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

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.