increased with radioligand agonist efficacy, reaching 61% for [C]3. The most antagonistic radioligand show

DOI： 10.1186/s13550-019-0570-1

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DOI： 10.1016/j.neuropharm.2019.107809

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DOI： 10.1021/acs.jmedchem.9b00847

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DOI： 10.1016/j.bmcl.2019.06.037

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DOI： 10.2967/jnumed.118.217372

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DOI： 10.1016/j.bmcl.2019.04.040

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DOI： 10.1007/s11307-018-1257-0

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DOI： 10.1093/ijnp/pyz003

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DOI： 10.1093/ijnp/pyy089

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DOI： 10.1016/j.nucmedbio.2019.10.003

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DOI： 10.1021/acschemneuro.8b00236

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DOI： 10.1007/s00259-018-4012-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/ijnp/pyy004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer New York LLC  

Purpose: Positron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BPND) of [11C]raclopride in NHP. Procedures: Three cynomolgus monkeys underwent two to three PET measurements with [11C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BPND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region. Results: In each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman’s ρ = − 0.79, p = 0.03), but not with BPND (ρ = − 0.25, p = 0.55). Conclusions: These data suggest that sevoflurane affects the shape of TACs but has no evident effect on BPND in consecutive PET measurements.

DOI： 10.1007/s11307-017-1120-8

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DOI： 10.1021/acs.jmedchem.7b01769

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DOI： 10.1186/s13550-017-0301-4

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DOI： 10.1002/anie.201708744

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NUCLEAR MEDICINE INC  

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (S,S)-C-11-MRB and (S,S)-F-18-FMeNER-D-2, have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using PET in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with (S,S)-C-11-MRB and defluorination with (S,S)-F-18-FMeNER-D-2, which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated F-18 radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including the cerebral cortex using (S,S)-F-18-FMeNER-D-2 PET. Methods: We analyzed our previous (S,S)-F-18-FMeNER-D-2 PET data of 10 healthy volunteers dynamically acquired for 240min with arterial blood sampling. The effects of defluorination on the NET quantification in the superficial cerebral cortex was evaluated by establishing a time stability of NET density estimations with an arterial input 2-tissue-compartment model, which guided the less-invasive reference tissue model and area under the time-activity curve methods to accurately quantify NET density in all brain regions including the cerebral cortex. Results: Defluorination of (S,S)-F-18-FMeNER-D-2 became prominent toward the latter half of the 240-min scan. Total distribution volumes in the superficial cerebral cortex increased with the scan duration beyond 120 min. We verified that 90-min dynamic scans provided a sufficient amount of data for quantification of NET density unaffected by defluorination. Reference tissue model binding potential values from the 90-min scan data and area under the time-activity curve ratios of 70-to 90-min data allowed for the accurate quantification of NET density in the cerebral cortex. Conclusion: We have established methods of quantification of NET densities in the brain including the cerebral cortex unaffected by defluorination using (S,S)-F-18-FMeNER-D-2. These results suggest that we can accurately quantify NET density with a 90-min (S,S)-F-18-FMeNER-D-2 scan in broad brain areas.

DOI： 10.2967/jnumed.116.178913

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC STUDY XENOBIOTICS  

The effect of drugs in the central nervous system (CNS) is closely related to occupancy of their target receptor. In this study, we integrated plasma concentrations, in vitro/in vivo data for receptor or protein binding, and in silico data, using a physiologically based pharmacokinetic model, to examine the predictability of receptor occupancy in humans. The occupancy of the dopamine D2 receptor and the plasma concentrations of the antipsychotic drugs quetiapine and perospirone in humans were collected from the literature or produced experimentally. Association and dissociation rate constants and unbound fractions in the serum and brain were determined in vitro/in vivo using human D2 receptor-expressing membrane fractions, human serum and mouse brain. The permeability of drugs across the blood-brain barrier was estimated based on their physicochemical properties. The effect of a metabolite of perospirone, ID-15036, was also considered. The time profiles of D2 receptor occupancy following oral dose of quetiapine and perospirone predicted were similar to the observed values. This approach could assist in the design of clinical studies for drug development and the prediction of the impact of drug-drug interactions on CNS function in clinical settings. (C) 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.dmpk.2016.07.003

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Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood.
We examined 32 healthy individuals using positron emission tomography (PET) and [C-11]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [C-11]PBR28 in brain and in blood cells.
TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbi.2016.01.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Sixteen healthy volunteers were enrolled and divided into four groups according to the single administration of 10 mg or 20 mg escitalopram, 50 mg sertraline, or 20 mg paroxetine. Four positron emission tomography scans with [C-11]DASB were performed on each subject, the first prior to taking the drug, followed by the others at 4, 24, and 48 h after. Serotonin transporter occupancies of the drugs at each time point were calculated. All drugs showed maximum occupancy at 4 h after dosing and then decreasing occupancies with time. Escitalopram and sertraline showed high occupancies of 69.1-77.9% at 4 h, remaining at 52.8-57.8% after 48 h. On the other hand, paroxetine showed relatively low occupancy of 44.6%, then decreasing to 10.3% at 48 h. Escitalopram (both 10 mg and 20 mg) and sertraline (50 mg) showed high and sustained occupancy. Paroxetine (20 mg) showed relatively low and rapidly decreasing occupancy, possibly due to the low plasma concentration by single dosing schedule. Applying the reported concentration of multiple dosing, 20 mg paroxetine will induce over 80% occupancy. The present study suggested that these drugs and doses would be sufficient for the treatment of depression. (C) 2016 Published by Elsevier Ireland Ltd.

DOI： 10.1016/j.pscychresns.2016.03.006

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Mazindol, an appetite suppressant, inhibits the reuptake of dopamine in the synaptic cleft. It has been considered that mazindol might enhance dopamine transmission in the human brain. However, there has been no study that investigated the extracellular dopamine concentration in vivo.
Using positron emission tomography (PET), we aimed to measure the effect of mazindol on the extracellular dopamine concentration and to evaluate how mazindol affects the dopamine system in the healthy human brain.
Eleven healthy individuals (six males, five females, age 30.9 +/- 4.9 years) were enrolled in this study. Each participant was scanned with [C-11]raclopride on 1 day without any medicine as baseline condition, and on another day with mazindol as drug condition. In the drug condition, participants took mazindol 0.5 mg (N = 5) or 1.5 mg (N = 6) 2 h before the PET scan. Plasma concentrations of mazindol were measured before the injection of [C-11]raclopride, and urine concentrations of mazindol were measured after the scan.
After taking mazindol, the calculated decrease in binding potential (Delta BP) in the striatum was 1.74 % for 0.5 mg and 8.14 for 1.5 mg, and the correlation with the blood concentration of mazindol was significant (P = 0.0016, R (2) = 0.69). Delta BP was not significantly correlated with the urine concentration of mazindol (P = 0.84, R (2) = 0.005).
Mazindol increased the extracellular concentration of dopamine in the human brain, and its effect was dose dependent. A single administration of mazindol, even at usual dosage, elevated dopamine concentration similarly to other addictive drugs, suggesting that the risk of dependence may increase with the mazindol dose.

DOI： 10.1007/s00213-013-3392-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

Tramadol is used for the treatment of pain, and it is generally believed to activate the -opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [C-11]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50mg and 50.2% at 100mg. The estimated median effective dose (ED50) of tramadol was 98.1mg, and the plasma concentration was 0.33g/ml 2h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs).

DOI： 10.1017/S1461145713001764

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Modafinil, a wake-promoting drug used to treat narcolepsy, is a dopamine transporter inhibitor and is said to have very low abuse liability; this, however, is still up for debate. We conducted a dopamine transporter (DAT) occupancy study with modafinil (200 or 300mg) in ten healthy volunteers using positron emission tomography (PET) with [F-18]FE-PE2I, a new PET radioligand with high affinity and selectivity for the dopamine transporter, to characterize its relation to abuse liability. Mean striatal DAT occupancies were 51.4% at 200mg and 56.9% at 300mg. There was a significant correlation between occupancy and plasma concentration, indicating dose dependency of DAT inhibition by modafinil in the striatum, and especially in the nucleus accumbens. This study showed that DAT occupancy by modafinil was close to that of methylphenidate, indicating that modafinil may be near the same level as methylphenidate in relation to abuse liability in terms of dopaminergic transmission.

DOI： 10.1017/S1461145713001612

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Dopamine transporter (DAT) density is considered as a marker of pre-synaptic function. Numerous neuroimaging studies have consistently demonstrated an age-related decrease in DAT density in normal human brain. However, the precise degree of the regional decline is not yet clear. The purpose of this study was to evaluate the effect of the normal aging process on DAT densities in human-specific brain regions including the substantia nigra and thalamus using positron emission tomography (PET) with [F-18]FE-PE2I, a new PET radioligand with high affinity and selectivity for DAT.
Thirty-six healthy volunteers ranging in age from 22 to 80 years were scanned with PET employing [F-18]FE-PE2I for measuring DAT densities. Region of interest (ROI)-based analysis was used, and ROIs were manually defined for the caudate, putamen, substantia nigra, thalamus, and cerebellar cortex. DAT binding was quantified using a simplified reference tissue model, and the cerebellum was used as reference region. Estimations of binding potential in the caudate, putamen, substantia nigra, and thalamus were individually regressed according to age using simple regression analysis. Estimates of DAT loss per decade were obtained using the values from the regression slopes.
There were 7.6, 7.7, and 3.4 % per-decade declines in DAT in the caudate, putamen, and substantia nigra, respectively. By contrast, there was no age-related decline of DAT in the thalamus.
[F-18]FE-PE2I allowed reliable quantification of DAT, not only in the caudate and putamen but also in the substantia nigra. From the results, we demonstrated the age-related decline in the caudate and putamen as reported in previous studies, and additionally for those in the substantia nigra for the first time.

