Development of Highly Affine and Selective Fluorinated Cannabinoid Type 2 Receptor Ligands

Cannabinoid type 2 receptors (CB2 receptors) are involved in various pathological processes,
and the visualization of their in vivo availability
with positron emission tomography (PET) is of high interest. The study
focuses on the introduction of fluorine into the structure of the
highly affine and selective CB2 receptor ligand N-(adamantan-1-yl)-5-ethyl-2-methyl-1-phenyl-1H-imidazole-4-carboxamide (5). A novel series of compounds
was developed by modifying (i) the adamantane-3-position, (ii) the
imidazole-N-phenyl ring, and (iii) the imidazole-2-position,
and the impact on the CB2 binding affinity and selectivity
toward cannabinoid type 1 receptors (CB1) was evaluated.
This study identified compound 15 as one of the most
potent (Ki(CB2) = 0.29 nM)
and selective (CB1/CB2 > 10000) CB2 receptor ligands discovered so far, eligible for the development
of an 18F-labeled PET radiotracer.