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 (Ki for CB2) of 0.8 nM and a remarkable selectivity factor
of >12,000 over CB1, RoSMA-18-d6 exhibited
outstanding in vitro performance characteristics
and was radiofluorinated with an average radiochemical yield of 10.6
± 3.8% (n = 16) and molar activities ranging
from 52 to 65 GBq/μmol (radiochemical purity > 99%). [18F]­RoSMA-18-d6 showed exceptional CB2
attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography
(PET). Further, [18F]­RoSMA-18-d6 was used to detect CB2 upregulation on postmortem human ALS spinal
cord tissues. Overall, these results suggest that [18F]­RoSMA-18-d6 is a promising CB2 PET radioligand for clinical
translation.