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

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.