In-vivo quantification analysis of activated microglia in the brain of dementia

• Project/Area Number: 16591177
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: National Institute of Radiological Sciences
• Principal Investigator: SUZUKI Kazutoshi National Institute of Radiological Sciences, Researcher, 分子認識研究グループ, 研究員 (90162932)
• Co-Investigator(Kenkyū-buntansha): SUHARA Tetsuya National Institute of Radiological Sciences, Special Researcher, 脳機能イメージング研究開発推進室, 研究員 (90216490) ; IKEJIRI Yoshitaka Graduate School of Medicine Osaka University, Psychiatry and Behavioral Science, Assistant Professor, 医学部精神神経科, 講師 (30294086) ; ASADA Takashi Institute of Clinical Medicine University of Tsukuba, Department of Neuropsychiatry, Professor, 医学部精神神経科, 教授 (90184142)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: Alzheimer disease / dementia / mild cognitive impairment / PET / peripheral benzodiazepine receptor / microglia / senile plaque / [^<11>C]DAA1106 / アルツハイマー型認知症 / 末梢型ベンゾジアゼピン受容体 / 早期診断 / 生体内神経画像 / 神経変性疾患 / DAA1106 / 中枢型ベンゾジアゼピン受容体

Research Abstract

As a maker for the early diagnosis of the dementia with PET, we developed the new radioactive ligand [^<11>C]DAA1106, which has high permeability to the brain and shows high affinity and specificity to the peripheral benzodiazepine receptor (PBR). In vitro and ex-vivo study using the model mouse of Alzheimer disease, we found the high density of PBR was localized in the activated microglia at surroundings of senile plaque of model mouse. The change of PBR in the brain of Alzheimer disease should reflect the activity of microglia related to the effect of senile plaque specific to neuronal degeneration in this disease.
We examined whether we can diagnose the dementia in early stage by the quantification of the PBR with PET using [^<11>C]DAA1106 in in-vivo human study. We performed the PET scan with [^<11>C]DAA1106 on the group of patients of Alzheimer disease (n=10) and age-matched control group (n=11). Results showed significant increase of PBR-binding potential (BP) in the broad brain regions in the group of Alzheimer disease when compared to the age-matched control group. Further, to examine whether we can diagnose the dementia in very early stage before appearance of demented symptoms, we performed the scan on the subjects who had mild cognitive impairment (MCI), but cannot be diagnosed as the dementia at the time of PET scanning (n=7). We found the significant increase of PBR-BP in this group in broad brain regions when compared to the control group.
In conclusion, it was shown that PET scan with [^<11>C]DAA1106 can show the increase of PBR which might be related to the neurodegenerative process in the Alzheimer disease. In most of the cases, MCI can be regarded as the pre-stage of dementia, and we can detect the abnormality of PBR-BP even before symptoms of dementia clearly appeared. PET scan with [^<11>C]DAA1106 should be useful method for the early diagnosis of the dementia and other neuronal degenerative diseases.

