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

• Published in: Journal of medicinal chemistry Vol. 63; no. 18; pp. 10287 - 10306
• Main Authors: Haider, Achi, 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.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.09.2020; Amer Chemical Soc
• Subjects: Animals; Brain - diagnostic imaging; Chemistry, Medicinal; Fluorine Radioisotopes - chemistry; Humans; Life Sciences & Biomedicine; Ligands; Male; Molecular Docking Simulation; Molecular Structure; Pharmacology & Pharmacy; Positron-Emission Tomography; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - pharmacology; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Radiopharmaceuticals - pharmacology; Rats, Wistar; Receptor, Cannabinoid, CB2 - metabolism; Science & Technology; Spinal Cord - diagnostic imaging; Spleen - diagnostic imaging; Structure-Activity Relationship; Tritium - chemistry; SYSTEM; PET RADIOLIGANDS; CB2 RECEPTORS; PHARMACOLOGY; HIGH-AFFINITY; IN-VIVO EVALUATION; EXPRESSION; BINDING; DISCOVERY; LIPOPHILICITY
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00778

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 (K i for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d 6 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-d 6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [18F]­RoSMA-18-d 6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [18F]­RoSMA-18-d 6 is a promising CB2 PET radioligand for clinical translation.