Song Zhendong, Li Yinlong, Dahl Kenneth, Sun Zhenkun, Chen Jiahui, Zhou Xin, Gao Yabiao, Rong Jian, Zhao Chunyu, Yuan Katherine, Chaudhary Ahmad F, Patel Jimmy S, Collier Thomas L, Ran Chongzhao, Muehlfenzl Kim S, Haider Achi, Elmore Charles S, Schou Magnus, Liang Steven H
Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States.
PET Science Centre, Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Karolinska Institutet, Stockholm 17176, Sweden.
J Med Chem. 2025 Aug 14;68(15):15372-15385. doi: 10.1021/acs.jmedchem.4c02924. Epub 2025 Jul 15.
The histamine subtype 3 receptor (HR) is a G protein-coupled receptor involved in various central nervous system (CNS) disorders. We herein describe the identification and preclinical evaluation of two HR antagonists: compounds (H3-2406, = 2.87 nM) and (H3-2407, = 3.15 nM) as potential PET radioligands. Both were radiolabeled with fluorine-18 using a copper-mediated method. Among them, [F] showed high radiochemical yield (32.4%), molar activity (103 GBq/μmol), and moderate brain uptake (SUV = 2.4), with regional distribution matching known HR expression. [F] also exhibited favorable pharmacokinetics, high metabolic stability and negligible efflux by transporter proteins. However, relatively high cerebellar uptake, along with dedicated blocking studies, suggested off-target binding to the sigma-1 receptor, likely due to limited selectivity over sigma-1 (69-fold). These findings highlight [F] as a promising lead for HR imaging, with future work aimed at improving its selectivity and minimizing off-target binding.
组胺3型受体（HR）是一种G蛋白偶联受体，参与多种中枢神经系统（CNS）疾病。我们在此描述了两种HR拮抗剂的鉴定和临床前评估：化合物（H3 - 2406，Kd = 2.87 nM）和（H3 - 2407，Kd = 3.15 nM）作为潜在的正电子发射断层扫描（PET）放射性配体。两者均采用铜介导的方法用氟 - 18进行放射性标记。其中，[F]显示出高放射化学产率（32.4%）、摩尔活性（103 GBq/μmol）和适度的脑摄取（SUV = 2.4），区域分布与已知的HR表达相匹配。[F]还表现出良好的药代动力学、高代谢稳定性以及转运蛋白介导的外排可忽略不计。然而，相对较高的小脑摄取以及专门的阻断研究表明，其可能由于对σ-1受体的选择性有限（69倍）而与σ-1受体存在脱靶结合。这些发现突出了[F]作为HR成像的一个有前景的先导物，未来的工作旨在提高其选择性并最小化脱靶结合。
