Development of highly affine and selective fluorinated cannabinoid receptor type 2 ligands

CB2 receptors are involved in various pathological processes and the visualization of the expression level alteration with a non-invasive technique like PET is of high interest. In this work we focused on the introduction of the fluorine atom by modifying at various positions the structure of the highly affine and selective CB2 ligand N-(adamantan-1-yl)-5-ethyl-2-methyl-1-phenyl-1H-imidazole-4-carboxamide (5, Ki(CB2) = 1 nM, Ki(CB1) >10,000 nM). The highest CB2 binding affinity was obtained by derivatization of the imidazole 2-position. This study allowed the identification of compound 15 as one of the most potent (Ki(CB2) = 0.29 nM) and selective (CB1/CB2 > xx), CB2 ligand discovered so far, eligible for the development of an [18F]-PET radiotracer.