TY - JOUR
T1 - Design, Synthesis, and Characterization of Benzimidazole Derivatives as Positron Emission Tomography Imaging Ligands for Metabotropic Glutamate Receptor 2
AU - Yuan, Gengyang
AU - Qu, Xiying
AU - Zheng, Baohui
AU - Neelamegam, Ramesh
AU - Afshar, Sepideh
AU - Iyengar, Suhasini
AU - Pan, Chuzhi
AU - Wang, Junfeng
AU - Kang, Hye Jin
AU - Ondrechen, Mary Jo
AU - Poutiainen, Pekka
AU - El Fakhri, Georges
AU - Zhang, Zhaoda
AU - Brownell, Anna Liisa
N1 - Funding Information:
This project was financially supported by NIH grants [1R01EB021708 and 1R01NS100164] and grants 1S10RR023452-01 and 1S10OD025234-01 for the imaging instrumentation and characterization of the organic compounds. mGluR1-6 and mGluR8 agonist and antagonist functional data as well as mGluR2 PAM activity were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, contract #HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth (mail to: bryan_roth@med.unc.edu ) at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll (mail to: jdrisco1@mail.nih.gov ) at NIMH, Bethesda MD, USA. For experimental details, please refer to the PDSP web site https://pdspdb.unc.edu/pdspWeb/ ( https://pdspdb.unc.edu/pdspWeb/ ).
Publisher Copyright:
©
PY - 2020/10/22
Y1 - 2020/10/22
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.0c01394
DO - 10.1021/acs.jmedchem.0c01394
M3 - Article
C2 - 32981322
AN - SCOPUS:85094220982
SN - 0022-2623
VL - 63
SP - 12060
EP - 12072
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 20
ER -