There is no suitable radioligand for positron emission tomography imaging of CB₂R overexpression for routine clinical usage. Herein, the synthesis, characterization, binding affinity, and docking studies of carborane-based halo-substituted naphthyridinone derivatives as CB₂R ligands are presented. The meta-carborane derivatives are identified as the most affine CB₂R ligands. Only small differences in selectivity to CB₂R are observed for the iodo- and bromo-substituted meta-carborane derivatives.

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.