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

Abstract

The cannabinoid receptor type 2 (CB2R) is overexpressed under pathological conditions. PET is a suitable non-invasive imaging technique for diagnosing disease states, but requires a radiotracer that binds to CB2R with high affinity and selectivity. Currently, there is no suitable candidate routinely used in the clinics. The naphthyridinone scaffold is a promising core structure that has been modified in the past years. The modification of naphthyridinone carboxamides with carboranes as hydrophobic surrogates for purely organic moieties could lead to a beneficial CB2R ligand with high affinity, selectivity and metabolic stability. We here report the synthesis and characterization of eight carborane-based naphthyridinone ligands, the determination of their in vitro binding affinity towards the human CB1R and CB2R and the results of in silico investigations. The meta- and para-carborane derivatives show high affinity in the low nanomolar range and a good selectivity towards CB2R. Only a minor influence of bromo- vs. iodo-substitution was observed experimentally, while in silico data suggested a stronger influence of the halogen atom, resulting in a different order of the respective carborane isomers regarding their affinity to CB2R. Although these compounds did not outperform the known organic derivatives, they extend the portfolio of potentially useful CB2R ligands.