Synthesis of 11C-labeled acyclic retinoids with high brain permeability

• Project/Area Number: 18K06575
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Gifu University
• Principal Investigator: Koyama Hiroko 岐阜大学, 工学部, 准教授 (50402160)
• Co-Investigator(Kenkyū-buntansha): 木村 泰之 国立研究開発法人国立長寿医療研究センター, 認知症先進医療開発センター, 室長 (20423171) ; 石井 英樹 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 先進核医学基盤研究部, 主任研究員(任常) (80425610) ; 鈴木 正昭 国立研究開発法人国立長寿医療研究センター, 認知症先進医療開発センター, 研究員 (90093046)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 非環式レチノイド（ペレチノイン） / 高速クロスカップリング / 11C標識 / PET / 脳イメージング / 血液脳関門透過性 / 非環式レチノイド / PET脳イメージング / 高い血液脳関門透過性 / 核内受容体 / 非環式レチノイド（4,5-ジデヒドロGGA） / PETイメージング / 11C標識分子プローブ / プロドラッグ / 脳内移行性

Outline of Final Research Achievements

All-trans-retinoic acid (ATRA) and its synthetic analogues (retinoic acids, RAs) play roles in inhibiting cancer development through activating nuclear receptors. Recently, the interest of RAs has been focused on their neuroprotection in central nervus system injury. In view of the chemical and metabolic instability of ATRA, we successfully synthesized the 11C-labeling of acyclic retinoid, which has the higher stability than ATRA, based on our original Palladium(0)-mediated rapid cross-coupling. PET studies on the both rat and monkey brains demonstrated that the 11C-labeled acyclic retinoid showed the high brain permeability. These results are important findings that could lead a retinoid drug candidate potential for chemotherapy of neurodegeneration.

Academic Significance and Societal Importance of the Research Achievements

本研究は，光や酸素に不安定なポリオレフィン構造から成り，化学的にも生物学的にも取扱いの難しい天然型環式レチノイドに代わるべく安定な非環式レチノイドの11C標識化と脳移行性の評価を主課題とし，実際に，パラジム0価錯体を介する独自の高速カップリング反応により11C標識化に成功するとともに，さらにPET研究により高い脳移行性を見出した。脳移行性の発見は，非環式レチノイド類のこれまでのがん研究に，新たな脳研究分野を加え，疾患診断や治療薬の開発を助長する重要な知見であり，学術的および社会的影響は大きい。