DOI： 10.1007/s12149-013-0798-1

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Purpose The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The F-18-labeled amyloid tracer, [F-18]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1,3-benzoxazol-6-yl)oxy]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [C-11]Pittsburgh compound B (PIB) and [F-18]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared.
Methods Two PET scans, one of each with [C-11]PIB and [F-18]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation.
Results No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [F-18]FACT studies without partial volume correction, while significant differences were observed in [C-11]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [F-18]FACT studies as well as [C-11]PIB. Relatively lower uptakes of [C-11]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [F-18]FACT. Relatively higher uptake of [C-11]PIB in distribution was observed in the frontal and parietal cortices.
Conclusion Since [F-18]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [C-11]PIB and [F-18]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic and histochemical assays of postmortem AD brain sections.

DOI： 10.1007/s00259-013-2620-7

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Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹⁸F]FMeNER-D₂ to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED₅₀) and concentration (EC₅₀) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

DOI： 10.1017/S1461145713001521

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[F-18]FMeNER-D-2 to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200mg/d of nortriptyline. The estimated effective dose (ED50) and concentration (EC50) required to induce 50% occupancy was 65.9mg/d and 79.8ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

DOI： 10.1017/S1461145713001521

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00749&link_issn=&doc_id=20140128110008&doc_link_id=10.11477%2Fmf.1405102636&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1405102636&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.

DOI： 10.1017/S1461145712001009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported &gt;80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [C-11]DASB and (S,S)-[F-18]FMeNER-D-2, in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED50 was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.

DOI： 10.1017/S1461145712001009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Blonanserin is a novel antipsychotic with high affinities for dopamine D-2 and 5-HT2A receptors, and it was recently approved for the treatment of schizophrenia in Japan and Korea. Although double-blind clinical trials have demonstrated that blonanserin has equal efficacy to risperidone, and with a better profile especially with respect to prolactin elevation, its profile of in vivo receptor binding has not been investigated in patients with schizophrenia. Using positron emission tomography (PET), we measured striatal and extrastriatal dopamine D-2 receptor occupancy by blonanserin in 15 patients with schizophrenia treated with fixed doses of blonanserin (ie, 8, 16, and 24 mg/d) for at least 4 weeks before PET scans, and in 15 healthy volunteers. Two PET scans, 1 with [C-11]raclopride for the striatum and 1 with [C-11]FLB 457 for the temporal cortex and pituitary, were performed on the same day. Striatal dopamine D2 receptor occupancy by blonanserin was 60.8% (3.0%) [mean (SD)] at 8 mg, 73.4% (4.9%) at 16 mg, and 79.7% (2.3%) at 24 mg. The brain/plasma concentration ratio calculated from D-2 receptor occupancy in the temporal cortex and pituitary was 3.38, indicating good blood-brain barrier permeability. This was the first study to show clinical daily dose amounts of blonanserin occupying dopamine D-2 receptors in patients with schizophrenia. The clinical implications obtained in this study were the optimal therapeutic dose range of 12.9 to 22.1 mg/d of blonanserin required for 70% to 80% dopamine D-2 receptor occupancy in the striatum, and the good blood-brain barrier permeability that suggested a relatively lower risk of hyperprolactinemia.

DOI： 10.1097/JCP.0b013e3182825bce

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DOI： 10.1111/pcn.12004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The serotonin system is involved in many physiological functions and clinical conditions. Serotonergic neurons originate from the raphe nuclei in the brainstem, and reliable estimates of receptor/transporter availability in the raphe in vivo are thus of interest. Though positron emission tomography (PET) can be used to quantify receptor distribution in the brain, high noise levels prevent reliable estimation of radioligand binding in small regions such as the raphe. For this purpose, parametric imaging in combination with high-resolution PET systems may provide images with reduced noise levels and sufficient contrast for reliable quantification. This study examined the potential to evaluate radioligand binding in brainstem nuclei, and assessed the effect of improved resolution on the outcome measures.
For comparative purposes, radioligand binding was measured with an ECAT EXACT HR PET system (resolution about 4.5 mm FWHM) and a high-resolution research tomograph (HRRT) system (resolution about 1.5 mm FWHM). Six subjects were examined with both systems on the same day using the serotonin transporter radioligand [C-11]MADAM. Parametric images of binding potential (BP (ND)) were obtained using a wavelet-aided approach. Regions of interest (ROIs) were delineated using a threshold-based semiautomatic delineation procedure for five brainstem structures. Regional BP (ND) values were estimated by applying the ROIs to the parametric images, and the percentage difference in BP (ND) between the systems was calculated.
Signals for [C-11]MADAM binding were obtained for all five brainstem structures. Overall, the HRRT provided 30-40 % higher BP (ND) values than the HR (p = 0.0017), independent of thresholds used in the ROI delineation procedure.
The methodology used enabled the estimation of [C-11]MADAM binding in the small nuclei of the brainstem. Differences in the BP (ND) values calculated using data from the two systems were mainly attributable to their differing resolutions. The estimated BP (ND) values provided lower across-subject variability than those previously obtained using compartment analysis. This procedure may therefore facilitate quantitative studies of receptor/transporter availability in the brainstem.

DOI： 10.1007/s00259-012-2260-3

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Aim The aim of this study was to investigate the influences of menopause on brain morphological changes in schizophrenia using magnetic resonance imaging (MRI). Methods Forty female schizophrenia patients, 20 premenopausal and 20 postmenopausal, and 50 female controls underwent cerebral MRI. Optimized voxel-based morphometry was performed with Statistical Parametric Mapping version 5. Results Compared with controls, regional gray matter reductions in schizophrenia patients were observed in the insula, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, and thalamus. Direct comparison between the patient groups showed that the gray matter of postmenopausal patients was significantly smaller when compared with premenopausal patients in the left middle frontal gyrus, and no region had significantly lower gray matter volume in premenopausal patients relative to postmenopausal patients. Significant negative correlation between gray matter volume and the interval after menopause was found in the right superior frontal gyrus in the postmenopause patient group. Conclusion Differential morphological alterations between postmenopausal and premenopausal schizophrenia patients were observed, suggesting that the female hormone plays a protective role against schizophrenia. © 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.

DOI： 10.1111/pcn.12003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aim The aim of this study was to investigate the influences of menopause on brain morphological changes in schizophrenia using magnetic resonance imaging (MRI). Methods Forty female schizophrenia patients, 20 premenopausal and 20 postmenopausal, and 50 female controls underwent cerebral MRI. Optimized voxel-based morphometry was performed with Statistical Parametric Mapping version 5. Results Compared with controls, regional gray matter reductions in schizophrenia patients were observed in the insula, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, and thalamus. Direct comparison between the patient groups showed that the gray matter of postmenopausal patients was significantly smaller when compared with premenopausal patients in the left middle frontal gyrus, and no region had significantly lower gray matter volume in premenopausal patients relative to postmenopausal patients. Significant negative correlation between gray matter volume and the interval after menopause was found in the right superior frontal gyrus in the postmenopause patient group. Conclusion Differential morphological alterations between postmenopausal and premenopausal schizophrenia patients were observed, suggesting that the female hormone plays a protective role against schizophrenia.

DOI： 10.1111/pcn.12003

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DOI： 10.1038/mp.2012.7

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Other Link： http://search.jamas.or.jp/link/ui/2014089220

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Dopamine D-2 receptor partial agonist antipsychotic drugs can modulate dopaminergic neurotransmission as functional agonists or functional antagonists. The effects of antipsychotics on presynaptic dopaminergic functions, such as dopamine synthesis capacity, might also be related to their therapeutic efficacy. Positron emission tomography (PET) was used to examine the effects of the partial agonist antipsychotic drug aripiprazole on presynaptic dopamine synthesis in relation to dopamine D-2 receptor occupancy and the resulting changes in dopamine synthesis capacity in healthy men. On separate days, PET studies with [C-11] raclopride and L-[beta-C-11]DOPA were performed under resting condition and with single doses of aripiprazole given orally. Occupancy of dopamine D-2 receptors corresponded to the doses of aripiprazole, but the changes in dopamine synthesis capacity were not significant, nor was the relation between dopamine D-2 receptor occupancy and these changes. A significant negative correlation was observed between baseline dopamine synthesis capacity and changes in dopamine synthesis capacity by aripiprazole, indicating that this antipsychotic appears to stabilize dopamine synthesis capacity. The therapeutic effects of aripiprazole in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

DOI： 10.1371/journal.pone.0046488

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UNLABELLED: (18)F-(E)-N-(3-iodoprop-2E-enyl)-2β-carbofluoroethoxy-3β-(4-methylphenyl)nortropane ((18)F-FE-PE2I) is a new PET radioligand with a high affinity and selectivity for the dopamine transporter (DAT). In nonhuman primates, (18)F-FE-PE2I showed faster kinetics and less production of radiometabolites that could potentially permeate the blood-brain barrier than did (11)C-PE2I. The aims of this study were to examine the quantification of DAT using (18)F-FE-PE2I and to assess the effect of radiometabolites of (18)F-FE-PE2I on the quantification in healthy humans. METHODS: A 90-min dynamic PET scan was obtained for 10 healthy men after intravenous injection of (18)F-FE-PE2I. Kinetic compartment model analysis with a metabolite-corrected arterial input function was performed. The effect of radiometabolites on the quantification was evaluated by time-stability analyses. The simplified reference tissue model (SRTM) method with the cerebellum as a reference region was evaluated as a noninvasive method of quantification. RESULTS: After the injection of (18)F-FE-PE2I, the whole-brain radioactivity showed a high peak (∼3-5 standardized uptake value) and fast washout. The radioactive uptake of (18)F-FE-PE2I in the brain was according to the relative density of the DAT (striatum > midbrain > thalamus). The cerebellum showed the lowest uptake. Tissue time-activity curves were well described by the 2-tissue-compartment model (TCM), as compared with the 1-TCM, for all subjects in all regions. Time stability analysis showed stable estimation of total distribution volume with 60-min or longer scan durations, indicating the small effect of radiometabolites. Binding potentials in the striatum and midbrain were well estimated by the SRTM method, with modest intersubject variability. Although the SRTM method yielded a slight underestimation and overestimation in regions with high and low DAT densities, respectively, binding potentials by the SRTM method were well correlated to the estimates by the indirect kinetic method with 2-TCM. CONCLUSION: (18)F-FE-PE2I is a promising PET radioligand for quantifying DAT. The binding potentials could be reliably estimated in both the striatum and midbrain using both the indirect kinetic and SRTM methods with a scan duration of 60 min. Although radiometabolites of (18)F-FE-PE2I in plasma possibly introduced some effects on the radioactivity in the brain, the effects on estimated binding potential were likely to be small.

