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DOI： 10.1016/j.nucmedbio.2019.10.003

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Language：Japanese   Publisher：(一社)日本総合病院精神医学会  

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Language：Japanese   Publisher：日本精神科救急学会  

CiNii Books

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Language：Japanese   Publisher：国立医療学会  

CiNii Books

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

UNLABELLED: Characteristic neuropathologic changes in Alzheimer disease (AD) are amyloid-β deposits and neurofibrillary tangles. Recently, a new radioligand for amyloid senile plaques, (11)C-labeled 5-(6-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzothiazol-2-yl)pyridin-2-amine ((11)C-AZD2184), was developed, and it was reported to show rapid brain uptake followed by rapid washout. In this study, (11)C-AZD2184 binding in control subjects and AD patients was examined in more detail by compartment model analysis using a metabolite-corrected arterial input function. The accuracy of simplified quantitative methods using a reference brain region was also evaluated. METHODS: After intravenous bolus injection of (11)C-AZD2184, a dynamic PET scan was obtained for 90 min in 6 control subjects and 8 AD patients. To obtain the arterial input function, arterial blood sampling and high-performance liquid chromatography analysis were performed. RESULTS: Time-activity curves in all brain regions could be described using the standard 2-tissue-compartment model. The total distribution volume ratios to reference region (DVR) in cerebral cortical regions were significantly higher in AD patients than in control subjects. Although there was no conspicuous accumulation of radioactivity in white matter as compared with other amyloid radioligands, DVR values in the centrum semiovale were more than 1 for both control subjects and AD patients, suggesting binding to myelin. The standardized uptake value ratio calculated from integrated time-activity curves in brain regions and the reference region was statistically in good agreement with DVR. CONCLUSION: Although the white matter binding of (11)C-AZD2184 may have some effect on cortical measurement, it can be concluded that the kinetic behavior of (11)C-AZD2184 is suitable for quantitative analysis. The standardized uptake value ratio can be used as a validated measure of (11)C-AZD2184 binding in clinical examinations without arterial input function.

DOI： 10.2967/jnumed.113.133793

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Publisher：6  

DOI： 10.2967/jnumed.113.133793

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Other Link： http://orcid.org/0000-0002-7927-9483

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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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Publisher：4  

DOI： 10.1017/S1461145713001521

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Publisher：3  

DOI： 10.1097/MNM.0000000000000052

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Other Link： http://orcid.org/0000-0002-7927-9483

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OBJECTIVE: Recent PET studies have indicated altered presynaptic function and relation with psychotic symptoms in patients with schizophrenia. The L-[β-(11)C]DOPA uptake rate reflects the dopamine synthesis capacity (kref), whereas the nondisplaceable binding potential (BPND) of [(18)F]FE-PE2I reflects the dopamine transporter availability. Although the kref values of L-[β-(11)C]DOPA and the BPND of [(18)F]FE-PE2I can be potential markers for evaluating the severity of positive symptoms, test-retest reproducibility has not been confirmed. The purpose of this study was to investigate the test-retest reproducibility of kref values of L-[β-(11)C]DOPA and that of BPND of [(18)F]FE-PE2I in the striatum and midbrain in healthy humans. MATERIALS AND METHODS: Twelve healthy male volunteers underwent two PET studies on separate days. Each PET study comprised two PET scans, one with L-[β-(11)C]DOPA and the other with [(18)F]FE-PE2I. Volumes of interest were defined for the caudate, putamen, midbrain, and thalamus. Test-retest reproducibility was assessed in terms of intrasubject variability (absolute variability) and reliability [intraclass correlation coefficient (ICC)]. RESULTS: The absolute variability values of kref and BPND were 4.8-25.7% on average for the caudate, putamen, midbrain, and thalamus. The ICC values of the kref values of L-[β-(11)C]DOPA were 0.78, 0.71, 0.77, and 0.77 for the caudate, putamen, midbrain, and thalamus, respectively. The ICC values of the BPND of [(18)F]FE-PE2I were 0.83, 0.88, 0.71, and 0.70 for the caudate, putamen, midbrain, and thalamus, respectively. CONCLUSION: We found good test-retest reproducibility for the kref values of L-[β-(11)C]DOPA and that for the BPND of [(18)F]FE-PE2I in the striatum and midbrain, indicating the reliability of clinical investigation using PET with L-[β-(11)C]DOPA and [(18)F]FE-PE2I.

DOI： 10.1097/MNM.0000000000000052

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

Positron emission tomography (PET) study has shown that dopamine synthesis capacity varied among healthy individuals. This interindividual difference might be due to a difference in the cell-level structure of presynaptic dopaminergic neurons, i.e., cellular density and/or number. In this study, the relations between the dopamine synthesis capacity measured by PET and the parameter estimates in diffusion tensor imaging (DTI) in striatal subregions were investigated in healthy human subjects. DTI and PET studies with carbon-11 labeled L-DOPA were performed in ten healthy subjects. Age-related changes in the above parameters were also considered. Fractional anisotropy showed a significant positive correlation with age in the posterior caudate. There was significant negative correlation between dopamine synthesis capacity and mean diffusivity in the posterior caudate and putamen. Assuming that mean diffusivity reflects the density of wide-spreading axonal terminals in the striatum, the result suggests that dopamine synthesis may be related to the density of dopaminergic neuronal fibers. It is evident that PET/DTI combined measurements can contribute to investigations of the pathophysiology of neuropsychiatric diseases involving malfunction of dopaminergic neurons.

DOI： 10.1371/journal.pone.0087886

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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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Publisher：5  

DOI： 10.1017/S1461145712001009

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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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DOI： 10.1111/pcn.12003

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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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Publisher：1  

DOI： 10.1007/s00213-011-2633-5

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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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Publisher：7  

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：English   Publishing type：Research paper (scientific journal)  

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：Japanese   Publisher：寺田国際事務所先端医療技術研究所  

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

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese  

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Language：Japanese  

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Language：Japanese   Publisher：(一社)日本心身医学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本総合病院精神医学会  

J-GLOBAL

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J-GLOBAL

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Language：Japanese  

統合失調症の脳形態変化における閉経の影響について、患者群を閉経患者と非閉経患者の2群に分けMRIを用いて調査した。最終月経からMRI撮像までの期間が12ヵ月以上である統合失調症女性患者20名と同時期が12ヵ月未満であり閉経患者群と年齢を一致させた統合失調症女性患者20名(平均41.8±9.0歳)を対象とした。分析の結果、非閉経患者群と比較し、閉経患者群において左中前頭回の灰白質に有意な体積減少を認めた。一方、非閉経患者群が閉経患者群と比較して有意に体積減少している部位は認められなかった。閉経患者20名において、閉経後経過年数と脳体積の相関を調べた結果、右上前頭回の灰白質体積と閉経後経過年数に負の相関が認められた。健常者が閉経する平均年齢は50から52歳の間であるとされるが、今回の閉経患者群においては、若年期に最終月経がきており、原因の一つに抗精神薬の副作用であることが考えられた。

CiNii Books

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

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