Radiosynthesis and evaluation of new PET ligands for peripheral cannabinoid receptor type 1 imaging.

Cannabinoid receptor type 1 (CB1) is mainly expressed in the brain, as well as being expressed in functional relevant concentrations in various peripheral tissues. 1-(4-Chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 1) was developed as a potent allosteric antagonist for CB1 and its oral administration led to reductions in the appetite and body weight of rats. Several analogs of 1 (compounds 2 and 3) were recently identified through a series of structure-activity relationship studies. Herein, we report the synthesis of radiolabeled analogs of these compounds using [11C]COCl2 and an evaluation of their potential as PET ligands for CB1 imaging using in vitro and in vivo techniques. [11C]2 and [11C]3 were successfully synthesized in two steps using [11C]COCl2. The radiochemical yields of [11C]2 and [11C]3 were 17±8% and 20±9% (decay-corrected to the end of bombardment, based on [11C]CO2). The specific activities of [11C]2 and [11C]3 were 42±36 and 37±13GBq/μmol, respectively. The results of an in vitro binding assay using brown adipose tissue (BAT) homogenate showed that the binding affinity of 2 for CB1 (KD=15.3µM) was much higher than that of 3 (KD=26.0µM). PET studies with [11C]2 showed a high uptake of radioactivity in BAT, which decreased in animals pretreated with AM281 (a selective antagonist for CB1). In conclusion, [11C]2 may be a useful PET ligand for imaging peripheral CB1 in BAT.