DOI： 10.2967/jnumed.111.101626

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D-2 receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D-2 receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D-2 receptors have reported inconsistent results regarding regional differences of dopamine D-2 receptor occupancy by aripiprazole.
To test the hypothesis of preferential binding to extrastriatal dopamine D-2 receptors by aripiprazole, we investigated its regional dopamine D-2 receptor occupancies in healthy young subjects.
Using PET and two radioligands with different affinities for dopamine D-2 receptors, [C-11]raclopride and [C-11]FLB457, striatal and extrastriatal dopamine D-2 receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects.
Our data showed that dopamine D-2 receptor occupancies in the striatum measured with [C-11]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [C-11]FLB457 ranging from 46.6% to 58.4%.
In the present study, preferential extrastriatal dopamine D-2 receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D-2 receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.

DOI： 10.1007/s00213-011-2633-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NUCLEAR MEDICINE INC  

F-18-(E)-N-(3-iodoprop-2E-enyl)-2 beta-carbofluoroethoxy-3 beta-(4-methylphenyl)nortropane (F-18-FE-PE2I) is a new PET radioligand with a high affinity and selectivity for the dopamine transporter (DAT). In nonhuman primates, F-18-FE-PE2I showed faster kinetics and less production of radiometabolites that could potentially permeate the blood-brain barrier than did C-11-PE2I. The aims of this study were to examine the quantification of DAT using F-18-FE-PE2I and to assess the effect of radiometabolites of F-18-FE-PE2I on the quantification in healthy humans. Methods: A 90-min dynamic PET scan was obtained for 10 healthy men after intravenous injection of F-18-FE-PE2I. Kinetic compartment model analysis with a metabolite-corrected arterial input function was performed. The effect of radiometabolites on the quantification was evaluated by time-stability analyses. The simplified reference tissue model (SRTM) method with the cerebellum as a reference region was evaluated as a noninvasive method of quantification. Results: After the injection of F-18-FE-PE2I, the whole-brain radioactivity showed a high peak (similar to 3-5 standardized uptake value) and fast washout. The radioactive uptake of F-18-FE-PE2I in the brain was according to the relative density of the DAT (striatum &gt; midbrain &gt; thalamus). The cerebellum showed the lowest uptake. Tissue time-activity curves were well described by the 2-tissue-compartment model (TCM), as compared with the 1-TCM, for all subjects in all regions. Time stability analysis showed stable estimation of total distribution volume with 60-min or longer scan durations, indicating the small effect of radiometabolites. Binding potentials in the striatum and midbrain were well estimated by the SRTM method, with modest intersubject variability. Although the SRTM method yielded a slight underestimation and overestimation in regions with high and low DAT densities, respectively, binding potentials by the SRTM method were well correlated to the estimates by the indirect kinetic method with 2-TCM. Conclusion: F-18-FE-PE2I is a promising PET radioligand for quantifying DAT. The binding potentials could be reliably estimated in both the striatum and midbrain using both the indirect kinetic and SRTM methods with a scan duration of 60 min. Although radiometabolites of F-18-FE-PE2I in plasma possibly introduced some effects on the radioactivity in the brain, the effects on estimated binding potential were likely to be small.

DOI： 10.2967/jnumed.111.101626

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RATIONALE: Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D₂ receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D₂ receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D₂ receptors have reported inconsistent results regarding regional differences of dopamine D₂ receptor occupancy by aripiprazole. OBJECTIVE: To test the hypothesis of preferential binding to extrastriatal dopamine D₂ receptors by aripiprazole, we investigated its regional dopamine D₂ receptor occupancies in healthy young subjects. MATERIALS AND METHODS: Using PET and two radioligands with different affinities for dopamine D₂ receptors, [¹¹C]raclopride and [¹¹C]FLB457, striatal and extrastriatal dopamine D₂ receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects. RESULTS: Our data showed that dopamine D₂ receptor occupancies in the striatum measured with [¹¹C]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [¹¹C]FLB457 ranging from 46.6% to 58.4%. CONCLUSIONS: In the present study, preferential extrastriatal dopamine D₂ receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D₂ receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.

DOI： 10.1007/s00213-011-2633-5

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Language：Japanese   Publisher：(公財)臨床薬理研究振興財団  

臨床で使用されているsulpirideを標識した[11C]sulpirideを開発し、まずサルを用いて基礎的な検討を行った後、ヒト(健常成人2名)を対象に、[11C]sulpirideの全身分布・脳移行性・脳内動態をPETで観察し、さらに臨床用量sulpiride内服後の変化について検討した。結果、サル・ヒトともsulpirideの脳への移行性は低いことが示唆された。臨床用量を内服した場合には、比較的多量のsulpirideが全身(脳外)に曝露されることにより、そのごく一部が脳へ移行し向精神薬としての作用を発現することが推測された。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness.

DOI： 10.1073/pnas.1118687109

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

The central serotonergic (5-HT) system is closely involved in regulating various mental functions such as mood and emotion. In this system, the serotonin transporter (5-HTT) and the 5-HT1A receptor play important roles in the pathophysiology and treatment of mood and anxiety disorders. However, only a few integrated databases have considered the intraindividual relationship between pre-and postsynaptic serotonergic transmission. In the present study, we constructed a database of 5-HTT and 5-HT1A receptors using positron emission tomography (PET) with [C-11]DASB and [C-11]WAY100635, respectively. Seventeen healthy young men participated in this study. After anatomic standardization of original images, BPND was calculated on a voxel-byvoxel basis using reference tissue methods. The highest binding to 5-HTT was observed in the dorsal raphe nucleus, striatum, and thalamus; moderate binding, in the insula and cingulate cortex; and very low binding, in the cerebral neocortex. In contrast, the highest binding to 5-HT1A receptors was seen in the hippocampal regions, insula, neocortical regions, and dorsal raphe nucleus, and very low binding was found in the thalamus and basal ganglia. These distribution patterns were in agreement with those reported in human postmortem studies and previous PET investigations. In addition, exploratory analysis indicated significant negative correlations between the BPND values with both radiotracers in certain regions of the brain, such as the cingulate, insula, and frontal, temporal and parietal cortices (Pearson&apos;s correlation, P &lt; 0.05). These databases facilitate the understanding of the regional distribution of serotonergic neurotransmission function in the living human brain and the pathophysiology of various neuropsychiatric disorders. Synapse 65: 624-633, 2011. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/syn.20883

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

Both presynaptic and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET). While both presynaptic and postsynaptic dopaminergic functions would be regulated by corresponding genes and related to personality traits, the relation between presynaptic and postsynaptic functions in terms of interindividual variation has hardly been investigated. In the present study, both striatal dopamine D(2) receptor binding and endogenous dopamine synthesis rate were measured in the same healthy subjects using PET with [(11)C]raclopride and L-[beta-(11)C]DOPA, respectively, and these two parameters were compared. Two PET studies with [(11)C] raclopride and L-[beta-(11)C] DOPA were performed sequentially at rest condition on 14 healthy men. For [(11)C] raclopride PET, the binding potential was calculated by the reference tissue model method. For L-[beta-(11)C]DOPAPET, the endogenous dopamine synthesis rate was estimated by graphical analysis. A significant negative correlation was observed between the binding potential of dopamine D(2) receptors and endogenous dopamine synthesis rate (r = -0.66, p &lt; 0.05). Although the interindividual variation of binding potential of [(11)C] raclopride would be due to both the interindividual difference in the receptor density and that in the concentration of endogenous dopamine in the synaptic cleft, the negative correlation between parameters for both presynaptic and postsynaptic functions might indicate a compensative relation between the two functions.

DOI： 10.1523/JNEUROSCI.6024-10.2011

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In conventional pharmacological research in the field of mental disorders, pharmacological effect and dose have been estimated by ethological approach and in vitro data of affinity to the site of action. In addition, the frequency of administration has been estimated from drug kinetics in blood. However, there is a problem regarding an objective index of drug effects in the living body. Furthermore, the possibility that the concentration of drug in blood does not necessarily reflect the drug kinetics in target organs has been pointed out. Positron emission tomography (PET) techniques have made progress for more than 20 years, and made it possible to measure the distribution and kinetics of small molecule components in living brain. In this article, we focused on rational drug dosing using receptor occupancy and proof-of-concept of drugs in the drug development process using PET.

