Design, synthesis and biological evaluation of small molecule based PET radioligand for 5-HT7 receptor

The 5-HT7 receptor is a recently cloned G-protein-coupled receptor (GPCR) that is important in regulatingsleep, depression, and circadian rhythms. However, the potential pathophysiological roles of 5-HT7 havenot been fully elucidated, and no 5-HT7 positron emission tomography (PET) radioligands are available,thus limiting imaging studies of this receptor in humans. Here, we present the radiosynthesis andbiological evaluation of 5-(4-([11C]methoxyphenyl)-1-methyl-4-nitro-1H-imidazole ([11C]1) as a new PETligand for 5-HT7. Three-dimensional pharmacophore evaluation and docking studies confirmed its highaffinity for 5-HT7, and in vitro binding assays showed that the binding affinity was 16.8 0.9 nM. Thespecific activity was found to be 48 29 GBq mmol 1 for [11C]1 in a synthetic time of 26 3 min (n ¼ 8),having 38 7% radiochemical yield (decay-corrected) based on [11C]CO2. Ligand interactions withhuman serum albumin were studied by fluorescence quenching to obtain a Stern–Volmer plot, whichshowed a binding constant of 1.15 104 M 1. Whole-body biodistribution patterns were evaluated innormal mice by 1 h dynamic PET imaging; this analysis showed rapid clearance of radioactivity from themain peripheral organs, with the exception of the liver. Preliminary PET studies in rat brains showed rapidaccumulation of radioactivity in the brain. The regional radioactivity reached a maximum within 0–2 minafter the radioligand injection and then decreased rapidly, resulting in minimal radiation burden in thebrain during the scan. In summary, this specific biaryl system has shown potential as a 5-HT7 ligand andfurther optimization and longitudinal studies may yield the first small molecule-based PET ligand for5-HT7 in clinical settings