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

Gengyang Yuan, Xiying Qu, Baohui Zheng, Ramesh Neelamegam, Sepideh Afshar, Suhasini Iyengar, Chuzhi Pan, Junfeng Wang, Hye Jin Kang, Mary Jo Ondrechen, Pekka Poutiainen, Georges El Fakhri, Zhaoda Zhang, Anna Liisa Brownell

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12060-12072
Number of pages13
JournalJournal of Medicinal Chemistry
Volume63
Issue number20
DOIs
StatePublished - Oct 22 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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