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 sub-nanomolar affinity ( for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18- exhibited outstanding performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% ( = 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [F]RoSMA-18- showed exceptional CB2 attributes as demonstrated by autoradiography, biodistribution, and positron emission tomography (PET). Further, [F]RoSMA-18- was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [F]RoSMA-18- is a promising CB2 PET radioligand for clinical translation.