Development of PET probes for visualization of neurodegenerative process

• Project/Area Number: 18K15538
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52040:Radiological sciences-related
• Research Institution: Tohoku University
• Principal Investigator: HARADA RYUICHI 東北大学, 医学系研究科, 助教 (60735455)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 放射性医薬品 / PET / アストロサイト / タウ / PETプローブ

Outline of Final Research Achievements

18F-THK-5351 PET have limited biomarker for tau pathology in Alzheimer’s disease because of off-target binding to monoamine oxidase-B, which is dominantly expressed in astrocytes. Selective imaging techniques to trace tau burden and astrogliosis selectively are required to elucidate neuronal circuit breakdown mechanisms in the humans. The aim of this study was to develop novel and selective PET probes for imaging tau pathology and MAO-B, respectively through compound optimization from 18F-THK-5351. We synthesized more than 200 compounds and screened against tau aggregates and MAO-B. Finally, we successfully discovered novel selective PET probes for imaging tau pathology and MAO-B that possess preferable pharmacokinetics.

Academic Significance and Societal Importance of the Research Achievements

タウ病変を非侵襲的に画像化することができればアルツハイマー病の診断や治療薬のサロゲートマーカーへの利用が期待できる。研究代表者らはこれまでにタウ病変を画像化する目的でPETプローブ18F-THK-5351を開発したが、オフターゲットの問題が発覚し、改良を余儀なくされた。本研究で改良した18F-SNFT-1はタウ病変に選択的であり、タウを標的とした治療薬のサロゲートマーカーとして有望であると考えられる。また、本研究で開発したMAO-B選択的なPETプローブ18F-SMBT-1によりアストログリオーシスを選択的に描出することが可能となり、治療薬が神経炎症に与える影響の効果判定への応用が期待される。

