2022 Fiscal Year Final Research Report
Novel PET probe for brain tumor imaging targeting specifically expressed enzymes
| Project/Area Number |
20K21260
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 37:Biomolecular chemistry and related fields
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| Research Institution | National Center for Geriatrics and Gerontology |
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Principal Investigator |
Suzuki Masaaki 国立研究開発法人国立長寿医療研究センター, 研究所 認知症先進医療開発センター, 研究員 (90093046)
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| Co-Investigator(Kenkyū-buntansha) |
古山 浩子 岐阜大学, 工学部, 准教授 (50402160)
木村 泰之 国立研究開発法人国立長寿医療研究センター, 研究所 認知症先進医療開発センター, 副部長 (20423171)
夏目 敦至 名古屋大学, 未来社会創造機構, 特任教授 (30362255)
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| Project Period (FY) |
2020-07-30 – 2023-03-31
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| Keywords | O6-メチルグアニン-DNA-トランスフェラーゼ / O6-ベンジルグアニン / 遺伝子変異イソクエン酸脱水素酵素１ / α-ケトグルタル酸 / 11C標識プローブ / 脳腫瘍PETイメージング |
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| Outline of Final Research Achievements |
In the field of brain tumors, O6-methylguanine-DNA methyltransferase (MGMT), which induces drug resistance to DNA methylating anticancer drugs, and mutant isocitrate dehydrogenase 1 (mIDH1), which is closely related to the formation and progression of malignant brain tumors, have attracted attention as potential factors to predict therapeutic efficacy and prognosis. In this study, we focused on an MGMT inactivator O6-benzylguanine (O6-BG), and mIDH1 substrate α-ketoglutaric acid, and provided guidelines for molecular design to enhance the brain permeability, which is important in the development of non-invasive molecular probes for brain disease diagnosis. Thus, we synthesized novel O6-BG derivatives with lipophilic and electrophilic substituent stably, and verified the high brain permeability by rat PET imaging with 11C-labeled O6-BG derivatives. A preliminary study on 18F-labeling ofα-ketoglutaric acid suggested that rapid fluorination of an enolate precursor would be effective.
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| Free Research Field |
生物分子化学関連
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は，難治性脳腫瘍の病態を非侵襲的に評価できる新医療技術の開発に関する挑戦であり，その研究の正否を握る探索的研究段階での独創的かつ学際的な共同研究システムの構築に重点を置いた魁的研究である．とくに，独自に開発した高速炭素－炭素カップリング反応を機軸として，first-in-man試験を視野に入れた精緻かつ高品位なPETプローブの創製による直接的な脳透過性評価法を導入して，脳腫瘍特異的な分子標的イメージング法を編み出すものであり，革新的かつ大きな学術的意義を持つ．
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