Design, Synthesis, and Characterization of [18F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2 | Zendy

Gengyang Yuan | Zendy; Maëva Dhaynaut | Zendy; Nicolas J. Guehl | Zendy; Sepideh Afshar | Zendy; Dalena Huynh | Zendy; SungHyun Moon | Zendy; Suhasini M. Iyengar | Zendy; Manish K. Jain | Zendy; Julie E. Pickett | Zendy; Hye Jin Kang | Zendy; Mary Jo Ondrechen | Zendy; Georges El Fakhri | Zendy; Marc D. Normandin | Zendy; AnnaLiisa Brownell | Zendy

Open Access

Design, Synthesis, and Characterization of [¹⁸F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2

Author(s) -

Gengyang Yuan,

Maëva Dhaynaut,

Nicolas J. Guehl,

Sepideh Afshar,

Dalena Huynh,

SungHyun Moon,

Suhasini M. Iyengar,

Manish K. Jain,

Julie E. Pickett,

Hye Jin Kang,

Mary Jo Ondrechen,

Georges El Fakhri,

Marc D. Normandin,

AnnaLiisa Brownell

Publication year - 2022

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.2c00593

Subject(s) - metabotropic glutamate receptor 2 , chemistry , metabotropic glutamate receptor , agonist , ligand (biochemistry) , glutamate receptor , metabotropic receptor , radioligand , allosteric regulation , pet imaging , specific activity , positron emission tomography , biophysics , receptor , stereochemistry , nuclear medicine , biochemistry , enzyme , biology , medicine

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 [ 18 F] 8 and [ 18 F] 9 in rats confirmed their excellent brain permeability and binding kinetics. Further evaluation of [ 18 F] 9 in a non-human primate confirmed its superior brain heterogeneity in mapping mGluR2 and higher affinity than [ 18 F] 6 . Pretreatment with different classes of PAMs in rats and a primate led to similarly enhanced brain uptake of [ 18 F] 9 . As a selective ligand, [ 18 F] 9 has the potential to be developed for translational studies.

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