Research Products

• [Int'l Joint Research] メルボルン大学(オーストラリア)
• [Int'l Joint Research] メルボルン大学(オーストラリア)
• [Journal Article] Brain histamine H1 receptor occupancy after oral administration of desloratadine and loratadine (2019)
  • Author(s): Nakamura Tadaho、Hiraoka Kotaro、Harada Ryuichi、Matsuzawa Takuro、Ishikawa Yoichi、Funaki Yoshihito、Yoshikawa Takeo、Tashiro Manabu、Yanai Kazuhiko、Okamura Nobuyuki
  • Journal Title: Pharmacology Research & Perspectives Volume: 7 Issue: 4
  • DOI: 10.1002/prp2.499
  • Peer Reviewed / Open Access
• [Journal Article] Longitudinal changes in 18F-THK5351 PET in corticobasal syndrome (2019)
  • Author(s): Ezura M, Kikuchi A, Ishiki A, Okamura N, Hasegawa T, Harada R, Watanuki S, Funaki Y, Hiraoka K, Baba T, Sugeno N, Oshima R, Yoshida S, Kobayashi J, Kobayashi M, Tano O, Nakashima I, Mugikura S, Iwata R, Taki Y, Furukawa K, Arai H, Furumoto S, Tashiro M, Yanai K, Kudo Y, Takeda A, Aoki M
  • Journal Title: Eur J Neurol Volume: 26 Issue: 9 Pages: 1205-1211
  • DOI: 10.1111/ene.13966
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site (2019)
  • Author(s): Tago Tetsuro、Toyohara Jun、Harada Ryuichi、Furumoto Shozo、Okamura Nubuyuki、Kudo Yukitsuka、Takahashi-Fujigasaki Junko、Murayama Shigeo、Ishii Kenji
  • Journal Title: Annals of Nuclear Medicine Volume: 33 Issue: 6 Pages: 1-8
  • DOI: 10.1007/s12149-019-01344-x
  • Peer Reviewed / Open Access
• [Journal Article] Heparan sulfate in pancreatic β-cells contributes to normal glucose homeostasis by regulating insulin secretion. (2018)
  • Author(s): Matsuzawa T, Yoshikawa T, Iida T, Karpati A, Kitano H, Harada R, Nakamura T, Sugawara A, Yamaguchi Y, Yanai K.
  • Journal Title: Biochem Biophys Res Commun Volume: - Issue: 3 Pages: 688-695
  • DOI: 10.1016/j.bbrc.2018.03.213
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Newly-Developed Positron Emission Mammography (PEM) Device for the Detection of Small Breast Cancer (2018)
  • Author(s): Yanai A, Itoh M, Hirakawa H, Yanai K, Tashiro M, Harada R, Yoshikawa A, Yamamoto S, Ohuchi N, Ishida T.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 245 Issue: 1 Pages: 13-19
  • DOI: 10.1620/tjem.245.13
  • NAID: 130006731329
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Histamine elicits glutamate release from cultured astrocytes (2018)
  • Author(s): Karpati Aniko、Yoshikawa Takeo、Nakamura Tadaho、Iida Tomomitsu、Matsuzawa Takuro、Kitano Haruna、Harada Ryuichi、Yanai Kazuhiko
  • Journal Title: Journal of Pharmacological Sciences Volume: 137 Issue: 2 Pages: 122-128
  • DOI: 10.1016/j.jphs.2018.05.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroimaging-pathological correlations of [(18)F]THK5351 PET in progressive supranuclear palsy (2018)
  • Author(s): Ishiki A, Furukawa K, et al.
  • Journal Title: Acta Neuropathol Commun Volume: 6 Issue: 1 Pages: 53-53
  • DOI: 10.1186/s40478-018-0556-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Site-Specific Labeling of F-18 Proteins Using a Supplemented Cell-Free Protein Synthesis System and O-2-[18F]Fluoroethyl-L-Tyrosine: [18F]FET-HER2 Affibody Molecule (2018)
  • Author(s): Yanai Ai、Harada Ryuichi、Iwata Ren、Yoshikawa Takeo、Ishikawa Yoichi、Furumoto Shozo、Ishida Takanori、Yanai Kazuhiko
  • Journal Title: Molecular Imaging and Biology Volume: - Issue: 3 Pages: 529-537
  • DOI: 10.1007/s11307-018-1266-z
  • Peer Reviewed
• [Journal Article] Imaging Protein Misfolding in the Brain Using β-Sheet Ligands (2018)
  • Author(s): Harada Ryuichi、Okamura Nobuyuki、Furumoto Shozo、Yanai Kazuhiko
  • Journal Title: Frontiers in Neuroscience Volume: 12 Pages: 585-585
  • DOI: 10.3389/fnins.2018.00585
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of the Precuneus/Posterior Cingulate Cortex Is Significant for the Development of Alzheimer’s Disease: A PET (THK5351, PiB) and Resting fMRI Study (2018)
  • Author(s): Yokoi Takamasa、Watanabe Hirohisa、Ishigaki Shinsuke、Katsuno Masahisa、Miyao Shinichi、Kato Katsuhiko、Naganawa Shinji、Harada Ryuichi、Okamura Nobuyuki、Yanai Kazuhiko、Yoshida Mari、Sobue Gen （ほか9名）
  • Journal Title: Frontiers in Aging Neuroscience Volume: 10 Pages: 304-304
  • DOI: 10.3389/fnagi.2018.00304
  • Peer Reviewed / Open Access
• [Presentation] Preclicanil characterization of [18F]THK-5562, a novel tau PET tracer with little off-target binding (2020)
  • Author(s): Ryuichi Harada, Pradith Lerdisirisuk, Yiqing Du, Michinori Ezura, Yuki Shimizu, Takahiro Morito, Hiroyuki Arai, Kazuhiko Yanai, Yukitsuka Kudo, Shozo Furumoto, Nobuyuki Okamura
  • Organizer: Human Amyloid Imging 2020
  • Int'l Joint Research
• [Presentation] Assessing Abeta, tau, and reactive astrocytosis in aging and AD (2020)
  • Author(s): Victor Villemagne, Ryuichi Harada, Dore, Shozo Furumoto, Rachel Mulligan, Yukitsuka Kudo, Natasha KrisKun Huang, Kazuhiko Yanai, Christopher C Rowe, Nobuyuki Okamura
  • Organizer: Human Amyloid Imging 2020
  • Int'l Joint Research
• [Presentation] アストロサイトのPETイメージング (2019)
  • Author(s): 原田龍一
  • Organizer: PETサマーセミナー 2019
  • Invited
• [Presentation] アストロサイトのPETトレーサー (2019)
  • Author(s): 原田龍一
  • Organizer: 第38回日本認知症学会学術集会
  • Invited
• [Presentation] Discovery of [18F]SMBT-1: a novel selective MAO-B PET trcer for imaging astrogliosis (2019)
  • Author(s): Ryuichi Harada
  • Organizer: Human Amyloid Imaging 2019
  • Int'l Joint Research
• [Presentation] Radiolabeled proteins for the development of biopharmaceuticals (2019)
  • Author(s): 原田龍一
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Pathological correlates of 18F-THK-5351 PET in tauopathies (2018)
  • Author(s): Ryuichi Harada
  • Organizer: Congress of the World Federation of Nuclear Medicine and Biology
  • Int'l Joint Research
• [Presentation] アンバーコドンを用いた無細胞蛋白質合成法による新規18F標識蛋白質合成法の開発 (2018)
  • Author(s): 原田龍一
  • Organizer: 第58回日本核医学会学術総会
• [Presentation] フェルラ酸誘導体によるミスフォールディング蛋白質の凝集抑制 (2018)
  • Author(s): 原田龍一
  • Organizer: 第69回日本薬理学会北部会
  • Invited
• [Presentation] Development of selective tau and MAO-B PET through compound optimization of [18F]THK-5351 (2018)
  • Author(s): Ryuichi Harada
  • Organizer: World Congress of Pharmacology 2018
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] タウを画像化する新規化合物 (2019)
  • Inventor(s): 原田龍一、他4名
  • Industrial Property Rights Holder: 原田龍一、他4名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-240189
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] モノアミンオキシダーゼBイメージングプローブ (2018)
  • Inventor(s): 原田龍一、古本祥三、工藤幸司、岡村信行
  • Industrial Property Rights Holder: 原田龍一、古本祥三、工藤幸司、岡村信行
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018