Structure–Activity Relationship Studies of Pyridine-Based Ligands and Identification of a Fluorinated Derivative for Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors

• Published in: Journal of medicinal chemistry Vol. 62; no. 24; pp. 11165 - 11181
• Main Authors: Haider, Achi, Kretz, Julian, Gobbi, Luca, Ahmed, Hazem, Atz, Kenneth, Bürkler, Markus, Bartelmus, Christian, Fingerle, Jürgen, Guba, Wolfgang, Ullmer, Christoph, Honer, Michael, Knuesel, Irene, Weber, Markus, Brink, Andreas, Herde, Adrienne Müller, Keller, Claudia, Schibli, Roger, Mu, Linjing, Grether, Uwe, Ametamey, Simon M.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.12.2019; Amer Chemical Soc
• Subjects: Animals; Brain - diagnostic imaging; Brain - metabolism; Chemistry, Medicinal; Cyclic AMP - metabolism; Fluorine Radioisotopes - chemistry; Fluorine Radioisotopes - metabolism; Hepatocytes - metabolism; Humans; Life Sciences & Biomedicine; Ligands; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Neuroimaging - methods; Pharmacology & Pharmacy; Positron-Emission Tomography - methods; Protein Conformation; Pyridines - chemistry; Radiochemistry; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - metabolism; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2 - chemistry; Receptor, Cannabinoid, CB2 - metabolism; Science & Technology; Structure-Activity Relationship; TARGET; CB2 RECEPTORS; RADIOLIGAND; VIVO EVALUATION; HIGH-AFFINITY; BINDING; AGONIST
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01280

The cannabinoid type 2 (CB2) receptor has emerged as a valuable target for therapy and imaging of immune-mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 positron emission tomography (PET) radioligand [11C]­RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a K i (hCB2) of 6 nM and a selectivity factor of nearly 700 over cannabinoid type 1 receptors, target compound 3 exhibited optimal in vitro properties and was selected for evaluation as a PET radioligand. [18F]3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [18F]3 to CB2 was demonstrated by in vitro autoradiography and in vivo PET experiments using the CB2 ligand GW-405 833. Metabolite analysis revealed only intact [18F]3 in the rat brain. [18F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.