Research Products

• [Journal Article] [2-^<11>C]Isopropyl-, [1-^<11>C]Ethyl- and [^<11>C]Methyl- labeled phenoxyphenyl acetamide derivatives as PET ligands for peripheral benzodiazepine receptor : radiosynthesis, uptake and in vivo binding in brain. (2006)
  • Author(s): Zhang M.-R., Ogawa M., Maeda J., Ito T., Noguchi J., Kumata K., Okauchi T., Suhara T., Suzuki K.
  • Journal Title: J Med Chem 49 Pages: 2735-2742
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Quantitative Analyses of 18F-FEDAA1106 Binding to Peripheral Benzodiazepine Receptors in Living Human Brain. (2006)
  • Author(s): Fujimura Y, Ikoma Y, Yasuno F, Suhara T, Ota M, Matsumoto R, Nozaki S, Takano A, Kosaka J, Zhang MR, Nakao R, Suzuki K, Kato N, Ito H.
  • Journal Title: J Nucl Med 47 Pages: 43-50
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] [2-^<11>C]Isopropyl-, [1-^<11>C]Ethyl- and [^<11>C]Methyl- labeled phenoxyphenyl acetamide derivatives as 'PET ligands for peripheral benzodiazepine receptor: radiosynthesis, uptake and in vivo binding in brain. (2006)
  • Author(s): Zhang M.-R., Ogawa M., Maeda J., Ito T., Noguchi J., Kumata K., Okauchi T., Suhara T., Suzuki K.
  • Journal Title: J Med Chem 49 Pages: 2735-2742
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Quantitative Analyses of 18F-FEDAA1106 Binding to Peripheral Benzodiazepine Receptors in Living Human Brain. (2006)
  • Author(s): Fujimura Y.et al.
  • Journal Title: J Nucl Med 47 Pages: 43-50
• [Journal Article] Synthesis and evaluation of N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[^<18F>fluoromethoxy-d_2-5-methoxy benzyl)acetamide : a deuterium-substituted radioligand for peripheral benzodiazepine receptor. (2005)
  • Author(s): Zhang M.-R., Maeda J., Ito T., Okauchi T., Ogawa M., Noguchi J., Suhara T., Halldin C., Suzuki K.
  • Journal Title: Bioorg Med Chem 13 Pages: 1811-1818
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[^<18>F]fluoromethoxy-d2-5-methoxybenzyl)acetamide: a deuterium- substituted radioligand for peripheral benzodiazepine receptor. (2005)
  • Author(s): Zhang M.-R., Maeda J., Ito T., Okauchi T., Ogawa M., Noguchi J., Suhara T., Halldin C., Suzuki K.
  • Journal Title: Bioorg Med Chem 13 Pages: 1811-1818
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Abnormal inter-regional relation of dopamine D2 receptor binding in schizophrenia. (2005)
  • Author(s): Yasuno F.et al.
  • Journal Title: Psychiatry Res 138 Pages: 197-207
• [Journal Article] The antipsychotic sultopride is overdosed-a PET study of drug-induced receptor occupancy in comparison with sulpiride. (2005)
  • Author(s): Takano A.et al.
  • Journal Title: Int J Neuropsychopharmacol Biol Psychiatry 17 Pages: 1-7
• [Journal Article] Time course of dopamine D2 receptor occupancy by clozapine with medium and high plasma concentrations. (2005)
  • Author(s): Takano A.et al.
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry 30 Pages: 75-81
• [Journal Article] Development of a new radioligand, N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[^<18F>fluoroethyl-5-methoxy benzyl)acetamide, for PET imaging of peripheral benzodiazepine receptor in primate brain. (2004)
  • Author(s): Zhang M.-R., Maeda J., Ogawa M., Noguchi J., Ito T., Yoshida Y., Okauchi T., Obayashi S., Suhara T., Suzuki K.
  • Journal Title: J Med Chem 47 Pages: 2228-2235
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Takano A, Obayashi S, Suzuki K. Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET : an imaging tool for glial cells in the brain. (2004)
  • Author(s): Maeda J, Suhara T, Zhang MR, Okauchi T, Yasuno F, Ikoma Y, Inaji M, Nagai Y
  • Journal Title: Synapse 52 Pages: 283-291
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Development of a new radioligand, N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[^<18>F]fluoroethyl-5-methox ybenzyl)acetamide, for PET imaging of peripheral benzodiazepine receptor in primate brain. (2004)
  • Author(s): Zhang M.-R., Maeda J., Ogawa M., Noguchi J., Ito T., Yoshida Y., Okauchi T., Obayashi S., Suhara T., Suzuki K.
  • Journal Title: J Med Chem 47 Pages: 2228-2235
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET: an imaging tool for glial cells in the brain. (2004)
  • Author(s): Maeda J, Suhara T, Zhang MR, Okauchi T, Yasuno F, Ikoma Y, Inaji M, Nagai Y, Takano A, Obayashi S, Suzuki K.
  • Journal Title: Synapse 52 Pages: 283-291
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Estimation of the time-course of dopamine D_2 receptor occupancy in living human brain from plasma pharmacokinetics of antipsychotics. (2004)
  • Author(s): Takano A. et al.
  • Journal Title: Int J Neuropsychopharmacol 7 Pages: 19-26
• [Journal Article] Decreased 5-HT_<1A> receptor binding in amygdala of schizophrenia. (2004)
  • Author(s): Yasuno F. et al.
  • Journal Title: Biol Psychiatry 55 Pages: 439-444
• [Journal Article] Novel peripheral benzodiazepine receptor ligand [^<11>C]DAA1106 for PET : an imaging tool for glial cells in the brain. (2004)
  • Author(s): Maeda J. t al.
  • Journal Title: Synapse 52 Pages: 283-291
• [Journal Article] Low dopamine D_2 receptor binding in subregions of thalamus in schizophrenia. (2004)
  • Author(s): Yasuno F. et al.
  • Journal Title: Am J Psychiatry 161 Pages: 1016-1022
• [Journal Article] [^<18>F]FMDAA1106 and [^<18>F]FMDAA1106 : Two positron-emitter labeled ligands for peripheral benzodiazepine receptor (PBR) (2003)
  • Author(s): Zhang M.-R., Maeda J., Furutsuka K., Yoshida Y., Ogawa M., Suhara T., Suzuki K.
  • Journal Title: Bioorg Med Chem Lett 13 Pages: 201-204
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] [^<11>C]DAA1106 : Radiosynthesis and In Vivo Binding to Peripheral Benzodiazepine Receptors in Mouse Brain (2003)
  • Author(s): Zhang M.-R., Kida T., Noguchi J., Furutsuka K., Maeda J., Suhara T., Suzuki K.
  • Journal Title: Nucl Med Biol 30 Pages: 513-519
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] [^<18>F]FMDAA1106 and [^<18>F]FEDAA1106: Two positron-emitter labeled ligands for peripheral benzodiazepine receptor (PBR) (2003)
  • Author(s): Zhang M.-R., Maeda J., Furutsuka K., Yoshida Y., Ogawa M., Suhara T., Suzuki K.
  • Journal Title: Bioorg Med Chem Lett 13 Pages: 201-204
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] [^<11>C]DAA1106: Radiosynthesis and In Vivo Binding to Peripheral Benzodiazepine Receptors in Mouse Brain (2003)
  • Author(s): Zhang M.-R., Kida T., Noguchi J., Furutsuka K., Maeda J., Suhara T., Suzuki K.
  • Journal Title: Nucl Med Biol 30 Pages: 513-519
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [^<11>C]DAA1106.
  • Author(s): Ikoma Y., Yasuno F., Ito H., Suhara T., Ota M., Toyama H., Fujimura Y., Takano A., Maeda J., Zhang M.-R., Nakao R., Suzuki K.
  • Journal Title: J Cereb Blood Flow Metab (In Press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [^<11>C]DAA1106.
  • Author(s): Ikoma Y., Yasuno F., Ito H., Suhara T., Ota M., Toyama H., Fujimura Y., Takano A., Maeda J., Zhang M.-R., Nakao R., Suzuki K.
  • Journal Title: J Cereb Blood Flow Metab (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Abnormal inter-regional relation of dopamine D2 receptor binding in schizophrenia.
  • Author(s): Yasuno F. et al.
  • Journal Title: Psychiatry Res (in press)