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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.

SUBMITTER: Yuan G

PROVIDER: S-EPMC8629109 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Yuan Gengyang G Qu Xiying X Zheng Baohui B Neelamegam Ramesh R Afshar Sepideh S Iyengar Suhasini S Pan Chuzhi C Wang Junfeng J Kang Hye Jin HJ Ondrechen Mary Jo MJ Poutiainen Pekka P El Fakhri Georges G Zhang Zhaoda Z Brownell Anna-Liisa AL

Journal of medicinal chemistry 20201007 20

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 ...[more]

PMID: 32981322

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Dataset Information

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

Publications

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

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