Synthesis and Characterization of 5-(2-Fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2 H-pyrano[2,3- b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2

  • J Med Chem. 2022 Feb 10;65(3):2593-2609. doi: 10.1021/acs.jmedchem.1c02004.
Gengyang Yuan  1 ,  Maeva Dhaynaut  1 ,  Yu Lan  2 ,  Nicolas J Guehl  1 ,  Dalena Huynh  1 ,  Suhasini M Iyengar  3 ,  Sepideh Afshar  1 ,  Manish Kumar Jain  4 ,  Julie E Pickett  4 ,  Hye Jin Kang  4 ,  Hao Wang  2 ,  Sung-Hyun Moon  1 ,  Mary Jo Ondrechen  3 ,  Changning Wang  2 ,  Timothy M Shoup  1 ,  Georges El Fakhri  1 ,  Marc D Normandin  1 ,  Anna-Liisa Brownell  1
Affiliations
  • 1. Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 3rd Avenue, Charlestown, Massachusetts 02129, United States.
  • 2. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • 3. Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
  • 4. Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
PMID: 35089713 DOI: 10.1021/acs.jmedchem.1c02004
Abstract

Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157998
    mG2N001
    mGluR2 Negative Allosteric Modulator
    target: mGluR; Src
    Research Areas: Others