Journal of Medicinal Chemistry p. 10287 - 10306 (2020)
Update date:2022-08-15
Topics:
Haider, Ahmed
Gobbi, Luca
Kretz, Julian
Ullmer, Christoph
Brink, Andreas
Honer, Michael
Woltering, Thomas J.
Muri, Dieter
Iding, Hans
Bürkler, Markus
Binder, Martin
Bartelmus, Christian
Knuesel, Irene
Pacher, Pal
Herde, Adrienne Müller
Spinelli, Francesco
Ahmed, Hazem
Atz, Kenneth
Keller, Claudia
Weber, Markus
Schibli, Roger
Mu, Linjing
Grether, Uwe
Ametamey, Simon M.
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.
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