Design, Synthesis, and Characterization of Benzimidazole Derivatives as Positron Emission Tomography Imaging Ligands...

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). [¹¹C]13 was synthesized via O-[¹¹C]methylation of its phenol precursor 25 with [¹¹C]methyl iodide. The achieved radiochemical yield was 20 ± 2% (n = 10, decay-corrected) based on [¹¹C]CO₂ with a radiochemical purity of >98% and molar activity of 98 ± 30 GBq/μmol EOS. Ex vivo biodistribution studies revealed reversible accumulation of [¹¹C]13 and hepatobiliary and urinary excretions. PET imaging studies in rats demonstrated that [¹¹C]13 accumulated in the mGluR2-rich brain regions. Pre-administration of mGluR2-selective PAM, 17 reduced the brain uptake of [¹¹C]13, indicating a selective binding. Therefore, [¹¹C]13 is a potential PET imaging ligand for mGluR2 in different central nervous system-related conditions.