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

Three benzimidazole derivatives (13-15) have been synthetized as potential positron emission tomography (PET) imaging ligands for mGluR2 in the brain. Of these compounds, 13 exhibits potent binding affinity (IC50 = 7.6 +/- 0.9 nM), positive allosteric modulator (PAM) activity (EC50 = 51.2 nM), and excellent selectivity against other mGluR subtypes (>100-fold). [C-11]13 was synthesized via O-[C-11]methylation of its phenol precursor 25 with [C-11]methyl iodide. The achieved radiochemical yield was 20 +/- 2% (n = 10, decay-corrected) based on [C-11]CO2 with a radiochemical purity of >98% and molar activity of 98 +/- 30 GBq/mu mol EOS. Ex vivo biodistribution studies revealed reversible accumulation of [C-11]13 and hepatobiliary and urinary excretions. PET imaging studies in rats demonstrated that [C-11]13 accumulated in the mGluR2-rich brain regions. Pre-administration of mGluR2-selective PAM, 17 reduced the brain uptake of [C-11]13, indicating a selective binding. Therefore, [C-11]13 is a potential PET imaging ligand for mGluR2 in different central nervous system-related conditions.