Development and Preclinical Characterization of [F]H3-2406 and [F]H3-2407 for Positron Emission Tomography Imaging of the Histamine Subtype-3 Receptor.

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.