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

Abstract

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.

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…Dynamic PET scans in rodents revealed a fast uptake in the spleen and liver, a fast hepatic clearance, and non-displaceable binding in the spleen. The overall increase in metabolic stability while maintaining high affinity and selectivity is a valuable starting point for future optimizations for CB2R PET ligands . Moldovan et al report [ 18 F] 5 (Figure ) with high affinity toward human CB2R (hCB2R) and no or low affinity for rat CB2R.…”

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…The overall increase in metabolic stability while maintaining high affinity and selectivity is a valuable starting point for future optimizations for CB2R PET ligands. 5 Moldovan et al report [ 18 F]5 (Figure 1) with high affinity toward human CB2R (hCB2R) and no or low affinity for rat CB2R. PET scans of a rat model with local hCB2R overexpression demonstrated that [ 18 F]5 was able to selectively and reversibly image cerebral CB2R.…”

Carboranylphosphines: B9‐Substituted Derivatives with Enhanced Reactivity for the Anchoring to Dendrimers

“…Icosahedral closo-dicarbadodecaboranes (carboranes) have been a focus of interest of many research groups in the past years as building blocks for applications in medicinal chemistry, [1][2][3][4] metal complexes, [5][6][7] supramolecular assemblies, macrocyclic molecules, [8] and luminescent materials. [9,10] Important modifications of carboranes include functionalization of both, boron and carbon vertices, which are influenced by two fundamental electronic properties: the electron delocalization and the electron-withdrawing character of the skeletal carbon atoms.…”