2003 Fiscal Year Annual Research Report

PETによる気分障害患の病態と治療法の作用機序に関する研究

Research Project

Project/Area Number	14370296
Research Institution	National Institute of Radiological Sciences
Principal Investigator	須原哲也放射線医学総合研究所, 研究員 (90216490)
Co-Investigator(Kenkyū-buntansha)	鈴木和年放射線医学総合研究所, 画像医学部・放射薬剤製造開発室, 研究員 (90162932) 中山和彦東京慈恵会医科大学, 大学院・精神医学講座, 助教授 (70155878) 大久保善朗日本医科大学, 精神医学教室, 教授 (20213663)
Keywords	抗うつ薬 / Positron emission tomography / 大うつ病 / セロトニントランスポーター / 占有率
Research Abstract	うつ病の薬物治療はSSRI(選択的セロトニン再取り込み阻害薬)などの選択的薬物の登場にもかかわらず、実際の臨床場面ではその服薬量や服薬回数に関しては経験に基づくことが多く、科学的根拠に乏しいのが現状である。向精神薬の多くは脳内の受容体やトランスポーターなどに高い親和性を持ち、その受容体やトランスポーターに結合し、その薬理作用を発揮している。そのような向精神薬の受容体やトランスポーターでの動態を生体内で検討することは薬物の作用機序の解明や用量用法を決定する際に重要である。本研究ではSSRIの一つであるフルボキサミンによるセロトニントランスポーター占有率の経時的変化に関してPETそ用いて検討を行った。本研究では健常男性5名を対象とし,[^<11>C]DASBを用いたPET検査を施行した。PET検査はフルボキサミン服用前およびフルボキサミン50mg単回服薬後5時間後、26時間後、53時間後に施行した。服薬後のPET検査前にフルボキサミン血中濃度の測定を施行した。視床に関心領域を設定し、小脳を参照領域としてsimplified reference tissue法を用いて結合能を算出した。服薬前後の結合能の差を用いてセロトニントランスポーター占有率を算出した。フルボキサミンによるセロトニントランスポーターの平均占有率は5時間後で75%、26時間後で52%、53時間後で28%であった。血中濃度の平均半減期は14時間、セロトニントランスポーター占有率の半減期は42時間であった。フルボキサミンによる脳内セロトニントランスポーター占有率の経時的変化は血中動態と解離していると考えられ、用量用法の決定の際には血中濃度のみならず脳内セロトニントランスポーター占有率の検討も重要であると考えられた。

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Obayashi S.et al.: "Fronto-parieto-cerebellar interaction associated with inermanual transfer of monkey tool-use learning."Neurosi Lett. 339. 123-126 (2003)
[Publications] Shioe K.et al.: "No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET."Synapse. 48. 184-188 (2003)
[Publications] Suhara T.et al.: "High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography"Arch Gen Psych. 60. 386-391 (2003)
[Publications] Zhang M.-R.et al.: "[^<11>C]DAA1106 : Radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain"Nucl Med Biol. 30. 513-519 (2003)
[Publications] Haradahira T.et al.: "Effects of endogenous agonists, glycine and D-serine, on in vivo specific binding of [^<11>C]L-703,717,a PET radioligand for the glycine-binding site of NMDA receptors"Synapse. 50. 130-136 (2003)
[Publications] Ichise M.et al.: "Linearized reference tissue parametric imaging methods : application to [^<11>C]DASB positron emission tomography studies of the serotonin transporter in human brain."J Cereb Blood Flow Metab. 23. 1096-1112 (2003)
[Publications] Kida T.et al.: "Metabolite analysis of[^<11>C]Ro15-4513 in mice, rat, monkeys and humans."Nucl Med Biol. 30. 779-784 (2003)
[Publications] Fuchigami T.et al.: "Synthesis and brain regional distribution of [^<11>C]NPS 1506 in mice and rat : an N-Methyl-D-aspartate(NMDA) receptor antagonist."Biol Pharm Bull. 26. 1570-1573 (2003)
[Publications] Semba J.et al.: "Nicotine withdrawal induces subsensitivity of hypothalamic-pituitary-adrenal axis to stress in rats : implications for precipitation of depression during smoking cessation."Physchoneuroendocrinology. 29. 215-226 (2004)
[Publications] Takano A.et al.: "Estimation of the time course of receptor occupancy in the human brain from the plasma pharmacokinetics of antichotics."Int J Neuropsychopharmacol. 7. 1-8 (2004)
[Publications] Obata T.et al.: "Neural damage due to temporal lobe epilepsy : dual-nuclei(proton and phosphorus) magnetic resonance spectroscopy study."Psychiatry Clin Neurosci. 58. 48-53 (2004)
[Publications] Yasuno F.et al.: "Decreased 5-HT_<1A> receptor binding in amygdale of schizophrenia."Biol Psychiatry. 55. 439-444 (2004)
[Publications] Takano A.et al.: "Relationship between cortical dopamine D_2 receptor occupancy and suppression of conditioned avoidance response in non-human primate."Psychiatry Clin Neurosci. (in press).
[Publications] Yasuno F.et al.: "Low dopamine D_2 receptor binding in subregions of the thalamus in patients with schizophrenia."Am J Psychiatry. (in press).
[Publications] Obayashi S.et al.: "Monkey brain areas underlying remote-controlled operation."Eur J Neurosci. (in press).
[Publications] Zhang M.-R.et al.: "Development of new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[^<18>F]fluoroethyl-5methoxybenzyl)acetamide, for PET imaging of'peripheral benzodiazepine receptor'(PBR)in primate brain."J Med Chem. (in press).
[Publications] Maeda J.et al.: "Imaging for brain glial cells by novel peripheral benzodiazepine receptor ligand[^<11>C]DAA1106 : study for in vivo rat autoradiography and monkey PET study."Synapse. (in press).
[Publications] 安野史彦ほか: "7.脳機能画像から見た認知機能新世紀の精神科治療第6巻認知の科学と臨床"中山書店. 12 (2003)

