Optimization of the metabolic stability of a fluorinated cannabinoid receptor subtype 2 (CB 2 ) ligand designed for PET studies

Abstract The central CB 2 receptor represents a promising target for the treatment of neuroinflammatory diseases as CB 2 activation mediates anti-inflammatory effects. Recently, the F-18 labeled PET radiotracer [ 18 F] 7a was reported, which shows high CB 2 affinity and high selectivity over the CB 1 subtype but low metabolic stability due to hydrolysis of the amide group. Based on these findings twelve bioisosteres of 7a were synthesized containing a non-hydrolysable functional group instead of the amide group. The secondary amine 23a ( K i  = 7.9 nM) and the ketone 26a ( K i  = 8.6 nM) displayed high CB 2 affinity and CB 2 :CB 1 selectivity in in vitro radioligand binding studies. Incubation of 7a , 23a and 26a with mouse liver microsomes and LC-quadrupole-MS analysis revealed a slightly higher metabolic stability of secondary amine 23a , but a remarkably higher stability of ketone 26a in comparison to amide 7a . Furthermore, a logD 7.4 value of 5.56 ± 0.08 was determined for ketone 26a by micro shake-flask method and LC-MS quantification.