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

An array of triazolopyridines based on JNJ-46356479 () were synthesized as potential positron emission tomography radiotracers for metabotropic glutamate receptor 2 (mGluR2). The selected candidates featured enhanced positive allosteric modulator (PAM) activity (20-fold max.) and mGluR2 agonist activity (25-fold max.) compared to compound in the cAMP GloSensor assays. Radiolabeling of compounds and (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 [F] and [F] in rats confirmed their excellent brain permeability and binding kinetics. Further evaluation of [F] in a non-human primate confirmed its superior brain heterogeneity in mapping mGluR2 and higher affinity than [F]. Pretreatment with different classes of PAMs in rats and a primate led to similarly enhanced brain uptake of [F]. As a selective ligand, [F] has the potential to be developed for translational studies.