Development of Carborane-Based Benzothiazole Analogues as Cannabinoid Receptor Type 2 (CB₂R) Ligands

Area of Science:

• Medicinal Chemistry
• Radiopharmaceutical Chemistry
• Neuroscience

Background:

• Cannabinoid receptor type 2 (CB2R) is upregulated in pathological brain conditions.
• Positron Emission Tomography (PET) requires selective CB2R radioligands for disease state imaging.
• Carboranes serve as hydrophobic surrogates in drug design.

Purpose of the Study:

• To synthesize and characterize novel carborane-substituted benzothiazole ligands for CB2R.
• To evaluate the binding affinity and selectivity of these ligands.
• To identify promising candidates for PET imaging of CB2R.

Main Methods:

• Synthesis and characterization of ortho-, meta-, and para-carborane derivatives.
• In vitro binding affinity assays for CB2R.
• Molecular docking studies.
• Preliminary biological evaluation of a related radiotracer.

Main Results:

• Three isomeric carborane-substituted benzothiazole ligands were synthesized.
• All derivatives exhibited nanomolar affinity and high selectivity for CB2R.
• The meta-carborane derivative showed the highest experimental binding affinity and was predicted as most affine by docking.

Conclusions:

• Carborane-substituted benzothiazoles are promising scaffolds for CB2R ligand development.
• The meta-carborane derivative is a particularly strong candidate for further investigation.
• These findings support the development of novel PET imaging agents for neurological disorders.