Design, Synthesis, and Characterization of Benzimidazole Derivatives as Positron Emission Tomography Imaging Ligands for Metabotropic Glutamate Receptor 2.

Three benzimidazole derivatives (-) have been synthetized as potential positron emission tomography (PET) imaging ligands for mGluR2 in the brain. Of these compounds, exhibits potent binding affinity (IC = 7.6 ± 0.9 nM), positive allosteric modulator (PAM) activity (EC = 51.2 nM), and excellent selectivity against other mGluR subtypes (>100-fold). [C] was synthesized via -[C]methylation of its phenol precursor with [C]methyl iodide. The achieved radiochemical yield was 20 ± 2% ( = 10, decay-corrected) based on [C]CO with a radiochemical purity of >98% and molar activity of 98 ± 30 GBq/μmol EOS biodistribution studies revealed reversible accumulation of [C] and hepatobiliary and urinary excretions. PET imaging studies in rats demonstrated that [C] accumulated in the mGluR2-rich brain regions. Pre-administration of mGluR2-selective PAM, reduced the brain uptake of [C], indicating a selective binding. Therefore, [C] is a potential PET imaging ligand for mGluR2 in different central nervous system-related conditions.