Development of novel SPECT probes for the diagnosis and treatment of Alzheimer's disease

• Project/Area Number: 17H05092
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Radiation science
• Research Institution: Kyoto University
• Principal Investigator: Watanabe Hiroyuki 京都大学, 薬学研究科, 講師 (40710786)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥25,220,000 (Direct Cost: ¥19,400,000、Indirect Cost: ¥5,820,000); Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
• Keywords: アルツハイマー病 / SPECT / タウ / 神経細胞死 / オリゴマー / イメージング

Outline of Final Research Achievements

Alzheimer's disease is a progressive degenerative brain disease and the most common form of dementia in the elderly, but diagnostic and treatment methods have not been established. Compared with positron emission tomography (PET), single photon emission computed tomography (SPECT) scanners show lower sensitivity and quantification, but are more accessible and less to use cost. Therefore, I developed SPECT probes targeting β-amyloid oligomer, tau aggregagtes, and synaptic vesicle protein 2A. Among them, we found that two novel scaffolds (pyridoimidazopyridine and benzimidazopyrimidine) may be applied to develop useful tau imaging probes.

Academic Significance and Societal Importance of the Research Achievements

SPECTは, 用いる標識核種の物理学的半減期が長く，検査施設もPET施設の10倍程度存在することから，PETよりも汎用性に優れた臨床核医学診断を可能にする.Aβオリゴマーの生成，タウ凝集体の蓄積，神経細胞死という AD の進行の段階に応じて診断・ 治療効果判定を行うことができる SPECT プローブの開発を行うことで，AD の汎用性の高い診断 法の確立のみならず，治療薬開発における患者選定，治療効果判定への貢献が期待できる.

