| Literature DB >> 35802702 |
Gengyang Yuan1, Maeva Dhaynaut1, Nicolas J Guehl1, Sepideh Afshar1, Dalena Huynh1, Sung-Hyun Moon1, Suhasini M Iyengar2, Manish Kumar Jain3, Julie E Pickett3, Hye Jin Kang3, Mary Jo Ondrechen2, Georges El Fakhri1, Marc D Normandin1, Anna-Liisa Brownell1.
Abstract
An array of triazolopyridines based on JNJ-46356479 (6) were synthesized as potential positron emission tomography radiotracers for metabotropic glutamate receptor 2 (mGluR2). The selected candidates 8-10 featured enhanced positive allosteric modulator (PAM) activity (20-fold max.) and mGluR2 agonist activity (25-fold max.) compared to compound 6 in the cAMP GloSensor assays. Radiolabeling of compounds 8 and 9 (mG2P026) was achieved via Cu-mediated radiofluorination with satisfactory radiochemical yield, >5% (non-decay-corrected); high molar activity, >180 GBq/μmol; and excellent radiochemical purity, >98%. Preliminary characterization of [18F]8 and [18F]9 in rats confirmed their excellent brain permeability and binding kinetics. Further evaluation of [18F]9 in a non-human primate confirmed its superior brain heterogeneity in mapping mGluR2 and higher affinity than [18F]6. Pretreatment with different classes of PAMs in rats and a primate led to similarly enhanced brain uptake of [18F]9. As a selective ligand, [18F]9 has the potential to be developed for translational studies.Entities:
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Year: 2022 PMID： 35802702 PMCID： PMC9434700 DOI： 10.1021/acs.jmedchem.2c00593
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039