Development of PET molecular probes for imaging alpha-synuclein in the brain

• Project/Area Number: 23659605
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Radiation science
• Research Institution: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
• Principal Investigator: TOYOHARA Jun 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, 専門副部長 (50425659)
• Co-Investigator(Renkei-kenkyūsha): ISHIWATA Kiichi 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, 研究部長 (50143037) ; SAKATA Muneyuki 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 (00403329) ; ISHII Kenji 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, 研究部長 (10231135) ; ODA Keiichi 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 (70224235)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 放射性医薬品・造影剤 / 脳神経疾患 / 認知症 / 核医学 / 薬学 / 放射性医薬品 / 放射線 / 痴呆

Research Abstract

Five phenothiazine and a polyphenol derivatives were radiolabeled as potential PET molecular imaging probes for alpha-synuclein imaging in the brain. The four of five phenothiazine derivatives were successfully radiolabeled by 11C-methyl iodide or 11C-methyl triflate in a good yield with high specific activity. Dedicated small animal PET imaging showed these phenothiazine derivatives crossed the blood-brain barrier (BBB) with rapid washout from the brain. Another one-phenothiazine and polyphenol derivatives did not cross the BBB.
In conclusion, our initial studies suggested that phenothiazine derivatives are good candidate for in vivo imaging of alpha-synuclein aggregation in the brain. Further structural optimizations of these compounds are needed.

Research Products

• [Journal Article] Application of[^<11>C]SA4503 to selection of novel sigmal selective agonists. (2012)
  • Author(s): Toyohara, J., Kobayashi, T., Mita, S. and Ishiwata, K.
  • Journal Title: Nucl. Med. Biol. Volume: 39 Issue: 8 Pages: 1117-1121
  • DOI: 10.1016/j.nucmedbio.2012.06.004
  • Peer Reviewed
• [Journal Article] Re-evaluation of in vivo selectivity of [^<11>C]SA4503 to sigmal receptors in the brain : contributions of emopamil binding protein. (2012)
  • Author(s): Toyohara, J., Sakata, M. and Ishiwata, K
  • Journal Title: Nucl. Med. Biol. Volume: 39 Issue: 7 Pages: 1049-1052
  • DOI: 10.1016/j.nucmedbio.2012.03.002
  • Peer Reviewed
• [Journal Article] Roles of sigmal receptors in the mechanisms of action of CNS drugs. (2012)
  • Author(s): Toyohara, J., Sakata, M. and Ishiwata, K.
  • Journal Title: Trans. Neurosci. Volume: 3 Issue: 3 Pages: 294-299
  • DOI: 10.2478/s13380-012-0030-0
  • Peer Reviewed
• [Presentation] PET プローブ開発の基礎 (2013)
  • Author(s): 豊原 潤
  • Organizer: PETサマーセミナー2013
  • Place of Presentation: 金沢
• [Presentation] Synthesis and evaluation of a fluorine-18-labeled 7α-(3-fluoropropyl)estradiol (2013)
  • Author(s): Okamoto, M., Matsui, A., Kitagawa, Y., Toyohara, J., Ishiwata, K., Yoshimoto, M. and Shimizu, I
  • Place of Presentation: Jeju
• [Presentation] PETプローブ開発の基礎 (2013)
  • Author(s): 豊原潤
  • Organizer: PETサマーセミナー2013
  • Place of Presentation: 金沢
  • Invited
• [Presentation] Synthesis and evaluation of a fluorine-18-labeled 7a-(3-fluoropropyl)estradiol. (2013)
  • Author(s): Okamoto, M.,Matsui, A., Kitagawa, Y., Toyohara, J., Ishiwata, K., Yoshimoto, M. and Shimizu, I.
  • Organizer: 20th International Symposium on Radiopharmaceutical Sciences
  • Place of Presentation: Jeju
• [Presentation] 新規PET 薬剤開発からfirst-in-human study まで―多施設共同研究への取り組み― (2012)
  • Author(s): 豊原 潤、坂田宗之、織田圭一、石井賢二、石渡喜一
  • Organizer: 第52回日本核医学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 化学薬学セッション : PET 薬剤の理解のために―PET 医師のための化学薬学の時間― (2012)
  • Author(s): 豊原 潤
  • Organizer: PET サマーセミナー2012
  • Place of Presentation: 松本
• [Presentation] Dose sigma1 ligand [^<11>C]SA4503 bind to the emopamil binding protein in the brain in vivo? (2012)
  • Author(s): Toyohara, J., Sakata, M. and Ishiwata, K
  • Organizer: The 9th international symposium on fuctional neuroreceptor mapping of the living brain
  • Place of Presentation: Baltimore
• [Presentation] Sigma receptors (2012)
  • Author(s): Toyohara J
  • Organizer: International symposium on PET and SPECT in neurology and psychiatry
  • Place of Presentation: Groningen
• [Presentation] Dose sigma1 ligand [11C]SA4503 bind to the emopamil binding protein in the brain in vivo? (2012)
  • Author(s): Toyohara, J., Sakata, M. and Ishiwata, K.
  • Organizer: The 9th international symposium on functional neuroreceptor mapping of the living brain (NRM12)
  • Place of Presentation: Baltimore
• [Presentation] 化学薬学セッションPET薬剤の理解のためにーPET医師のための化学薬学の時間ー (2012)
  • Author(s): 豊原潤
  • Organizer: PETサマーセミナー2012
  • Place of Presentation: 松本
  • Invited
• [Presentation] 新規PET薬剤開発からfirst-in-human studyまでー多施設共同研究への取り組みー (2012)
  • Author(s): 豊原潤、坂田宗之、織田圭一、石井賢二、石渡喜一
  • Organizer: 第52回日本核医学会学術総会
  • Place of Presentation: 札幌
  • Invited
• [Book] Trends on the role of PET in drug development (2012)
  • Author(s): Toyohara, J. and Ishiwata, K
  • Publisher: World scientific publishing Co
• [Book] Trends on the role of PET in drug development (2012)
  • Author(s): Toyohara, J. and Ishiwata, K.
  • Total Pages: 768
  • Publisher: World scientific publishing Co.