Synthesis and biological evaluation of F-18 labeled tetrahydroisoquinoline derivatives targeting orexin 1 receptor. Issue 13 (1st July 2019)

• Record Type: Journal Article
• Authors: Watanabe, Hiroyuki; Fukui, Kengo; Shimizu, Yoichi; Idoko, Yuki; Nakamoto, Yuji; Togashi, Kaori; Saji, Hideo; Ono, Masahiro
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 13(2019)
• Page Start: 1620
• Page End: 1623
• Publication Date: 2019-07-01
• Subjects: Orexin 1 receptor -- PET -- 18F -- Tetrahydroisoquinoline; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.04.044
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Orexin 1 receptor (OX1 R) is thought to be involved in various body functions, including arousal maintenance and emotional control, but the full details of its function remain unknown. OX1 R imaging with positron emission tomography (PET) would be useful in elucidating the orexin system including OX1 R, but no PET probes targeting OX1 R have been reported. We, therefore, designed and synthesized tetrahydroisoquinoline (THIQ) derivatives as novel PET probes targeting OX1 R, and evaluated their utility. In an in vitro competitive binding assay, THIQ-1 and THIQ-2 showed significantly higher binding to OX1 R (IC50 = 30 and 31 nM, respectively) than OX2 R (IC50 = 160 and 332 nM, respectively). These features were also observed in a cell binding assay using [ 18 F]THIQ-1 and [ 18 F]THIQ-2, demonstrating their OX1 R-specific binding property in vitro . In a biodistribution study using normal mice, the brain uptake of [ 18 F]THIQ-1 was higher than that of [ 18 F]THIQ-2, but further improvement is required for in vivo imaging with PET. Taken together, [ 18 F]THIQ-1 and [ 18 F]THIQ-2 have the potential to become useful imaging probes for PET targeting the OX1 R, but require additional structural changes to improve their brain uptake.