DOI： 10.9758/cpn.2011.9.1.9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

The increased proportion of the high-affinity state of dopamine D-2/3 receptors (D-2,D-high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [C-11](R)-2-CH3O-N-n-propylnorapomorphine ([C-11]MNPA), which has an agonistic property to dopamine D-2 receptors (D(2)Rs), is expected to bind preferentially to D-2,D-high. The occupancy of dopamine D(2)Rs by antagonists to receptors has not been investigated using [C-11]MNPA. We compared dopamine D2R occupancies by risperidone, an antagonist to receptors, between [C-11]MNPA and [C-11]raclopride to confirm whether risperidone occupies D-2,D-high and D-2,D-low at almost identical proportions. PET studies were performed on 11 healthy men under resting condition and following oral administration of a single dose of risperidone (0.5-2.0 mg). Striatal receptor occupancy for each radioligand was calculated. The relationship between dose or plasma concentration of risperidone and dopamine D2R occupancy was calculated. Striatal dopamine D2R occupancies measured with [C-11]MNPA and [C-11]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED50 values measured with [C-11]MNPA and [C-11]raclopride were 0.98 and 1.03 mg, respectively. The striatal ED50 values as calculated from plasma concentration were 9.15 ng/ml and 8.01 ng/ml, respectively. Almost identical occupancies and ED50 values were observed between the two radioligands, indicating that risperidone bound to D-2,D-high and D-2,D-low at almost identical proportions in a dose-dependent manner.

DOI： 10.1017/S1461145710001148

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Misestimating risk could lead to disadvantaged choices such as initiation of drug use (or gambling) and transition to regular drug use (or gambling). Although the normative theory in decision-making under risks assumes that people typically take the probability-weighted expectation over possible utilities, experimental studies of choices among risks suggest that outcome probabilities are transformed nonlinearly into subjective decision weights by a nonlinear weighting function that overweights low probabilities and underweights high probabilities. Recent studies have revealed the neurocognitive mechanism of decision-making under risk. However, the role of modulatory neurotransmission in this process remains unclear. Using positron emission tomography, we directly investigated whether dopamine D-1 and D-2 receptors in the brain are associated with transformation of probabilities into decision weights in healthy volunteers. The binding of striatal D-1 receptors is negatively correlated with the degree of nonlinearity of weighting function. Individuals with lower striatal D-1 receptor density showed more pronounced overestimation of low probabilities and underestimation of high probabilities. This finding should contribute to a better understanding of the molecular mechanism of risky choice, and extreme or impaired decision-making observed in drug and gambling addiction.

DOI： 10.1523/JNEUROSCI.3933-10.2010

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It is well known that the positron emission tomography (PET) system is subject to inter-scanner differences of regional radioactivity distribution. In the present study, the effect of inter-scanner difference of regional radioactivity on estimated binding potential (BPND) of [C-11]FLB457 using the simplified reference tissue model (SRTM) was investigated.
Each of the 11 subjects was given two PET scans using [C-11]FLB457, one each with both SET-3000 GCT/X (Shimadzu) and with ECAT EXACT HR+ (Siemens/CTI). In order to assess regional differences between the two scanners, estimated BPND values in six volumes of interest (VOIs) by SRTM method were compared in both individual PET space and anatomical template space after anatomical normalization. Statistical voxel-by-voxel paired t test of BPND images between SET-3000 GCT/X and ECAT EXACT HR+ was also performed.
Shapes of time-activity curves of the two PET scanners were slightly different in each VOI, with estimated BPND values from ECAT EXACT HR+ appearing greater in the cerebral cortical regions and thalamus than that of SET-3000 GCT/X in both individual PET space and anatomical template space after anatomical normalization. Statistical voxel-by-voxel analysis showed similar tendency to BPND value estimation, with greater BPND values from ECAT EXACT HR+ than from SET-3000 GCT/X.
We demonstrated the inter-scanner differences in dopamine D-2 receptor binding measured with [C-11]FLB457. In particular, statistically significant differences of BPND in certain regions were observed between two PET scanners, despite the subject groups being the same. Our results suggest that we reconsider the effect of the scanner model on the measurement of receptor binding.

DOI： 10.1007/s12149-010-0407-5

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHYSICIANS POSTGRADUATE PRESS  

Objective: Hyperprolactinemia is a common side effect of antipsychotic drugs used in the treatment of schizophrenia. However, the magnitude of hyperprolactinemia differs among antipsychotics, and there is no reliable mechanism-related marker for the risk of hyperprolactinemia that would allow us to characterize antipsychotics.
Method: In this study, 11 healthy male subjects taking different doses of sulpiride and 24 male patients with DSM-IV-diagnosed schizophrenia taking different antipsychotic drugs (risperidone, olanzapine, haloperidol, and sulpiride) participated. Positron emission tomography scanning using [C-11] FLB 457 was performed on all subjects. The dopamine D-2 receptor occupancy of antipsychotics in the pituitary and temporal cortex was calculated. Correlations between plasma concentration of prolactin and dopamine D-2 receptor occupancies were evaluated. The ratio of drug concentration of cerebral receptor site to that of pituitary receptor site (brain/plasma concentration ratio; B/P ratio) was calculated from the receptor occupancies in the 2 regions. Data were collected between November 2001 and September 2007.
Results: Significant positive correlation was observed between the plasma concentration of prolactin and dopamine D-2 receptor occupancy in the pituitary by all 4 antipsychotics (P = .001). Dopamine D-2 receptor occupancies of sulpiride were markedly different between the pituitary and temporal cortex, and the B/P ratio for sulpiride (0.34) was significantly lower than for olanzapine (P = .007) and risperidone (P = .015). Olanzapine had a relatively high B/P ratio (2.70), followed by haloperidol (2.40) and risperidone (1.61).
Conclusions: Dopamine D-2 receptor occupancy in the pituitary is a good indicator of hyperprolactinemia. B/P ratio, indicating the penetrating capability across the blood-brain barrier, seems to be a good characteristic biomarker of each antipsychotic drug for the risk of hyperprolactinemia at therapeutic dose. J Clin Psychiatry 2010;71(9):1131 1137 (C) Copyright 2010 Physicians Postgraduate Press, Inc.

DOI： 10.4088/JCP.08m04307yel

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Language：English   Publisher：(一社)日本核医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

Inflammatory/immunological process and glial contribution are suggested in the pathophysiology of schizophrenia. We investigated peripheral benzodiazepine receptors in brains of patients with chronic schizophrenia, which were reported to be located on mitochondria of glial cells, using [C-11]DAA1106 with positron emission tomography. Fourteen patients and 14 age- and sex-matched normal controls participated in this study. PET data were analysed by two-tissue compartment model with metabolite-corrected plasma input. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale. There was no significant difference between [C-11]DAA1106 binding of the cortical regions of normal controls and patients with schizophrenia, whereas the patients showed a positive correlation between cortical [C-11]DAA1106 binding and positive symptom scores. There was also a positive correlation between [C-11]DAA1106 binding and duration of illness. Although the correlations need to be interpreted very cautiously, involvement of glial reaction process in the pathophysiology of positive symptoms or progressive change of schizophrenia might be suggested.

DOI： 10.1017/S1461145710000313

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In our previous positron emission tomography (PET) study, we demonstrated that ECT decreased dopamine D, receptor in major depressive disorder (MDD). Although many animal studies have focused on the effect of ECT on serotonergic neurotransmission, no human study has directly examined the effect of ECT on brain serotonin [5-hydroxytryptamine (5-HT)] 1A receptors (5-HT(1A)Rs). Using PET with [C-11]WAY 100635, we aimed to evaluate the effect of ECT on 5-HT(1A)Rs in patients with MDD. Nine patients underwent PET scans before and after a series of 6-7 bilateral ECTs. Region-of-interest analysis was performed based on the simplified reference tissue model. There were no significant changes in 5-HT1AR binding in patients between before and after ECT. ECT did not alter [C-11]WAY 100635 binding even after recovery from depressive episode. Although the present finding does not exclude the involvement of brain 5-HT1A systems in the antidepressant action of ECT, it may indicate the involvement of other neurotransmission mechanisms.

DOI： 10.1017/S1461145709991209

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Background: Microglial activation and disrupted neurotransmissions may herald symptomatic manifestations in neurodegenerative tauopathies.
Methods: We investigated microglial activation with [(11)C]DAA1106 positron emission tomography (PET), striatal dopaminergic function with L-[beta-(11)C]dopa PET, acetylcholinesterase (AChE) activity with [(11)C]N-methylpiperidin-4-yl acetate PET, and morphologic brain changes with MRI in three persons (aged 38-41 years) with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), who were presymptomatic gene carriers (PGCs) from an American kindred with pallidopontonigral degeneration. The results from these 3 PGCs were compared with [(11)C]DAA1106 PET results from age-matched 9 healthy volunteers (HV), and with L-[beta-(11)C]dopa and [(11)C]MP4A PET results from 10 HV. Values considered significant were more than 2 SDs greater or less than the normal control mean, as the number of subjects was small for group comparisons.
Results: Glial activities were increased in the frontal cortex of one PGC, the occipital cortex of two PGCs, and the posterior cingulate cortex of one PGC, although none of the PGCs showed overt glial activation in the brain. Only one of the PGCs showed reduced AChE activity in the temporo-parietal cortex. Three PGCs showed low dopamine synthesis rates in the putamen. Hippocampal atrophy was observed in two PGCs.
Conclusions: Hippocampal atrophy and striatal dopaminergic dysfunction may be early disease processes in the pathogenesis of FTDP-17. Neuroinflammation may also be an in vivo signature of tau pathology at a prodromal stage, although current PET techniques may not constantly reveal it as the earliest neuroimaging abnormality. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.parkreldis.2010.04.004

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Central norepinephrine transporter (NET) is one of the main targets of antidepressants. Although the measurement of NET occupancy has been attempted in humans, the outcomes have been inconclusive.
In this study, the occupancy of NET by different doses of an antidepressant, nortriptyline, was measured using positron emission tomography (PET) with (S,S)-[F-18]FMeNER-D-2.
PET scans using (S,S)-[F-18]FMeNER-D-2 were performed on six healthy men before and after oral administration of a single oral dose of nortriptyline (10-75 mg). After a bolus i.v. injection of (S,S)-[F-18]FMeNER-D-2, dynamic scanning was performed for 0-90 min, followed by scanning for 120-180 min. The ratio of the thalamus-to-caudate areas under the curve (120-180 min) minus 1 was used as the binding potential (BPND) for NET. NET occupancy was calculated as the percentage reduction of BPND. Venous blood samples were taken to measure the concentrations of nortriptyline just before injection of the tracer and at 180 min after the injection.
Mean NET occupancies by nortriptyline were 16.4% at 10 mg, 33.2% at 25 mg, and 41.1% at 75 mg. The mean plasma concentration of nortriptyline was less than the lower limit of detection at 10 mg, 23.7 ng/mL at 25 mg, and 50.5 ng/mL at 75 mg. Estimated ED50 was 76.8 mg of administration dose and 59.8 ng/mL of plasma concentration.
NET occupancy by nortriptyline corresponding to the administration dose of 10-75 mg or plasma concentration was observed from 16% to 41%.

