Development of HDAC6 PET imaging probes for proteinopathies

• Project/Area Number: 16H07486
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Radiation science
• Research Institution: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
• Principal Investigator: Tago Tetsuro 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (50780649)
• Project Period (FY): 2016-08-26 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: PET / HDAC6 / 分子イメージング / プロテイノパチー / 核医学 / 放射性医薬品 / イメージング

Outline of Final Research Achievements

Histone deacetylases (HDACs) are enzymes responsible for lysine deacetylation of histones. In particular, HDAC6 is a unique enzyme that is mainly found in the cytosol and regulates deacetylation of cytosolic proteins including α-tubulin and tau protein. HDAC6 has been implicated in neurodegeneration with abnormal protein accumulation in the brain. Thus, research into the role of HDAC6 with in vivo imaging will facilitate development of drugs targeting HDAC6. Our goal was to develop radiolabeled probes for positron emission tomography (PET) imaging of HDAC6. Two radiolabeled Tubastatin A derivatives were successfully synthesized. However, biological evaluations suggested that brain uptake of these probes were poor. Structural optimization which improves the blood-brain barrier permeability is needed.

Research Products

• [Journal Article] Correlations of (18)F-THK5351 PET with Postmortem Burden of Tau and Astrogliosis in Alzheimer Disease. (2018)
  • Author(s): Harada R, Furukawa K, et al.
  • Journal Title: J Nucl Med Volume: 59 Issue: 4 Pages: 671-674
  • DOI: 10.2967/jnumed.117.197426
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Response of cerebral blood flow and blood pressure to dynamic exercise: A study using PET (2018)
  • Author(s): Hiura, M., Nariai, T. Muta, A., Sakata, M., Ishibashi, K. Toyohara, J. Wagatsuma, K. Tago, T., Ishii, K. Maehara, T.
  • Journal Title: International Journal of Sports Medicine Volume: 39 Issue: 03 Pages: 181-188
  • DOI: 10.1055/s-0043-123647
  • Peer Reviewed
• [Journal Article] Advances in the Development of PET Ligands Targeting Histone Deacetylases for the Assessment of Neurodegenerative Diseases (2018)
  • Author(s): Tago Tetsuro、Toyohara Jun
  • Journal Title: Molecules Volume: 23 Issue: 2 Pages: 300-300
  • DOI: 10.3390/molecules23020300
  • Peer Reviewed / Open Access
• [Journal Article] Potential Use of 18F-THK5351 PET to Identify Wallerian Degeneration of the Pyramidal Tract Caused by Cerebral Infarction (2017)
  • Author(s): Ishibashi Kenji、Kameyama Masashi、Tago Tetsuro、Toyohara Jun、Ishii Kenji
  • Journal Title: Clinical Nuclear Medicine Volume: 42 Issue: 12 Pages: e523-e524
  • DOI: 10.1097/rlu.0000000000001868
  • Peer Reviewed
• [Journal Article] ヒストンデアセチラーゼ6のイメージングを目的としたPETプローブの開発 (2017)
  • Author(s): 多胡哲郎、豊原潤、酒井昌成、林薫平、石井賢二
  • Journal Title: JSMI Report Volume: 11 Pages: 25-28
  • Peer Reviewed
• [Presentation] Radiosynthesis of carbon-11- and fluorine-18-labeled Tubastatin A derivatives for PET imaging of histone deacetylase 6 (2017)
  • Author(s): Tetsuro Tago、Kunpei Hayashi、Masanari Sakai、Kenji Ishii、Jun Toyohara
  • Organizer: 22nd International Symposium on Radiopharmaceutical Sciences
  • Int'l Joint Research
• [Presentation] Development of PET probes for imaging of histone deacetylase 6 (2017)
  • Author(s): Tetsuro Tago、Kunpei Hayashi、Masanari Sakai、Kenji Ishii、Jun Toyohara
  • Organizer: FASMI 2017
  • Int'l Joint Research
• [Presentation] Development of PET probes for imaging of histone deacetylase 6 (2017)
  • Author(s): 多胡哲郎、林薫平、酒井昌成、石井賢二、豊原潤
  • Organizer: 第12回日本分子イメージング学会学術集会
• [Presentation] ヒストンデアセチラーゼ6のPETイメージングを目的とした放射性標識ツバスタチンA誘導体の開発 (2017)
  • Author(s): 多胡哲郎、豊原潤、酒井昌成、林薫平、石井賢二
  • Organizer: 第57回日本核医学会学術総会
• [Presentation] コンフォメーション病のイメージングを目的としたPETプローブ開発 (2016)
  • Author(s): 多胡哲郎
  • Organizer: 首都大バイオコンファレンス2016
  • Place of Presentation: 首都大学東京（東京・八王子）
  • Year and Date: 2016-11-18
• [Presentation] 臨床応用を目指したPET薬剤の次世代化 (2016)
  • Author(s): 豊原潤、多胡哲郎、坂田宗之、石橋賢士、我妻慧、石渡喜一、石井賢二
  • 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・名古屋）
  • Year and Date: 2016-11-03