Imaging of microglial functions by P2X7 and P2Y12 receptor PET ligands

• Project/Area Number: 17K10387
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: National Institutes for Quantum and Radiological Science and Technology
• Principal Investigator: Maeda Jun 国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 脳機能イメージング研究部, 主任研究員(任常) (30415426)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 陽電子断層撮像法 / プリン受容体 / 神経炎症 / 認知症 / 陽電子撮像法 / ミクログリア / PET / 脳・神経 / 放射線 / トランスレーショナルリサーチ

Outline of Final Research Achievements

In order to image the microglial functions, a purinergic P2X7 receptor (R) ligand [11C]JNJ42253432 and P2Y12R ligand [11C]AZD1283 were radiosynthesized, and the binding characterization of these ligands were determined by small animal PET and autoradiography. The binding of [11C]JNJ42253432 was unchanged by cold ligand in the PET and autoradiography studies. The [11C]AZD1283 was unable to detect P2Y12Rs by PET due to low brain permeability, while the P2Y12R specific bindings were confirmed by ARG. These results have suggested [11C]AZD1283 is beneficial for the quantitation of P2Y12R on the microglia.

Academic Significance and Societal Importance of the Research Achievements

脳内の免疫および老廃物の搬出を司るミクログリア細胞は認知症および多発性硬化症の発症に重要な役割を果たしている。ミクログリア細胞に発現するプリン受容体は内在性のATP等の刺激によりミクログリア細胞の遊走、形状変化、貪食および炎症性サイトカインの放出を誘導する。このことからプリン受容体に結合する放射性化合物を開発することにより、脳機能の解明や神経炎症病態の解明につながるものと考えられる。

Research Products

• [Journal Article] Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model. (2020)
  • Author(s): Shimojo M, Takuwa H, Takado Y, Tokunaga M, Tsukamoto S, Minatohara K, Ono M, Seki C, Maeda J, Urushihata T, Minamihisamatsu T, Aoki I, Kawamura K, Zhang MR, Suhara T, Sahara N, Higuchi M.
  • Journal Title: J Neurosci. Volume: 40 Issue: 17 Pages: 3491-3501
  • DOI: 10.1523/jneurosci.2880-19.2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microglial Activation During Pathogenesis of Tauopathy in rTg4510 Mice: Implications for the Early Diagnosis of Tauopathy. (2018)
  • Author(s): Naruhiko Sahara, Jun Maeda, Ai Ishikawa, Masaki Tokunaga, Tetsuya Suhara, Makoto Higuchi
  • Journal Title: Journal of Alzheimer's Disease Volume: 64 Issue: s1 Pages: S353-S359
  • DOI: 10.3233/jad-179933
  • Peer Reviewed
• [Journal Article] In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510 (2018)
  • Author(s): Ishikawa Ai、Tokunaga Masaki、Maeda Jun、Minamihisamatsu Takeharu、Shimojo Masafumi、Takuwa Hiroyuki、Ono Maiko、Ni Ruiqing、Hirano Shigeki、Kuwabara Satoshi、Ji Bin、Zhang Ming-Rong、Aoki Ichio、Suhara Tetsuya、Higuchi Makoto、Sahara Naruhiko
  • Journal Title: Journal of Alzheimer's Disease Volume: 61 Issue: 3 Pages: 1037-1052
  • DOI: 10.3233/jad-170509
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Distinct microglial response against Alzheimer’s pathologies characterized by P2Y12 receptor (2019)
  • Author(s): Naruhiko Sahara , Jun Maeda , Takeharu Minamihisamatsu , Masafumi Shimojo , Maiko Ono , Keiichiro Minatohara , Hiroyuki Takuwa , Yuhei Takado , Bin Ji , Ming-Rong Zhang , Makoto Higuchi
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Microglia engulfment of tangle-bearing neurons in a living tauopathy model (2018)
  • Author(s): 佐原 成彦, 田桑 弘之, 高堂 裕平, 漆畑 拓弥, 下條 雅文, 高橋 真奈美, 小野 麻衣子, 木村 妙子, 関 千江, 前田 純, 季 斌, 冨田 裕, 張 明栄, 須原 哲也, 樋口 真人
  • Organizer: Society for Neuroscience Annual meeting 2018
  • Int'l Joint Research
• [Presentation] モデルマウスにおけるタウ病態と炎症の経時PETおよび画像病理相関解析 (2017)
  • Author(s): 石川 愛、徳永 正希、田桑 弘之、前田 純、平野 成樹、桑原 聡、須原 哲也、樋口 真人、佐原 成彦
  • Organizer: 第36回日本認知症学会学術集会
• [Presentation] Visualization of microglial response to tau-induced neurodegeneration in a model of tauopathy (2017)
  • Author(s): Naruhiko Sahara , Jun Maeda , Ai Ishikawa , Maiko Ono , Hiroyuki Takuwa , Masafumi Shimojo , Takeharu Minamihisamatsu , Masaki Tokunaga , Shoko Uchida , Izumi Matsumoto , Ming-Rong Zhang , Tetsuya Suhara , Makoto Higuchi
  • Organizer: Alzheimer's Association International Conference
  • Int'l Joint Research
• [Book] 臨床精神薬理 第20巻9号〈特集〉向精神薬の多剤規制と減量・離脱の実際 (2017)
  • Author(s): 前田 純、樋口 真人、須原 哲也
  • Total Pages: 8
  • Publisher: 星和書店
  • ISBN: 9784791152391
• [Remarks] Department of Functional Brain Imaging
  • URL: https://www.nirs.qst.go.jp/seika/brain/
• [Remarks]
  • URL: https://www.nirs.qst.go.jp/seika/brain/index.html
• [Remarks]
  • URL: http://www.nirs.qst.go.jp/seika/brain/index.html