DOI： 10.1007/s00213-010-1824-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHYSICIANS POSTGRADUATE PRESS  

Objective: Electroconvulsive therapy (ECT) has been confirmed as one of the most effective treatments in drug-resistant major depression. However, the mechanism of ECT is still poorly understood. Although several lines of studies have focused on its effect on dopamine neurotransmission, the effects of ECT on dopamine D-2 receptors in a living human brain have not been investigated. Using positron emission tomography (PET) scans with the radioligand [C-11] FLB 457, we aimed to evaluate the effect of ECT on extrastriatal D-2 receptor binding in medicated patients with major depressive disorder (MDD).
Method: Seven patients with a DSM-IV diagnosis of MDD underwent PET scans before and after a series of 6-7 treatments with bilateral ECT. Eleven healthy controls were scanned for comparison. All participants were scanned at the National Institute of Radiological Sciences, Chiba, Japan, between November 2000 and September 2005. The parametric images of II ICIFLB 457 binding were generated on the basis of a simplified reference tissue model. Voxel-based methods were used to assess the effect of ECT on D-2 receptor binding.
Results: There were no significant differences in D-2 receptor binding between patients with MDD and controls. All 7 patients showed clinical improvements in response to ECT treatment (P &lt;.001). Significant changes in D2 receptor binding, a mean of 25.2% reduction, were found in the right rostra] anterior cingulate (AC) following ECT (P&lt;.001).
Conclusions: Electroconvulsive therapy decreased D2 receptor binding in the rostral AC in MDD patients responding to ECT. Our finding suggests that one of the biologic mechanisms of ECT could be related to dopaminergic alteration in the rostral AC. Clin Psychiatry 2010;71(6):793-799 Copyright (C) 2009 Physicians Postgraduate Press, Inc.

DOI： 10.4088/JCP.08m04746blu

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER HEIDELBERG  

Olanzapine is described as a multi-acting receptor-targeted antipsychotic agent. Although regional differences of dopamine D-2 receptor occupancy, i.e., limbic selectivity, were reported for olanzapine, contradictory results were also reported. We measured dopamine D-2 receptor occupancy of olanzapine in extrastriatal regions in patients with schizophrenia using positron-emission tomography with [C-11]FLB457 and the plasma concentrations of olanzapine. Ten patients with schizophrenia taking 5-20 mg/day of olanzapine participated. Dopamine D-2 receptor occupancy in the temporal cortex ranged from 61.1 to 85.8%, and plasma concentration was from 12.7 to 115.4 ng/ml. The ED50 value was 3.4 mg/day for dose and 10.5 ng/ml for plasma concentration. The ED50 values obtained in this study were quite similar to those previously reported in the striatum. In conclusion, although the subjects and methods were different from previous striatal occupancy studies, these results suggest that limbic occupancy by olanzapine may not be so different from that in the striatum.

DOI： 10.1007/s00406-009-0082-5

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Dopamine transporter (DAT) is a reuptake carrier of dopamine at presynapse that regulates dopaminergic neural transmission. [C-11]PE2I is a cocaine analog developed as a potent positron emission tomography (PET) ligand for DAT with high selectivity. The aim of this study was to evaluate the applicability of quantification methods using reference tissue models for [C-11]PE2I.
Dynamic PET scans were performed in 6 young healthy male volunteers after an intravenous bolus injection of [C-11]PE2I. Metabolite-corrected arterial plasma-input functions were obtained. Compartment model analysis and plasma-input Logan analysis were performed to determine the kinetic parameters and distribution volume (V (T)). The distribution volume ratio (DVR) was calculated as the ratio of V (T) in the cerebral region to that in the cerebellum. DVRs were also determined by the original multilinear reference tissue model method (MRTMo) and the simplified reference tissue model method (SRTM), comparing the results with those obtained from graphical analysis using arterial input function. To estimate errors in DVR calculated using the reference tissue model, a simulation study that focused on cerebellar kinetics and scan duration was performed.
The highest [C-11]PE2I binding was observed in the striatum, followed by the midbrain and thalamus. The 2-tissue model was preferable to the 1-tissue model for describing the [C-11]PE2I kinetics in the cerebellum. Both the measured and 90-min simulated data showed that reference tissue models caused an underestimation of DVR in the striatum. The simulation showed that 90-min scan duration was insufficient when cerebellar kinetics was described as a 1-tissue model. Nevertheless, DVR values determined by MRTMo and SRTM were in good agreement with those by the graphical approach in other lower binding regions.
Due to the [C-11]PE2I kinetics in the cerebellum and limited scan duration for C-11, MRTMo and SRTM underestimated the striatal DVR. Despite this limitation, the present study demonstrated the applicability of reference tissue models. Since DAT in the midbrain and thalamus is of interest in the pathophysiology of neuropsychiatric disease, this noninvasive quantitative analysis will be useful for clinical investigations.

DOI： 10.1007/s12149-010-0364-z

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Perospirone is a novel second-generation antipsychotic drug with high affinity to dopamine D-2 receptor and short half-life of plasma concentration. There has been no investigation of dopamine D-2 receptor occupancy in patients with schizophrenia and the time course of occupancy by antipsychotics with perospirone-like properties.
We investigated dopamine D-2 receptor occupancy by perospirone in patients with schizophrenia and the time course of occupancy in healthy subjects.
Six patients with schizophrenia taking 16-48 mg/day of perospirone participated. Positron emission tomography (PET) scans using [C-11]FLB457 were performed on each subject, and dopamine D-2 receptor occupancies were calculated. Moreover, baseline and three serial PET using [C-11]raclopride were performed at 1.5, 8, and 25.5 h after administration of a single dose of 16 mg of perospirone on four healthy male subjects, and occupancy was calculated for each scan.
Dopamine D-2 receptor occupancy in the temporal cortex of patients ranged from 39.6% to 83.8%. Especially, occupancy in two patients who took 16 mg of perospirone 2.5 h before PET was over 70%. Mean occupancy in the striatum of healthy subjects was 74.8% at 1.5 h, 60.1% at 8 h, and 31.9% at 25.5 h after administration.
Sixteen milligrams of perospirone caused over 70% dopamine D-2 receptor occupancy near its peak level, and then occupancy dropped to about half after 22 h. The time courses of receptor occupancy and plasma concentration were quite different. This single dosage may be sufficient for the treatment of schizophrenia and might be useful as a new dosing schedule choice.

DOI： 10.1007/s00213-010-1783-1

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To investigate the effects of the clinical dose of clarithromycin, a substrate of P-glycoprotein (P-gp), on P-gp function using positron emission tomography (PET) with [C-11]verapamil.
Two PET scanning with [C-11]verapamil were performed before and after administration of 400 mg/day of clarithromycin on each of four healthy male subjects. The rate constant of transfer from plasma to brain (K (1)) was estimated by integration plot method.
K (1) values of [C-11]verapamil before administration of clarithromycin were 0.042-0.070 mL/cm(3)/min (0.054 +/- A 0.012) and those after administration were 0.037-0.066 mL/cm(3)/min (0.055 +/- A 0.013). No significant change in K (1) values of [C-11]verapamil was observed between before and after administration of clarithromycin (P = 0.85).
K (1) values of [C-11]verapamil were not changed by clinical dose administration of clarithromycin, suggesting that a clinical dose of clarithromycin does not affect P-gp function at the blood-brain barrier.

DOI： 10.1007/s12149-009-0336-3

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Several animal studies have demonstrated functional roles of dopamine (DA) D1 and D2 receptors in amygdala activity. However, the contribution of DA D1 and D2 receptors to amygdala response induced by affective stimuli in human is unknown. To investigate the contribution of DA receptor subtypes to amygdala reactivity in human, we conducted a multimodal in vivo neuroimaging study in which DA D1 and D2 receptor bindings in the amygdala were measured with positron emission tomography (PET), and amygdala response induced by fearful faces was assessed by functional magnetic resonance imaging (fMRI) in healthy volunteers. We used multimodality voxelwise correlation analysis between fMRI signal and DA receptor binding measured by PET. DA D1 binding in the amygdala was positively correlated with amygdala signal change in response to fearful faces, but DA D2 binding in the amygdala was not related to amygdala signal change. DA D1 receptors might play a major role in enhancing amygdala response when sensory inputs are affective.

