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PET microdose study for finding appropriate dose of isoproterenol as a disease modifying treatment of dementia

Research Project

Project/Area Number 17H04269
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Radiation science
Research InstitutionNational Center for Geriatrics and Gerontology

Principal Investigator

Ito Kengo  国立研究開発法人国立長寿医療研究センター, 治験・臨床研究推進センター, センター長 (70184653)

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)
関 千江  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, 研究員(任常) (40443080)
古山 浩子  岐阜大学, 工学部, 准教授 (50402160)
山田 貴史  名古屋経済大学, 人間生活科学部管理栄養学科, 准教授 (50531860)
加藤 隆司  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 (60242864)
鈴木 啓介  国立研究開発法人国立長寿医療研究センター, 治験・臨床研究推進センター, 部長 (70635408)
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) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000)
Fiscal Year 2019: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Keywordsイソプロテレノール / マイクロドーズ試験 / 陽電子断層撮像法 / PET / アルツハイマー / タウ蛋白 / アルツハイマー病 / 被曝線量 / MIRD法
Outline of Final Research Achievements

Isoproterenol has been reported to have the potential as a drug for the treatment of Alzheimer’s disease by inhibiting the aggregation of tau protein. It is critical to know if potentially effective therapeutic levels of isoproterenol can be achieved, maintaining safe plasma levels without any untoward pharmacological effects. We found that the concentration of C-11 labeled isoproterenol in the rat brain at equilibrium was about two-fold higher than in the plasma using positron emission tomography and blood analysis. However, a microdosing study in humans was not able to conduct because of the high potency of the drug, causing increases in heart rates even with a dose of 11C-isoproterenol for positron emission tomography study.

Academic Significance and Societal Importance of the Research Achievements

本研究は、既存治療薬の新たな薬効の発見によって、アルツハイマー病の病態に基づいた新規治療薬を開発する過程において、最適な用量を決定するためのマイクロドーズ試験で行うプロセスをラットにおいて実施したものである。今後の同様な創薬に応用可能な学術的意義を有し、実際の創薬の効率を向上させうる社会的意義も有している。同様のプロセスを臨床で実施することによって、直接的に至適容量を決定できる可能性があるが、今回のように活性が非常に高い物質の場合は解決すべき技術的な課題があることも明確になった。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (9 results)

All 2020 2019 2018 2017

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (7 results) (of which Int'l Joint Research: 4 results)

  • [Journal Article] Brain pharmacokinetics and biodistribution of 11C-labeled isoproterenol in rodents2020

    • 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

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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]acetone2019

    • 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

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] Improved (R,S)-[11C]isoproterenol formulation toward clinical study2019

    • Author(s)
      池沼宏、古山浩子、木村泰之、阿部潤一郎、川角保広、小縣綾、山田貴史、加藤隆司、伊藤健吾、鈴木正昭
    • Organizer
      第59回日本核医学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Formulation of 11C-labeled (R,S)-isoproterenol and pharmacokinetic studies in rats.2019

    • Author(s)
      Ikenuma H, Ogata A, Kimura Y, Koyama H, Abe J, Yamada T, Ichise M, Kato T, Suzuki M, Ito K
    • Organizer
      Brain & Brain PET 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Synthesis of 11C-Labeled (R,S)-Isoproterenol and Preclinical PET Study2018

    • Author(s)
      Ikenuma H, Koyama H, Kajino N, Kimura Y, Ogata A, Abe J, Kawasumi Y, Kato T, Suzuki M, Ito K
    • Organizer
      The World Molecular Imaging Congress 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Synthesis of highly-qualified 11C-labeled (R,S)-isoproterenol aimed at a clinical study2017

    • Author(s)
      Ikenuma H, Koyama H, Kimura Y, Abe J, Kawasumi K, Ogata A, Kato T, Ito K, Suzuki M.
    • Organizer
      The 12th Asia Oceania Congress of Nuclear Medicine and Biology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Brain penetration of isoproterenol as a drug of dementia measured in rats with a micro-PET2017

    • Author(s)
      Ogata A, Kimura Y, Ikenuma H, Koyama H, Seki C, Yamada T, Suzuki M, Kato T, Ito K.
    • Organizer
      The 12th Asia Oceania Congress of Nuclear Medicine and Biology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 臨床研究を目的とした11C標識化(R,S)-イソプロテレノールの高効率合成法の開発2017

    • Author(s)
      池沼 宏、古山浩子、木村泰之、阿部潤一郎、川角保広、小縣 綾、加藤隆司、伊藤健吾、鈴木正昭
    • Organizer
      第57回日本核医学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 認知症治療薬としてのイソプロテレノールの小動物PETを用いたラット脳内移行性の検討2017

    • Author(s)
      小縣 綾、木村泰之、池沼 宏、古山浩子、関千江、山田貴史、鈴木正昭、加藤隆司、伊藤健吾
    • Organizer
      第57回日本核医学会学術総会
    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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