Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors

Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a subnanomolar affinity (K-i for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d(6) exhibited outstanding in vitro performance characteristics and was radio-fluorinated with an average radiochemical yield of 10.6 +/- 3.8% (n = 16) and molar activities ranging from 52 to 65 GBq/mu mol (radiochemical purity > 99%). [F-18]RoSMA-18-d(6) showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [F-18]RoSMA-18-d(6) was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [F-18]RoSMA-18-d(6) is a promising CB2 PET radioligand for clinical translation.