DOI： 10.1523/JNEUROSCI.5689-09.2010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The purpose of this study is to investigate errors in quantitative analysis for estimating dopamine D-2 receptor occupancy of antipsychotics with agonist radioligand [C-11]MNPA by numerical simulation, with particular attention to the validity of a quantitative approach based on the use of a reference region. Synthetic data were validated using clinical data combined with a bootstrap approach. Time-activity curves (TACs) of [C-11]MNPA were simulated, and the reliability of binding potential (BPND) and occupancy estimated by nonlinear least square (NLS) fitting and a simplified reference tissue model (SRTM) were investigated for various noise levels and scan durations. In the human positron emission tomography (PET) study with and without antipsychotic, risperidone, the uncertainty of BPND and occupancy estimated by SRTM was investigated using resampled TACs based on bootstrap approach with weighted residual errors of fitting. For both NLS and SRTM, it was possible to have &lt; 3% of bias in occupancy estimates of [C-11]MNPA by 60 mins. However, shortened scan duration degrades the quantification of very small binding potentials, especially in case of SRTM. Observations were replicated on the clinical data. Results showed that dopamine D-2 receptor occupancy by antipsychotics can be estimated precisely in region of interest analysis by SRTM with a longer than 60-min [C-11]MNPA PET scan duration. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 187-195; doi: 10.1038/jcbfm.2009.193; published online 16 September 2009

DOI： 10.1038/jcbfm.2009.193

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The serotonin transporter (5-HTT) and other markets of the serotonergic system have been of interest in the pathophysiology of obsessive-compulsive disorder (OCD). Previous studies using single photon emission computed tomography (SPECT) with [I-123]beta-CIT or positron emission tomography (PET) with [C-11]McN5652 have not shown consistent findings about 5-HTT in OCD patients. The aim of the present study was to investigate 5-HTT binding using [C-11]DASB, which has higher selectivity or specific binding-to-nonspecific binding ratios for 5-HTT compared to the aforementioned radioligands. Four drug-naive and 6 drug-free patients with OCD who were free of comorbid depression and 18 gender and age-matched healthy subjects underwent PET scans with [C-11]DASB. The severity of OCD was assessed by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (mean +/- SD: 22 +/- 7.6, range: 7-32). The binding potential (BPND) of [C-11]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2). The parametric images of BPND were analyzed using a statistical parametric mapping system. Significant reductions of BPND were observed in the right posterior and left anterior insular cortices in patients with OCD compared to controls. Region-of-interest analysis has also confirmed significant reduction of BPND in the insular cortex. Although significantly reduced BPND in the orbitolfrontal cortex was also observed in patients with OCD compared to controls, this finding should be considered with caution because of the very low 5-HTT binding in the region. On the other hand, no significant correlation was observed between the Y-BOCS score and BPND. The change in [C-11]DASB binding in the insular cortex suggests that dysfunction of the serotonergic system in the limbic area might be involved in the pathophysiology of OCD. (c) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2009.07.069

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aim:
Somatoform pain disorder is characterized by persistent and chronic pain at one or more sites without an associated general medical condition and in which psychological factors are thought to play a role. This study aimed to investigate the pathological features of somatoform pain disorder localized to the oral region by single photon emission computed tomography (SPECT).
Methods:
Ten patients (nine females and one male; average age 55.0 +/- 14.4 years) having somatoform pain disorder with oral symptoms participated. SPECT was performed using N-isopropyl-4-[123I] iodoamphetamine intravenous injections, and regional cerebral blood flow (rCBF) was assessed by three-dimensional stereotactic surface projections. We also selected 12 healthy individuals (seven females and five males; average age 61.8 +/- 13.2 years) to act as controls.
Results:
Both the patient and control groups showed no atrophy or infarction on CT or magnetic resonance imaging. The patient group showed higher rCBF in the subcortical area, especially in the thalamus and cingulate gyri, than the control group. In contrast, the patient group showed lower rCBF in the bilateral frontal and occipital lobes as well as in the left temporal lobe.
Conclusions:
These results suggest that the biological process involved in somatoform pain disorder of the oral region is characterized by changes in limbic and cortical functions. The finding that somatoform pain disorder with oral symptoms is associated with brain functional changes will help to develop treatment regimes for this disorder and clarify the underlying pathology.

DOI： 10.1111/j.1440-1819.2010.02119.x

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Previous in vivo imaging studies reported no difference in dopamine transporter (DAT) bindings in the striatum between control subjects and patients with schizophrenia. However, as the signals of radioligands with moderate affinity were insufficient for allowing the evaluation of small amounts of DAT, DAT binding in extrastriatal regions has not been determined. Positron emission tomography scanning using [C-11]PE2I was performed on eight patients with schizophrenia and twelve normal control subjects. Binding potential (BPND) for DAT in the caudate, putamen, thalamus and substantia nigra was calculated, using the cerebellum as reference region. In patients with schizophrenia, clinical symptoms were evaluated by Positive and Negative Syndrome Scale (PANSS). BPND in the thalamus of patients with schizophrenia was significantly higher than in control subjects (P = 0.044). In patients with schizophrenia, there were significantly positive correlations between BPND in the thalamus and total (r = 0.75), positive (r = 0.78) and negative PANSS scores (r = 0.82). Altered DAT in the thalamus might be related to the pathophysiology and clinical symptoms of schizophrenia. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jpsychires.2009.04.009

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Effects of antipsychotic drugs have widely been considered to be mediated by blockade of postsynaptic dopamine D-2 receptors. Effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission might also be related to therapeutic effects of antipsychotics. To investigate the effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission in relation with occupancy of dopamine D-2 receptors, changes in dopamine synthesis capacity by antipsychotics and occupancy of dopamine D-2 receptors were measured by positron emission tomography (PET) in healthy men. PET studies using [C-11] raclopride and L-[beta-C-11] DOPA were performed under resting condition and oral administration of single dose of the antipsychotic drug risperidone on separate days. Although occupancy of dopamine D-2 receptors corresponding dose of risperidone was observed, the changes in dopamine synthesis capacity by the administration of risperidone were not significant, nor was the relation between the occupancy of dopamine D-2 receptors and these changes. A significant negative correlation was observed between the baseline dopamine synthesis capacity and the changes in dopamine synthesis capacity by risperidone, indicating that this antipsychotic can be assumed to stabilize the dopamine synthesis capacity. The therapeutic effects of risperidone in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

DOI： 10.1523/JNEUROSCI.4172-09.2009

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Peripheral benzodiazepine receptor (PBR) is upregulated in activated glial cells and is therefore a useful biomarker for inflammation in the brain and neurodegenerative disorders. We developed a new PET radioligand, (11)C-AC-N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-pheyl-7,8-dihydro-9H-purin-9-yl)acetamide ((11)C-AC-5216), that allows the imaging and quantification of PBRs in monkey and mouse brains. The aim of this study was to evaluate a quantification method of (11)C-AC-5216 binding in the human brain. Methods: A 90-min dynamic PET scan was obtained for each of 12 healthy men after an intravenous injection of (11)C-AC-5216. Regions of interest were drawn on several brain regions. Binding potential, compared with nondisplaceable uptake (BP(ND)), was calculated by a nonlinear least-squares fitting (NLS) method with the 2-tissue-compartment model, and total volume of distribution (V(T)) was estimated by NLS and graphical analysis methods. Results: BPND was highest in the thalamus (4.6 +/- 1.0) and lowest in the striatum (3.5 +/- 0.7). V(T) obtained by NLS or graphical analysis showed regional distribution similar to BPND. However, there was no correlation between BPND and VT because of the interindividual variation of K(1)/k(2). BPND obtained with data from a scan time of 60 min was in good agreement with that from a scan time of 90 min (r = 0.87). Conclusion: Regional distribution of (11)C-AC-5216 was in good agreement with previous PET studies of PBRs in the human brain. BP(ND) is more appropriate for estimating (11)C-AC-5216 binding than is VT because of the interindividual variation of K(1)/k(2). (11)C-AC-5216 is a promising PET ligand for quantifying PBR in the human brain.

DOI： 10.2967/jnumed.109.062554

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The effects of antipsychotic drugs have generally been considered to be mediated by blockade of dopamine D-2 receptors. The concept of limbic and cortical selectivity of second-generation antipsychotics, i.e. higher dopamine D-2 receptor occupancy in the cerebral cortices than in the striatum, has been Suggested to explain their clinical efficacy with lower incidence of extrapyramidal side-effects. In this study, regional distribution of dopamine D-2 receptor occupancy by risperidone was determined in order to elucidate the limbic and cortical selectivity of second-generation antipsychotics. Striatal and extrastriatal dopamine D-2 receptor binding at baseline and after oral administration of 2 mg risperidone were measured in ten healthy men by positron emission tomography (PET) using different tracers with different affinity for the receptors, [C-11]raclopride and [C-11]FLB 457, respectively. Striatal and extrastriatal occupancies of dopamine D-2 receptors were calculated for each brain region. Occupancies of dopamine D-2 receptors were about 70%, and 60% in the striatum and extrastriatum, respectively. A simulation study showed that non-negligible specific binding in the reference region (cerebellum), could cause systemic underestimation of occupancy in [C-11]FLB 457 PET studies, indicating that occupancies in both the striatum and extrastriatum may not have differed. Among the extrastriatal regions including limbic and neocortical regions, no significant regional differences in dopamine D receptor occupancy were observed. Thus, limbic and cortical selectivity was not observed by one of the second-generation antipsychotics, risperidone.

