Development of Carborane-Based Halogenated Naphthyridinone-Analogues as Cannabinoid Receptor Type 2 (CB2R) Ligands.

The cannabinoid receptor type 2 (CB2R) is overexpressed under pathological conditions. Positron emission tomography is a noninvasive imaging technique for diagnosing disease states, but requires radiotracers with high affinity and selectivity towards CB2R. Currently, there is no suitable candidate routinely used in the clinics. The naphthyridinone scaffold, a promising core structure, has been modified in the past years. The modification of naphthyridinone carboxamides with carboranes as hydrophobic surrogates for purely organic moieties can lead to beneficial CB2R ligands with high affinity, selectivity, and metabolic stability. Herein, synthesis and characterization of eight ortho-, meta-, para-, and nido-carborane-based naphthyridinone ligands are reported, along with their in vitro binding affinity towards human CB1R and CB2R. Additionally, the results of in silico investigations are presented. The meta- and para-carborane derivatives show high affinity in the low nanomolar range and good selectivity towards CB2R. Only a minor influence of bromo- versus iodo-substitution of the compounds is observed experimentally, while in silico data suggest a stronger influence of the halogen atom, resulting in a different order of the respective carborane isomers regarding their CB2R affinity. Although these compounds do not outperform the known organic derivatives, these promising carborane-based naphthyridinones extend the portfolio of potentially useful CB2R ligands.