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

• 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: American Chemical Society 13.04.2023
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00195

The development of cannabinoid receptor type 2 (CB 2 R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB 2 R 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 CB 2 R ligands. All tested compounds showed low nanomolar CB 2 R affinity, with ( Z )- N -[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3 H )-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 CB 2 R ligands and gaining access to a new class of high-affinity CB 2 R ligands, while the in vivo pharmacology still needs to be addressed.