DOI： 10.1017/S1461145708009577

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It has been demonstrated in vitro that the dopamine D-2 receptor has 2 interconvertible affinity states for endogenous dopamine, referred to as the high-and the low-affinity states. C-11-(R)-2-CH3O- N-n-propylnorapomorphine (C-11-MNPA) is a new agonist radioligand for in vivo imaging of the high-affinity state of dopamine D-2 receptors using PET. In the present study, the kinetics of C-11-MNPA were examined for the first time, to our knowledge, in the human brain and analyzed using quantitative approaches with or without an arterial input function. Methods: A 90-min dynamic PET scan was obtained for 10 healthy men after an intravenous injection of C-11-MNPA. The binding potential (BPND) was calculated using the indirect kinetic method, a kinetic compartment analysis with a metabolite-corrected arterial input function. BPND was also calculated by the simplified reference tissue model (SRTM) and transient equilibrium methods, both with the cerebellum as the reference brain region. The results of the quantitative methods were compared in a cross-validation approach. Results: The highest regional radioactivity was observed in the putamen. BPND values obtained by kinetic analysis were 0.82 +/- 0.09, 0.59 +/- 0.11, and 0.28 +/- 0.06, respectively, in the putamen, caudate, and thalamus. BPND values obtained by the SRTM and transient equilibrium methods were in good agreement with those obtained by the indirect kinetic method (r = 0.98 and r - 0.93, respectively). For all quantification methods, the BPND values based on data acquired from 0 to 60 min were in good agreement with those based on data acquired from 0 to 90 min (r = 0.90-0.99). Conclusion: The regional distribution of C-11-MNPA binding was in good agreement with previous PET studies of dopamine D-2 receptors in the human brain using antagonist radioligands. The results support routine use of the SRTM and transient equilibrium methods, that is, methods that do not require an arterial input function and need a scan time of only about 60 min. C-11-MNPA should thus be useful for clinical research on the pathophysiology of neuropsychiatric disorders and estimation of dopamine D-2 receptor occupancy by dopaminergic drugs.

DOI： 10.2967/jnumed.108.058503

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The dopamine hypothesis has been the most widely known theory concerning schizophrenia. However, the exact mechanism including presynaptic dopaminergic activity and its relationship with symptom severity still remains to be revealed. We measured presynaptic dopamine synthesis using positron emission tomography (PET) with L-[beta-C-11]DOPA in 18 patients with schizophrenia (14 drug-naive and 4 drug-free patients) and 20 control participants. Dopamine synthesis rates, expressed as k(i) values, were obtained using a graphical method, and the occipital cortex was used as reference region. Regions of interest were placed on the prefrontal cortex, temporal cortex, anterior cingulate, parahippocampus, thalamus, caudate nucleus, and putamen. Psychopathology was assessed with the Positive and Negative Symptom Scale (PANSS). We found significantly higher ki values in patients than in controls in the left caudate nucleus, but not in the other regions. The ki values in the thalamus exhibited a significant positive correlation with the PANSS total scores. Furthermore, a significant positive correlation was observed between the PANSS positive subscale scores and ki values in the right temporal cortex. Patients with schizophrenia showed higher dopamine synthesis in the left caudate nucleus, and dopaminergic transmission in the thalamus and right temporal cortex might be implicated in the expression of symptoms in schizophrenia. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2008.11.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

Dopamine D-1 receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D-1 receptors induces an inverted U-shaped response, such that too little or too much D-1 receptor stimulation impairs prefrontal functions. Less is known of the role of D-2 receptors in cognition, but previous studies showed that D-2 receptors in the hippocampus (HPC) might play some roles via HPC-PFC interactions. We measured both D-1 and D-2 receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D-1 and D-2 receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D-1 receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D-2 binding has no relation with any neuropsychological measures. Hippocampal D-2 receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D-1 receptor binding had no association with any memory and prefrontal functions. Hippocampal D-2 receptors seem to contribute to local hippocampal functions (long-term memory) and to modulation of brain functions outside HPC ("frontal lobe functions"), which are mainly subserved by PFC, via the HPC-PFC pathway. Our findings suggest that orchestration of prefrontal D-1 receptors and hippocampal D-2 receptors might be necessary for human executive function including working memory.

DOI： 10.1523/JNEUROSCI.3446-08.2008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NUCLEAR MEDICINE INC  

F-18-fluoroethyl-SPA-RQ (F-18-FE-SPA-RQ) was recently developed as a radioligand for the measurement of neurokinin 1 (NK1) receptor with PET. In this study, we used F-18-FE-SPA-RQ with PET to visualize and quantify NK1 receptor in the human brain. Methods: PET scans were performed on 7 healthy men after intravenous injection of F-18-FE-SPA-RQ. Binding potential (BPNp) was calculated by the indirect kinetic, simplified reference tissue model (SRTM), and ratio methods. The indirect kinetic method was used as the gold standard method and was compared with the SRTM method, with scan times of 180, 270, and 330 min, and with the ratio method, with time integration intervals of 120-180, 210-270, and 300-330 min. The cerebellum was used as the reference brain region. Results: Regional radioactivity was highest in the caudate head and putamen; mid level in the parahippocampus, cerebral cortex, and thalamus; and lowest in the cerebellum. BPND values by the indirect kinetic method were 3.15 +/- 0.36, 3.11 +/- 0.66, 1.17 +/- 0.25, and 0.46 +/- 0.14 in the caudate, putamen, parahippocampal region, and thalamus, respectively. For cerebral cortical regions, BPNp values by the indirect kinetic method were 0.94 +/- 0.23, 0.82 +/- 0.15, 0.76 +/- 0.15, and 0.69 +/- 0.16 in the occipital, temporal, frontal, and anterior cingulate cortices, respectively. BPNp values by the SRTM and ratio methods were in good agreement with those by the indirect kinetic method (r = 0.94-0.98). Conclusion: The regional distribution of F-18-FE-SPA-RQ was in agreement with previous PET studies and postmortem studies of NK1 receptor in the human brain. The ratio method will be useful for clinical research of psychiatric disorders, for the estimation of NK1 receptor without arterial blood sampling and long dynamic PET.

DOI： 10.2967/jnumed.108.054353

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Dopamine D(2) receptor occupancy by antipsychotic drugs has been measured with positron emission tomography (PET) by comparing the binding potential (BP) values before and after drug administration. This occupancy has been found to be related to clinical effects and side effects. in this study, we evaluated the in simulation and human studies of [(11)C]raclopride and for the high affinity ligand [(11)C]FLB 457. Time-activity curves of [(11)C]raclopride and [(11)C]FLB 457 were simulated, and the reliability of BP estimated by a simplified reference tissue model and the calculated Occupancy were investigated for various noise levels, BP values, and scan durations. Then, in the human PET study with and without antipsychotics, the uncertainty of BP and occupancy estimates and the scan duration required for a reliable estimation were investigated by a bootstrap approach. Reliable and unbiased estimates of [(11)C]raclopride BP(ND) could be obtained with recording as short as 32 min, with the relative standard deviation (SD) of the striatal occupancy remaining less than 10%. Conversely, in [(11)C]FLB 457 Studies, the mean value increased and SD of the temporal cortex and thalamus exceeded 10% when the scan duration was shorter than 60 min. These results demonstrated that dopamine D(2) receptor occupancy by antipsychotics can be estimated precisely with an optimal scan duration with [(11)C]raclopride and [(11)C]FLB 457. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2008.05.056

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Language：Japanese   Publisher：(一社)日本核医学会  

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(S,S)-F-18-FMeNER-D-2 was recently developed as a radioligand for the measurement of norepinephrine transporter imaging with PET. In this study, a norepinephrine transporter was visualized in the human brain using this radioligand with PET and quantified by several methods. Methods: PET scans were performed on 10 healthy men after intravenous injection of (S,S)-(FFMeNER)-F-18-D-2. Binding potential relative to nondisplaceable binding (BPND) was quantified by the indirect kinetic, simplified reference-tissue model (SRTM), multilinear reference-tissue model (MRTM), and ratio methods. The indirect kinetic method was used as the gold standard and was compared with the SRTM method with scan times of 240 and 180 min, the MRTM method with a scan time of 240 min, and the ratio method with a time integration interval of 120-180 min. The caudate was used as reference brain region. Results: Regional radioactivity was highest in the thalamus and lowest in the caudate during PET scanning. BPND values by the indirect kinetic method were 0.54 +/- 0.19 and 0.35 +/- 0.25 in the thalamus and locus coeruleus, respectively. BPND values found by the SRTM, MRTM, and ratio methods agreed with the values demonstrated by the indirect kinetic method (r = 0.81-0.92). Conclusion: The regional distribution of (S,S)-F-18-FMeNER-D-2 in our study agreed with that demonstrated by previous PET and postmortem studies of norepinephrine transporter in the human brain. The ratio method with a time integration interval of 120-180 min will be useful for clinical research of psychiatric disorders for estimation of norepinephrine transporter occupancy by antidepressants without requiring arterial blood sampling and dynamic PET.

DOI： 10.2967/jnumed.108.051292

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Rationale Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects.
Objectives In this study, we measured striatal and extrastriatal dopamine D(2) receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose.
Materials and methods Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [(11)C]raclopride and one with [(11)C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D(2) receptor occupancy was calculated.
Results The dopamine D(2) receptor occupancies in the striatum measured with [(11)C]raclopride and the temporal cortex measured with [(11)C]FLB 457 were 54.2-85.5% and 34.5-87.3%, respectively. ED(50) values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D(2) receptor occupancy between the striatum and the temporal cortex.
Conclusions The data from this study suggest that paliperidone ER at 6-9 mg provides an estimated level of dopamine D(2) receptor occupancy between 70-80% and that the magnitude of dopamine D(2) receptor occupancy is similar between the striatum and temporal cortex.

