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

Publication

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

Journal Paper/Review - Sep 1, 2020

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

Citation

Haider A, Pacher P, Herde A, Spinelli F, Ahmed H, Atz K, Keller C, Weber M, Schibli R, Mu L, Grether U, Knuesel I, Bartelmus C, Gobbi L, Kretz J, Ullmer C, Brink A, Honer M, Woltering T, Muri D, Iding H, Bürkler M, Binder M, Ametamey S. 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)

Journal

J Med Chem 2020; 63

Publication Date

Sep 1, 2020

Issn Electronic

1520-4804

Pages

10287-10306

Brief description/objective

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.