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). [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.