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

Abstract

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 (<i>K</i>_i for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-<i>d</i>₆ exhibited outstanding <i>in vitro</i> performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% (<i>n</i> = 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [¹⁸F]RoSMA-18-<i>d</i>₆ showed exceptional CB2 attributes as demonstrated by <i>in vitro</i> autoradiography, <i>ex vivo</i> biodistribution, and positron emission tomography (PET). Further, [¹⁸F]RoSMA-18-<i>d</i>₆ was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [¹⁸F]RoSMA-18-<i>d</i>₆ is a promising CB2 PET radioligand for clinical translation.