Research Products

• [Journal Article] Structure-Activity and Brain Kinetics Relationships of 18F-Labeled Benzimidazopyridine Derivatives as Tau PET Tracers (2021)
  • Author(s): Hiroyuki Watanabe, Yuta Tarumizu, Sho Kaide, Yoichi Shimizu, Shimpei Iikuni, Yuji Nakamoto, Masahiro Ono
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 12 Issue: 2 Pages: 262-266
  • DOI: 10.1021/acsmedchemlett.0c00641
  • Peer Reviewed
• [Journal Article] Characterization and Optimization of Benzimidazopyrimidine and Pyridoimidazopyridine Derivatives as Tau-SPECT Probes (2021)
  • Author(s): Hiroyuki Watanabe, Takeaki Kishimoto, Sho Kaide, Yuta Tarumizu, Haruka Tatsumi, Shimpei Iikuni, Masahiro Ono
  • Journal Title: ACS Medicinal Chemistry Letters Volume: - Issue: 5 Pages: 805-811
  • DOI: 10.1021/acsmedchemlett.1c00071
  • Peer Reviewed
• [Journal Article] SPECT用タウイメージングプローブの開発 (2021)
  • Author(s): 渡邊裕之、小野正博
  • Journal Title: 細胞 Volume: 53 Pages: 41-43
  • NAID: 40022468828
• [Journal Article] Structure?Activity Relationships of Radioiodinated 6,5,6-Tricyclic Compounds for the Development of Tau Imaging Probes (2020)
  • Author(s): Watanabe H，Tatsumi H，Kaide S，Shimizu Y，Iikuni S，Ono M.
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 11 Issue: 2 Pages: 120-126
  • DOI: 10.1021/acsmedchemlett.9b00456
  • Peer Reviewed
• [Journal Article] 18F-labeled benzimidazopyridine derivatives for PET imaging of tau pathology in Alzheimer’s disease (2019)
  • Author(s): Kaide S，Watanabe H，Shimizu Y，Tatsumi H，Iikuni S，Nakamoto Y，Togashi K，Ihara M，Saji H，Ono M.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 27 Issue: 16 Pages: 3587-3594
  • DOI: 10.1016/j.bmc.2019.06.039
  • Peer Reviewed
• [Journal Article] Structure-Activity Relationships of Radioiodinated Benzoimidazopyridine Derivatives for Detection of Tau Pathology (2018)
  • Author(s): Kaide S, Ono M, Watanabe H, Kitada A, Yoshimura M, Shimizu Y, Ihara M, Saji H.
  • Journal Title: ACS Med. Chem. Lett. Volume: 9 Issue: 5 Pages: 478-483
  • DOI: 10.1021/acsmedchemlett.8b00092
  • Peer Reviewed
• [Journal Article] Conversion of iodine to fluorine-18 based on iodinated chalcone and evaluation for β-amyloid PET imaging (2018)
  • Author(s): Kaide Sho, Ono Masahiro, Watanabe Hiroyuki, Shimizu Yoichi, Nakamoto Yuji, Togashi Kaori, Yamaguchi Aiko, Hanaoka Hirofumi, Saji Hideo.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 26 Issue: 12 Pages: 3352-3358
  • DOI: 10.1016/j.bmc.2018.05.001
  • Peer Reviewed
• [Journal Article] Novel fluorescence probes based on the chalcone scaffold for in vitro staining of β-amyloid plaques (2018)
  • Author(s): Watanabe Hiroyuki, Saji Hideo, Ono Masahiro.
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 28 Issue: 19 Pages: 3242-3246
  • DOI: 10.1016/j.bmcl.2018.08.009
  • Peer Reviewed
• [Journal Article] Development of SPECT Probes for <i>In Vivo</i> Imaging of &beta;-Amyloid and Tau Aggregates in the Alzheimer's Disease Brain (2017)
  • Author(s): Watanabe H,
  • Journal Title: YAKUGAKU ZASSHI Volume: 137 Issue: 11 Pages: 1361-1365
  • DOI: 10.1248/yakushi.17-00156
  • NAID: 130006191239
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2017-11-01
  • Peer Reviewed
• [Journal Article] Synthesis and biological evaluation of novel radioiodinated benzimidazole derivatives for imaging α-synuclein aggregates (2017)
  • Author(s): Watanabe H, Ariyoshi T, Ozaki A, Ihara M, Ono M, Saji H
  • Journal Title: Bioorg Med Chem Volume: 25 Issue: 24 Pages: 6398-6403
  • DOI: 10.1016/j.bmc.2017.10.010
  • Peer Reviewed
• [Presentation] 含窒素縮合3環系構造を基盤とした新規SPECT用タウイメージングプローブの開発 (2021)
  • Author(s): 渡邊 裕之、岸本 峻明、貝出 翔、垂水 勇太、飯國 慎平、小野 正博
  • Organizer: 日本薬学会 第141年会
• [Presentation] アルツハイマー病脳内タウを標的とするSPECT用プローブの開発を目的とした125I標識ベンゾイミダゾピリミジン誘導体の構造活性動態相関研究 (2020)
  • Author(s): 岸本峻明，渡邊裕之，辰巳悠華，貝出 翔，垂水勇太，飯國慎平，志水陽一，小野正博
  • Organizer: 第140年会日本薬学会
• [Presentation] Synthesis and evaluation of 18F-labeled benzimidazopyridine derivatives as novel PET tracers for tau imaging (2019)
  • Author(s): Hiroyuki Watanabe, Sho Kaide, Yuta Tarumizu, Yoichi Shimizu, Simpei Iikuni, Masahiro Ono
  • Organizer: 23rd International Symposium on Radiopharmaceutical Sciences
  • Int'l Joint Research
• [Presentation] Development of PET/SPECT Imaging Probes Based on Benzimidazopyridine Scaffold for Detection of Tau Pathology in Alzheimer's Disease (2019)
  • Author(s): Sho Kaide, Hiroyuki Watanabe, Yoichi Shimizu, Shimpei Iikuni, Hideo Saji, Masahiro Ono
  • Organizer: The 11th Seoul-Kyoto-Osaka Joint Symposium on Pharmaceutical Sciences for Young Scientists
  • Int'l Joint Research
• [Presentation] 新規PET用タウイメージングプローブの開発を目的とした18F標識ベンゾイミダゾピリジン誘導体の合成と評価 (2019)
  • Author(s): 垂水勇太，渡邊裕之，貝出 翔，飯國慎平，志水陽一，小野正博
  • Organizer: 第59回日本核医学会学術総会
• [Presentation] ヒト剖検脳切片を用いたBIP-NMe2に関する生化学評価 (2019)
  • Author(s): 貝出 翔，渡邊裕之，志水陽一，飯國慎平，伊東恭子，小野正博
  • Organizer: 第59回日本核医学会学術総会
• [Presentation] アルツハイマー病脳内タウのPETイメージングを目的とした18F標識ベンゾイミダゾピリジン誘導体の開発 (2019)
  • Author(s): 貝出 翔，渡邊裕之，志水陽一，辰巳悠華，飯國慎平，小野正博
  • Organizer: 第17回次世代を担う若手のためのフィジカル・ファーマフォーラム
• [Presentation] アルツハイマー病脳内タウのPETイメージングを目的とした18F標識ベンゾイミダゾピリジン誘導体の構造活性動態相関 (2019)
  • Author(s): 垂水 勇太, 渡邊 裕之, 貝出 翔, 飯國 慎平, 志水 陽一, 小野 正博
  • Organizer: 日本薬学会 第138年会
• [Presentation] ベンゾイミダゾピリジン骨格を基盤とする新規PET用タウイメージングプローブの開発 (2018)
  • Author(s): 貝出 翔, 渡邊 裕之, 辰巳 悠華, 志水 陽一, 佐治 英郎, 小野 正博
  • Organizer: 第58回日本核医学会学術総会
• [Presentation] アルツハイマー病脳内タウを標的とした放射性ヨウ素標識ベンゾイミダゾピリジン誘導体に関する構造活性相関研究 (2018)
  • Author(s): 貝出 翔, 小野正博, 渡邊裕之, 志水陽一, 佐治英郎
  • Organizer: 第138年会日本薬学会
• [Presentation] αシヌクレインイメージングプローブの開発を目的とした新規ベンゾイミダゾール誘導体の合成と評価 (2017)
  • Author(s): 有吉泰亮、渡邊裕之、小野正博、佐治英郎
  • Organizer: 第12回日本分子イメージング学会
• [Presentation] アルツハイマー病脳のβアミロイド、タウの生体イメージングに資する放射性プローブの開発 (2017)
  • Author(s): 渡邊裕之
  • Organizer: 第67回日本薬学会近畿支部総会・大会