Development of Carborane-Based Benzothiazole Analogues as Cannabinoid Receptor Type 2 (CB2R) Ligands

The Cannabinoid Receptor type 2 (CB₂R) is upregulated in the brain under pathological conditions. To distinguish between the healthy and disease states, Positron Emission Tomography (PET), as a noninvasive imaging technique, is employed, for which suitable highly affine and selective CB₂R radioligands are required. The benzothiazole scaffold is a promising core structure that has been modified with different substituents. Recently, we have reported naphthyridinone- and thiazole-based carborane-substituted CB₂R ligands and investigated the first carborane-based CB₂R radiotracer [ ¹⁸ F]-LUZ5- d ₈ in preliminary biological tests. Carboranes are cluster compounds that are used as hydrophobic surrogates in drug design. We here report the synthesis, characterization, binding affinity data and docking results of three promising isomeric carborane-substituted benzothiazole-based CB₂R ligands. The ortho-, meta- and para-carborane derivatives exhibit a nanomolar affinity and high selectivity toward CB₂R, with the meta-carborane derivative being the most affine compound experimentally and in docking studies.