Research Products

• [Journal Article] Brain pharmacokinetics and biodistribution of 11C-labeled isoproterenol in rodents (2020)
  • Author(s): Ogata Aya、Kimura Yasuyuki、Ikenuma Hiroshi、Yamada Takashi、Abe Junichiro、Koyama Hiroko、Suzuki Masaaki、Ichise Masanori、Kato Takashi、Ito Kengo
  • Journal Title: Nuclear Medicine and Biology Volume: － Pages: 52-58
  • DOI: 10.1016/j.nucmedbio.2020.06.002
  • Peer Reviewed / Open Access
• [Journal Article] 21.Organozinc-aided, HMPA-free, stoichiometric three-component coupling for the general synthesis of prostaglandins and stable prostacyclin analogs with biological significance (2019)
  • Author(s): Hiroko Koyama, Atsuto Izumiseki, Masaaki Suzuki
  • Journal Title: Tetrahedron Lett. Volume: 60 Issue: 22 Pages: 1467-1470
  • DOI: 10.1016/j.tetlet.2019.04.037
  • Peer Reviewed
• [Journal Article] Synthesis of (R,S)-isoproterenol, an inhibitor of tau aggregation, as an 11C-labeled PET tracer via reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone (2019)
  • Author(s): Ikenuma Hiroshi、Koyama Hiroko、Kajino Naoya、Kimura Yasuyuki、Ogata Aya、Abe Junichiro、Kawasumi Yasuhiro、Kato Takashi、Takashima Akihiko、Ito Kengo、Suzuki Masaaki
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 29 Issue: 16 Pages: 2107-2111
  • DOI: 10.1016/j.bmcl.2019.07.005
  • Peer Reviewed
• [Journal Article] First prototyping of a dedicated PET system with the hemisphere detector arrangement (2019)
  • Author(s): Tashima Hideaki、Yoshida Eiji、Iwao Yuma、Wakizaka Hidekatsu、Maeda Takamasa、Seki Chie、Kimura Yasuyuki、Takado Yuhei、Higuchi Makoto、Suhara Tetsuya、Yamashita Taichi、Yamaya Taiga
  • Journal Title: Physics in Medicine & Biology Volume: 64 Issue: 6 Pages: 065004-065004
  • DOI: 10.1088/1361-6560/ab012c
  • Peer Reviewed / Open Access
• [Journal Article] Tau imaging detects distinctive distribution of tau pathology in ALS/PDC on the Kii Peninsula (2018)
  • Author(s): Shinotoh Hitoshi、Shimada Hitoshi、Kokubo Yasumasa、Tagai Kenji、Niwa Fumitoshi、Kitamura Soichiro、Endo Hironobu、Ono Maiko、Kimura Yasuyuki、Hirano Shigeki、Mimuro Maya、Ichise Masanori、Sahara Naruhiko、Zhang Ming-Rong、Suhara Tetsuya、Higuchi Makoto
  • Journal Title: Neurology Volume: 92 Issue: 2
  • DOI: 10.1212/wnl.0000000000006736
  • Peer Reviewed / Open Access
• [Presentation] In vitro脳内出血病理モデルに対するレチノイドの組織保護効果 (2021)
  • Author(s): 中西咲乃，倉内祐樹，関貴弘，木村泰之，鈴木正昭，鈴木恵一，古山浩子，香月博志
  • Organizer: 第141年会日本薬学会
• [Presentation] Improved (R,S)-[11C]isoproterenol formulation toward clinical study (2019)
  • Author(s): Hiroshi Ikenuma, Hiroko Koyama, Yasuyuki Kimura, Junichiro Abe, Yasuhiro Kawasumi, Aya Ogata, Takashi Yamada, Takashi Kato, Kengo Ito, Masaaki Suzuki
  • Organizer: The 59th Annual Scientific Meeting of the Japanese Society of Nuclear Medicine
• [Presentation] PET imaging of colony stimulating factor 1 receptor (2019)
  • Author(s): Aya Ogata, Yasuyuki Kimura, Takashi Yamada, Masanori Ichise, Junichiro Abe, Hiroshi Ikenuma, Hiroko Koyama, Masaaki Suzuki, Takashi Kato, and Kengo Ito
  • Organizer: The 59th Annual Scientific Meeting of the Japanese Society of Nuclear Medicine
• [Presentation] 脳移行性グルコース・ギンゴライド連結体の設計とPETプローブ化 (2019)
  • Author(s): 鈴木 恵一，古山 浩子，池沼 宏，沢田 知辰，石井 里咲，石井 英樹，土居 久志，木村 泰之，鈴木 正昭
  • Organizer: 第50回中部化学関係学協会支部連合秋季大会
• [Presentation] Formulation of 11C-labeled (R,S)-isoproterenol and pharmacokinetic studies in rats (2019)
  • Author(s): Hiroshi Ikenuma, Aya Ogata, Yasuyuki Kimura, Hiroko Koyama, Junichiro Abe, Takashi Yamada, Masanori Ichise, Takashi Kato, Masaaki Suzuki, and Kengo Ito
  • Organizer: Brain & Brain PET 2019
  • Int'l Joint Research
• [Presentation] PET imaging of colony stimulating factor 1 receptor in rat brains (2019)
  • Author(s): A. Ogata,Y. Kimura, T. Yamada, M. Ichise, H. Ikenuma, J, Abe, H. Koyama, M. Suzuki, T. Kato, K. Ito
  • Organizer: Brain & Brain PET 2019
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 1.[11C]標識非環式レチノイド、中枢神経系活性化剤及びそれらの製造方法 (2020)
  • Inventor(s): 鈴木 正昭、伊藤 健吾、木村 泰之、古山 浩子、他
  • Industrial Property Rights Holder: 鈴木 正昭、伊藤 健吾、木村 泰之、古山 浩子、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020