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

Abstract

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.

Design, synthesis, and characterization of [18F]mG2P026 as a high contrast PET imaging ligand for metabotropic glutamate receptor 2

“…Compounds 8-13 were characterized for their functional affinity as mGluR2 PAMs and their binding selectivity against mGluR1-6 and 8 following our previous methods. 32,34 As shown in Figures 2a-c and Table 1, compound 8 showed an enhanced PAM activity than that of compound 6 in our cAMP biosensor assay (EC50, 20 nM versus 166 nM). By screening its mGluR2/3 agonist activity, compound 8 was also found to have a more potent mGluR2 agonist activity (IC50 = 136 nM) but a similar mGluR3 agonist activity (IC50 = 3 µM) than compound 6 (mGluR2, IC50 = 2 µM; mGluR3, IC50 = 9 µM).…”

PET imaging studies to investigate functional expression of mGluR2 using [11C]mG2P001

“…In vivo characterization of [ 11 C]mG2P001 as a reversible and specific PET radioligand for mGluR2 was described in our previous report. 19 Herein, the selfblocking effect using a pretreatment with unlabeled mG2P001 was investigated. As Fig.…”

“…22 Our previous studies have confirmed [ 11 C]mG2P001 as a suitable ligand to characterize mGluR2 in rat brain. 19 Herein, we demonstrated the unique feature of mG2P001-induced positive allosteric modulation in affecting the brain uptake of [ 11 C]mG2P001, where a significant radioactivity enhancement was observed in rats. This functional effect was then investigated in mGluR2expressing CHO cells with [ 3 H]mG2P001 considering the binding cooperativity of glutamate and the presence of unlabeled mG2P001.…”

“…The radiolabeling precursor 2-(1-((1-Methyl-1Himidazo [4,5-b]pyridin-2-yl)methyl)piperidin-4-yl)-5-(trifluoromethyl)phenol was synthesized as previously described. 19 Radiosynthesis of [ 11 C]mG2P001: [ 11 C]mG2P001was synthetized using the previously published method. 19 Radiosynthesis of [ 3 H]mG2P001: 20 μL [ 3 H]Methyl iodide in DMF (American Radiolabeled Chemicals, Inc., 1 Ci/mL in DMF, molar activity 80 Ci/mmol) was added to a solution of DMF (0.1 mL) containing 2-(1-((1-Methyl-1H-imidazo [4,5-b]pyridin-2-yl)methyl)piperidin-4-yl)-5-(trifluoromethyl)phenol (2 mg, 5.12 μmol) and sodium hydride (10 mg, 0.42 mmol).…”

“…19 Radiosynthesis of [ 11 C]mG2P001: [ 11 C]mG2P001was synthetized using the previously published method. 19 Radiosynthesis of [ 3 H]mG2P001: 20 μL [ 3 H]Methyl iodide in DMF (American Radiolabeled Chemicals, Inc., 1 Ci/mL in DMF, molar activity 80 Ci/mmol) was added to a solution of DMF (0.1 mL) containing 2-(1-((1-Methyl-1H-imidazo [4,5-b]pyridin-2-yl)methyl)piperidin-4-yl)-5-(trifluoromethyl)phenol (2 mg, 5.12 μmol) and sodium hydride (10 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for 20 minutes and diluted with 200 μL 1N HCl and 2 mL acetonitrile/water (v/v = 50:50).…”