Design, Synthesis, and Characterization of Benzimidazole Derivatives as Positron Emission Tomography Imaging Ligands for Metabotropic Glutamate Receptor 2
| Autor: | Pekka Poutiainen, Sepideh Afshar, Hye Jin Kang, Xiying Qu, Mary Jo Ondrechen, Zhaoda Zhang, Anna-Liisa Brownell, Junfeng Wang, Baohui Zheng, Chuzhi Pan, Ramesh Neelamegam, Suhasini Iyengar, Georges El Fakhri, Gengyang Yuan |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Biodistribution Benzimidazole Allosteric modulator Ligands 01 natural sciences Article Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery medicine Animals Humans Tissue Distribution Receptors AMPA 030304 developmental biology Mice Knockout 0303 health sciences medicine.diagnostic_test Dose-Response Relationship Drug Molecular Structure Brain Ligand (biochemistry) 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry HEK293 Cells chemistry Metabotropic glutamate receptor Positron emission tomography Drug Design Positron-Emission Tomography Molecular Medicine Benzimidazoles Metabotropic glutamate receptor 2 Methyl iodide Nuclear chemistry |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 |
| Popis: | Three benzimidazole derivatives (13-15) have been synthetized as potential PET imaging ligands for mGluR2 in the brain. Of these compounds, 13 exhibits potent binding affinity (IC(50) = 7.6 ± 0.9 nM), PAM activity (EC(50) = 51.2 nM), and excellent selectivity against other mGluR subtypes (> 100-fold). [(11)C]13 was synthesized via O-[(11)C]methylation of its phenol precursor 25 with [(11)C]methyl iodide. The achieved radiochemical yield was 20 ± 2% (n = 10, decay-corrected) based on [(11)C]CO(2) with radiochemical purity > 98% and molar activity 98±30 GBq/µmol EOS. Ex vivo biodistribution studies revealed reversible accumulation of [(11)C]13 and hepatobiliary and urinary excretions. PET imaging studies in rats demonstrated that [(11)C]13 accumulated in the mGluR2-rich brain regions. Pre-administration of mGluR2-selective PAM, 17 reduced the brain uptake of [(11)C]13, indicating a selective binding. However, pre-administration of 13 significantly enhanced [(11)C]13 uptake in the brain. Therefore, [(11)C]13 is both a potential PET imaging ligand for mGluR2 and a drug candidate for the treatment of CNS disorders. |
| Databáze: | OpenAIRE |
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