Pharmacological application study using PET probe targeting for glutamate receptors

• Project/Area Number: 16K19870
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Radiation science
• Research Institution: National Institutes for Quantum and Radiological Science and Technology
• Principal Investigator: Yamasaki Tomoteru 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 標識薬剤開発部, 研究員(定常) (80627563)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: PET / mGluR1 / てんかん / グルタミン酸 / MAGL / ジアシルグリセロール / N-Acetylcysteine / カンナビノイド / mGluR5 / 癲癇 / [11C]ITDM / 分子認識 / 放射線 / 薬学 / 薬理学

Outline of Final Research Achievements

In this study, PET imaging for mGluR1 was conducted using animal model with epilepsy or chronic high glutamate release as a one of pharmacological applications.
In PET study with epilepsy model, it was found out that decline of specific bindings of [11C]ITDM, a selective PET probe for mGluR1, accompanied with neuroinflammation occurred on glutamatergic neural circuit. In case of PET study with chronic high glutamate release model, it was indicated that specific bindings of [11C]ITDM increased depending on basal glutamate concentrations.
These results suggest that the mGluR1 is involved in both of neuroexcitotoxicity and neuronal protection.

Academic Significance and Societal Importance of the Research Achievements

本研究で、mGluR1が神経炎症時に発現量が減少すること、一方で、細胞外グルタミン酸濃度の上昇した場合には発現量が上昇することをPETイメージングにより明らかにした。これらの研究成果は、mGluR1が神経炎症または未病段階での細胞外グルタミン酸の上昇を検知できるバイオマーカーとして有用であることを示した。そのため、mGluR１を標的としたPETイメージングは、グルタミン酸神経毒性が関与する疾患の早期診断や治療薬開発に大きく貢献できると考えられ、今後の更なる研究への発展が期待できる。

Research Products

• [Journal Article] First demonstration of in vivo mapping for regional brain monoacylglycerol lipase using PET with [ 11 C]SAR127303 (2018)
  • Author(s): Yamasaki Tomoteru、Mori Wakana、Zhang Yiding、Hatori Akiko、Fujinaga Masayuki、Wakizaka Hidekatsu、Kurihara Yusuke、Wang Lu、Nengaki Nobuki、Ohya Tomoyuki、Liang Steven H.、Zhang Ming-Rong
  • Journal Title: NeuroImage Volume: 176 Pages: 313-320
  • DOI: 10.1016/j.neuroimage.2018.05.015
  • Peer Reviewed
• [Journal Article] In Vivo Monitoring for Regional Changes of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Pilocarpine-Induced Epileptic Rat Brain by Small-Animal PET (2017)
  • Author(s): Yamasaki Tomoteru、Fujinaga Masayuki、Mori Wakana、Zhang Yiding、Wakizaka Hidekatsu、Nengaki Nobuki、Xie Lin、Hatori Akiko、Zhang Ming-Rong
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 14945-14945
  • DOI: 10.1038/s41598-017-15015-2
  • Peer Reviewed / Open Access
• [Presentation] Quantitative analysis for fatty acid amide hydrolase (FAAH) using PET with [11C]DFMC (2018)
  • Author(s): 山崎友照、大矢智之、森若菜、張一鼎、脇坂秀克、小川政直、張明栄
  • Organizer: 第58回日本核医学会学術総会
• [Presentation] In vivo mapping for monoacylglycerol lipase activity using PET with [11C]SAR127303 (2018)
  • Author(s): Tomoteru Yamasaki, Wakana Mori, Yiding Zhang, Akiko Hatori, Yusuke Kurihara, Masanao Ogawa, Nobuki Nengaki, Hidekatsu Wakizaka, Masayuki Fujinaga, Lu Wanag, Huan Liang, Ming-Rong Zhang
  • Organizer: 12th Congress of the World Federation of Nuclear Medicine and Biology
  • Int'l Joint Research
• [Presentation] In vivo mapping for monoacylglycerol lipase activity using PET with [11C]SAR127303 (2018)
  • Author(s): Tomoteru Yamasaki, Wakana Mori, Yiding Zhang, Akiko Hatori, Yusuke Kurihara, Masanao Ogawa, Nobuki Nengaki, Hidekatsu Wakizaka, Masayuki Fujinaga, Lu Wang, Steven H. Liang, Ming-Rong Zhang
  • Organizer: 12th Congress of the World Federation of Nuclear Medicine and Biology
  • Int'l Joint Research
• [Presentation] [11C]SAR127303を用いたモノアシルグリセロールリパーゼ（MAGL）PET定量解析 (2017)
  • Author(s): 山崎友照、森若菜、張一鼎、脇坂秀克、藤永雅之、栗原祐輔、念垣信樹、張明栄
  • Organizer: 第57回日本核医学会学術総会
• [Presentation] てんかんモデルラットにおける代謝型グルタミン酸受容体1を標的としたPETイメージング (2016)
  • Author(s): 山崎友照、由井譲二、藤永雅之、脇坂秀克、森若菜、下田陽子、栗原雄祐，張明栄
  • Organizer: 第56回日本核医学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県、名古屋市）
  • Year and Date: 2016-11-03
• [Presentation] PET imaging with [11C]ITDM, a selective radioligand for metabotropic glutamate receptor subtype 1 (mGluR1), in pilocarpine-induced epileptic rat brain (2016)
  • Author(s): Tomoteru Yamasaki, Joji Yui, Masayuki Fujinaga, Yoko Shimoda, Wakana Mori, Yusuke Kurihara, Hidekatsu Wakizaka, Ming-Rong Zhang
  • Organizer: European Association of Nuclear Medicine Congress 2016
  • Place of Presentation: Barcelona (Spain)
  • Year and Date: 2016-10-15
  • Int'l Joint Research