Synthesis and biological evaluation of novel 18F-labeled phenylbenzofuran-2-carboxamide derivative for detection of orexin 1 receptor in the brain. (1st July 2021)

• Record Type: Journal Article
• Authors: Watanabe, Hiroyuki; Idoko, Yuki; Iikuni, Shimpei; Ide, Takuji; Shimizu, Yoichi; Nakamoto, Yuji; Ono, Masahiro
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 43(2021)
• Publication Date: 2021-07-01
• Subjects: Orexin 1 receptor -- PET probe -- 18F -- Benzofuran; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128098
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Although the orexin 1 receptor (OX1 R) in the brain is considered to regulate reward and feeding, the in vivo function of OX1 R has not been fully elucidated. In vivo imaging of OX1 R with positron emission tomography (PET) may be useful to further understand the molecular details of OX1 R. In this study, we newly designed and synthesized a phenylbenzofuran-2-carboxamide (PBC) derivative ([ 18 F]PBC-1) and evaluated its utility as a PET probe targeting OX1 R in the brain. The results of cell binding assays suggested that [ 18 F]PBC-1 has affinity for OX1 R. In an in vitro competitive inhibition assay, PBC-1 showed selective binding affinity for OX1 R (IC50 = 19.5 nM) over orexin 2 receptor (IC50 = 456.7 nM). Furthermore, [ 18 F]PBC-1 displayed sufficient brain uptake for in vivo imaging with PET in a biodistribution study using normal mice, but in vivo instability was observed. These results suggest that further modifications for improvement of the pharmacokinetics are needed, but the PBC scaffold has potential for the development of useful PET probes targeting OX1 R in the brain.