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

Area of Science:

• Medicinal Chemistry
• Radiopharmaceutical Development
• Neuroscience

Background:

• Cannabinoid receptor type 2 (CB2R) radioligands are crucial for positron emission tomography (PET) imaging.
• Existing CB2R radioligands often suffer from low metabolic stability and suboptimal binding affinity.
• Bioisosteric replacement is a strategy to enhance ligand properties.

Purpose of the Study:

• To synthesize and characterize novel carborane-based 1,8-naphthyridinones and thiazoles as CB2R ligands.
• To evaluate the binding affinity and metabolic stability of these new compounds.
• To assess the potential of carborane moieties in developing improved CB2R PET imaging agents.

Main Methods:

• Synthesis and characterization of carborane-containing 1,8-naphthyridinone and thiazole derivatives.
• In vitro assessment of CB2R binding affinity for the synthesized compounds.
• Radiosynthesis of the lead compound [18F]LUZ5 using an automated radiosynthesizer.
• In vivo evaluation of metabolic stability and PET imaging in rats.

Main Results:

• All tested compounds demonstrated low nanomolar CB2R affinity.
• (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide (LUZ5) exhibited the highest affinity (0.8 nM).
• [18F]LUZ5 was produced in high radiochemical yield and purity.
• In vivo studies showed [18F]LUZ5 possesses improved metabolic stability compared to [18F]JHU94620.
• PET imaging in rats revealed high uptake in the spleen and low uptake in the brain.

Conclusions:

• Incorporating a carborane moiety is an effective strategy for enhancing the affinity of known CB2R ligands.
• Carborane-based compounds represent a new class of high-affinity CB2R ligands.
• Further investigation into the in vivo pharmacology of these novel ligands is warranted.