DOI： 10.1007/s00213-007-1029-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Dysfunction of the GABA system is considered to play a role in the pathology of schizophrenia. Individual subunits of GABA(A)/Benzodiazepine (BZ) receptor complex have been revealed to have different functional properties. alpha 5 subunit was reported to be related to learning and memory. Changes of a5 subunit in schizophrenia were reported in postmortem studies, but the results were inconsistent. In this study, we examined GABA(A)/BZ receptor using [C-11]Rol5-4513, which has relatively high affinity for (alpha 5 subunit, and its relation to clinical symptoms in patients with schizophrenia. [C-11]Rol5-4513 bindings of I I patients with schizophrenia (6 drug-naive and 5 drug-free) were compared with those of 12 age-matched healthy control subjects using positron emission tomography. Symptoms were assessed using the Positive and Negative Syndrome Scale. [C-11]Rol5-4513 binding was quantified by binding potential (BP) obtained by the reference tissue model. [C-11] Ro15-4513 binding in the prefrontal cortex and hippocampus was negatively correlated with negative symptom scores in patients with schizophrenia, although there was no significant difference in BP between patients and controls. GABAA/BZ receptor including alpha 5 subunit in the prefrontal cortex and hippocampus might be involved in the pathophysiology of negative symptoms of schizophrenia. (C) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2007.10.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The central dopaminergic system is of interest in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Both pre- and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET) with different radiotracers. However, an integrated database of both pre- and postsynaptic dopaminergic neurotransmission components including receptors, transporter, and endogenous neurotransmitter synthesis has not yet been reported. In the present study, we constructed a normal database for the pre- and postsynaptic dopaminergic functions in the living human brain using PET. To measure striatal and extrastriatal dopamine D-1 and D-2 receptor bindings, dopamine transporter binding, and endogenous dopamine synthesis rate, PET scans were performed on healthy men after intravenous injection of [C-11]SCH23390, [C-11]raclopride, [C-11]FLB457, [C-11]PE21, or L-[beta-C-11]DOPA. All PET images were anatomically standardized using SPM2, and a database was built for each radiotracer. Gray matter images were segmented and extracted from all anatomically standardized magnetic resonance images using SPM2, and they were used for partial volume correction. These databases allow the comparison of regional distributions of striatal and extrastriatal dopamine D, and D2 receptors, dopamine transporter, and endogenous dopamine synthesis capability. These distributions were in good agreement with those from human postmortem studies. This database can be used in various researches to understand the physiology of dopaminergic functions in the living human brain. This database could also be used to investigate regional abnormalities of dopaminergic neurotransmission in neuropsychiatric disorders. (C) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2007.09.011

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

N-methyl-D-aspartate (NMDA) receptors are of major interest in brain functions and neuropsychiatric disorders. However, at present there are few suitable radioligands for in vivo imaging of NMDA receptors. 7-Choloro-4-hydroxy-3[3-(4-methoxybenzyl) phenyl]-2(1H)-quinolone (L-703,717) is one of the potent ligands for the glycine-binding site of NMDA receptors. 4-Acetoxy derivative of L-703,717 (AcL703) is a candidate, as a positron emission tomography (PET) ligand for NMDA receptors, because of its better permeability at the blood-brain barrier compared with L-703,717. After intravenous injection of 624-851 MBq of [C-11]AcL703, dynamic PET scan was performed on six healthy males for 90 min. Regions-of-interest were located on the cerebral cortices, cerebellar cortex, and cerebral white matter. The binding potential (BP) was calculated from the ratio of the area under the curve (AUC) of radioactivities from 40 to 90 min in the target region to that in white matter. Regional radioactivities reached close to equilibrium in all regions after about 40 min postinjection. Regional brain uptake of [C-11]AcL703 at 40 min after injection was 0.00028-0.00065% of the injected dose/milliliter. Radioactivity concentration of [C-11]AcL703 was highest in the cerebellar cortex and lowest in white matter. AUC in the cerebellar cortex was higher than those of cerebral cortices, thalamus, striatum, and white matter. BP in the cerebellar cortex was twofold higher than in the cerebral cortices (cerebellar cortex: BP = 2.20 +/- 0.72; cerebral cortices: BP = 1.05 +/- 0.45). Despite the low brain uptake of [C-11]AcL703, regional distributions were in good agreement with our previous studies of rodents. This indicates the possibility of in vivo evaluation of NMDA receptors using PET with [C-11]AcL703 in living human brain. Synapse 61:795-800, 2007. (C) 2007 Wiley-Liss, Inc.

DOI： 10.1002/syn.20415

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background: Personality trait is thought to be one of the important factors for vulnerability to depression. The relation between serotonin transporter (5-HTT) polymorphism and anxiety-related personality has been investigated in genetic research. In this study, we investigated the relation between in vivo regional 5-HTT binding in the brain and personality inventory measures in normal male volunteers.
Methods: Thirty-one healthy male volunteers underwent positron emission tomography scans with C-11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl) benzonitrile ([C-11]DASB) to measure 5-HTT and completed revised NEO Personality Inventory. Correlation of [C-11]DASB binding potentials (BP) with personality inventory measures was calculated using region-of-interest analysis and statistical parametric mapping based on the BP images.
Results: Neuroticism was positively correlated with 5-HTT binding in the thalamus (p = .004). No significant correlation was observed in any other brain region. Within the neuroticism dimension, the facet of depression was positively correlated with 5-HTT binding in the thalamus (P = .001).
Conclusions: Subjects with higher thalamic 5-HTT binding are more likely to express higher levels of neuroticism and depressive feeling. Serotonin transporter binding in the thalamus might be a marker of vulnerability to depression.

DOI： 10.1016/j.biopsych.2006.11.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objectives C-11-WAY 100635 has been used widely in the PET research field to measure 5-HT1A receptors in the living human brain. Reference tissue model analysis, in which the cerebellum was used as the reference tissue, was employed in clinical studies. However, the reported binding potentials varied greatly among the reports. In this study, regions of interest (ROIs) of the cerebellum for C-11-WAY 100635 were determined in five different approaches for six healthy male volunteers, and the effects on binding potential parametric images were compared.
Methods First, ROIs on the cerebellar cortex were decided based on information from magnetic resonance imaging (MRI), and then divided into upper and lower parts. They were then refined according to coregistered positron emission tomography (PET) image information, generating upper-refined and lower-refined parts. In a different approach, circular ROIs were decided upon, based on the PET images, and the areas under the curve (AUCs) of five ROIs were compared. Parametric images of binding potentials were calculated with the five ROIs as the reference, and compared with each other.
Results The AUCs of the lower-refined parts were the lowest among the first four ROIs. The ratio of the AUCs between the upper part and lower-refined part was 1.54 +/- 0.17, that between the upper-refined part and lower-refined part was 1.27 +/- 0.21, that between the lower part and lower-refined part was 1.04 +/- 0.02, and that between the circular ROIs and lower-refined part was 1.01 +/- 0.04. The differences in AUCs among the five cerebellar parts led to significant differences in the binding potential parametric images.
Conclusion The binding potential parametric images of C-11-WAY100635 could vary significantly according to the different methods of establishing ROIs, using the cerebellum as the reference tissue, because radioactivity in the cerebellum for C-11-WAY100635 is very low.

DOI： 10.1097/MNM.0b013e328013ebec

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Language：English   Publishing type：Research paper (international conference proceedings)  

Background and aims: Obsessive compulsive disorder (OCD) is psychiatric disorder characterized by recurrent obsessions and compulsions. Based on the selective efficacy of serotonin reuptake inhibitors (SRIs) and comorbid depression that is often observed in OCD, the serotonergic system including serotonin transporter (SERT) has been of interest in pathophysiology of OCD. Previous study using positron emission tomography (PET) with a radiotracer [11C]McN5642 for SERT failed to changes in density of SERT in OCD patients. The aim of the present study is to investigate SERT density using [11C]DASB which shows high selectivity and affinity to SERT as compared with [11C]McN5642. Methods: Ten patients with OCD, free of psychiatric medication and comorbid depression, and 18 gender and age-matched healthy subjects participate in this study. OCD was diagnosed according to the DSM-IV. OCD severity was assessed by Yale?Brown Obsessive?Compulsive Scale (Y-BOCS, scale range: 0?40). After intravenous infusion of [11C]DASB, a dynamic PET scanning was performed for 90 min. Regions-of-interest were defined on the frontal cortex, thalamus, striatum and midbrain on the coregistered magnetic resonance images. The binding potential (BP) of [11C]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2) developed by Ichise et at al. Results: As shown that Y-BOCS score was 22±7.6 (range: 7-32), the degree of severity in the present subjects varied relatively widely. BP values for OCD patients were 0.17±0.05, 1.48±0.10, 1.20±0.09, and 1.35±0.28, and values for healthy controls were 0.22±0.10, 1.60±0.24, 1.53±0.33, and 1.24±0.20 in the frontal cortex, thalamus, striatum and midbrain, respectively. No significant group differences were observed in BP of [11C]DASB in any of brain regions. No significant correlations were observed between severity of OCD and BP. Conclusions: Although SERT has been of interest in pathophysiology of OCD, no significant differences were observed in SERT density between OCD and healthy controls, same as the previous study using [11C]McN5642. OCD without comorbid depression may not be associated in only serotonergic system, but also other neurotransmission systems.

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Other Link： http://search.jamas.or.jp/link/ui/2006191975

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Language：Japanese   Publisher：(国研)国立精神・神経医療研究センター精神保健研究所  

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DOI： 10.1038/mp.2012.7

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

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DOI： 10.1016/j.neuroimage.2010.04.076

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DOI： 10.1016/j.neuroimage.2010.04.081

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CAMBRIDGE UNIV PRESS  

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DOI： 10.1016/j.neuroimage.2006.04.010

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