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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

Ahmed Haider, Luca Gobbi, Julian Kretz, Christoph Ullmer, Andreas Brink, Michael Honer, Thomas J Woltering, Dieter Muri, Hans Iding, Markus Bürkler, Martin Binder, Christian Bartelmus, Irene Knuesel, Pal Pacher, Adrienne Müller Herde, Francesco Spinelli, Hazem Ahmed, Kenneth Atz, Claudia Keller, Markus Weber, Roger Schibli, Linjing Mu, Uwe Grether & Simon M Ametamey

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 ( 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.
   
citation Haider A, Gobbi L, Kretz J, Ullmer C, Brink A, Honer M, Woltering T J, Muri D, Iding H, Bürkler M, Binder M, Bartelmus C, Knuesel I, Pacher P, Herde A M, Spinelli F, Ahmed H, Atz K, Keller C, Weber M, Schibli R, Mu L, Grether U, Ametamey S M. 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. J Med Chem 2020; 63:10287-10306.
   
type journal paper/review (English)
date of publishing 01-09-2020
journal title J Med Chem (63/18)
ISSN electronic 1520-4804
pages 10287-10306
PubMed 32787079
DOI 10.1021/acs.jmedchem.0c00778