Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [18F]LUZ5‑d 8

• Published in: Journal of medicinal chemistry Vol. 66; no. 7; pp. 5242 - 5260
• Main Authors: Ueberham, Lea, Gündel, Daniel, Kellert, Martin, Deuther-Conrad, Winnie, Ludwig, Friedrich-Alexander, Lönnecke, Peter, Kazimir, Aleksandr, Kopka, Klaus, Brust, Peter, Moldovan, Rareş-Petru, Hey-Hawkins, Evamarie
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.04.2023
• Subjects: Animals; Brain - diagnostic imaging; Brain - metabolism; Ligands; Positron-Emission Tomography - methods; Protein Binding; Rats; Receptors, Cannabinoid - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00195

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 [ 18 F]­LUZ5-d 8 was obtained with an automated radiosynthesizer in high radiochemical yield and purity. In vivo evaluation revealed the improved metabolic stability of [ 18 F]­LUZ5-d 8 compared to that of [ 18 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.