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 carboranebased
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 [18F]LUZ5-d8 was obtained with an automated radiosynthesizer in
high radiochemical yield and purity. In vivo evaluation revealed the improved metabolic stability of [18F]LUZ5-d8 compared
to that of [18F]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,