2003 Fiscal Year Annual Research Report

PETによる気分障害患の病態と治療法の作用機序に関する研究

Principal Investigator

須原 哲也 放射線医学総合研究所, 研究員 (90216490)

Research Products

[Publications] Obayashi S.et al.: "Fronto-parieto-cerebellar interaction associated with inermanual transfer of monkey tool-use learning."Neurosi Lett. 339. 123-126 (2003)

[Publications] Shioe K.et al.: "No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET."Synapse. 48. 184-188 (2003)

[Publications] Suhara T.et al.: "High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography"Arch Gen Psych. 60. 386-391 (2003)

[Publications] Zhang M.-R.et al.: "[^<11>C]DAA1106 : Radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain"Nucl Med Biol. 30. 513-519 (2003)

[Publications] Haradahira T.et al.: "Effects of endogenous agonists, glycine and D-serine, on in vivo specific binding of [^<11>C]L-703,717,a PET radioligand for the glycine-binding site of NMDA receptors"Synapse. 50. 130-136 (2003)

[Publications] Ichise M.et al.: "Linearized reference tissue parametric imaging methods : application to [^<11>C]DASB positron emission tomography studies of the serotonin transporter in human brain."J Cereb Blood Flow Metab. 23. 1096-1112 (2003)

[Publications] Kida T.et al.: "Metabolite analysis of[^<11>C]Ro15-4513 in mice, rat, monkeys and humans."Nucl Med Biol. 30. 779-784 (2003)

[Publications] Fuchigami T.et al.: "Synthesis and brain regional distribution of [^<11>C]NPS 1506 in mice and rat : an N-Methyl-D-aspartate(NMDA) receptor antagonist."Biol Pharm Bull. 26. 1570-1573 (2003)

[Publications] Semba J.et al.: "Nicotine withdrawal induces subsensitivity of hypothalamic-pituitary-adrenal axis to stress in rats : implications for precipitation of depression during smoking cessation."Physchoneuroendocrinology. 29. 215-226 (2004)

[Publications] Takano A.et al.: "Estimation of the time course of receptor occupancy in the human brain from the plasma pharmacokinetics of antichotics."Int J Neuropsychopharmacol. 7. 1-8 (2004)

[Publications] Obata T.et al.: "Neural damage due to temporal lobe epilepsy : dual-nuclei(proton and phosphorus) magnetic resonance spectroscopy study."Psychiatry Clin Neurosci. 58. 48-53 (2004)

[Publications] Yasuno F.et al.: "Decreased 5-HT_<1A> receptor binding in amygdale of schizophrenia."Biol Psychiatry. 55. 439-444 (2004)

[Publications] Takano A.et al.: "Relationship between cortical dopamine D_2 receptor occupancy and suppression of conditioned avoidance response in non-human primate."Psychiatry Clin Neurosci. (in press).

[Publications] Yasuno F.et al.: "Low dopamine D_2 receptor binding in subregions of the thalamus in patients with schizophrenia."Am J Psychiatry. (in press).

[Publications] Obayashi S.et al.: "Monkey brain areas underlying remote-controlled operation."Eur J Neurosci. (in press).

[Publications] Zhang M.-R.et al.: "Development of new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[^<18>F]fluoroethyl-5methoxybenzyl)acetamide, for PET imaging of'peripheral benzodiazepine receptor'(PBR)in primate brain."J Med Chem. (in press).

[Publications] Maeda J.et al.: "Imaging for brain glial cells by novel peripheral benzodiazepine receptor ligand[^<11>C]DAA1106 : study for in vivo rat autoradiography and monkey PET study."Synapse. (in press).

[Publications] 安野史彦 ほか: "7.脳機能画像から見た認知機能 新世紀の精神科治療 第6巻認知の科学と臨床"中山書店. 12 (2003)

須原哲也放射線医学総合研究所, 研究員 (90216490)

[Publications] 安野史彦ほか: "7.脳機能画像から見た認知機能新世紀の精神科治療第6巻認知の科学と臨床"中山書店. 12 (2003)