Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [¹⁸F]LUZ5-d₈

The development of cannabinoid receptor type 2 (CB₂R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB₂R radioligands, a carborane moiety was used as a bioisostere. Here we report the synthesis and characterization of carborane-based 1,8-naphthyridinones and thiazoles as novel CB₂R ligands. All tested compounds showed low nanomolar CB₂R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide (LUZ5) exhibiting the highest affinity (0.8 nM). Compound [F]LUZ5- was obtained with an automated radiosynthesizer in high radiochemical yield and purity. In vivo evaluation revealed the improved metabolic stability of [F]LUZ5- compared to that of [F]JHU94620. PET experiments in rats revealed high uptake in spleen and low uptake in brain. Thus, the introduction of a carborane moiety is an appropriate tool for modifying literature-known CB₂R ligands and gaining access to a new class of high-affinity CB₂R ligands, while the in vivo pharmacology still needs to be addressed.