Design, synthesis, and characterization of [18F]mG2P026 as a high contrast PET imaging ligand for metabotropic glutamate receptor 2

ABSTRACT An array of triazolopyridines based on JNJ-46356479 ( 6 ) were synthesized as potential PET imaging ligands for metabotropic glutamate receptor 2 (mGluR2) in the brain. The selected candidates 8 - 11 featured an enhanced positive allosteric modulator (PAM) activity (37-fold max.) and an apparent mGluR2 agonist activity (25-fold max.) compared to compound 6 . Radiolabeling of compounds 8 and 9 (also named mG2P026) was achieved via the Cu(I)-mediated radiofluorination in the automated TRACERLab TM FXF-N platform. Both [ 18 F] 8 and [ 18 F] 9 were obtained with satisfactory radiochemical yields (> 5%, non-decay corrected), high molar activity (> 180 GBq/μmol), and excellent chemical and radiochemical purities (> 98%). Preliminary characterization of [ 18 F] 8 and [ 18 F] 9 in rats confirmed their excellent brain permeability with [ 18 F] 9 showing better brain heterogeneity and favorable binding kinetics. Pretreatment with different classes of PAMs enhanced the radioactivity uptake for both [ 18 F] 8 and [ 18 F] 9 at the regions of interest by 20.3-40.9% and 16.7-81.6%, respectively, due to their pharmacological effects. Further evaluation of [ 18 F] 9 in a nonhuman primate confirmed its superior brain heterogeneity in mapping mGlu2 receptors and its higher specific binding than [ 18 F] 6 . Pretreatment with 0.5 mg/kg BINA led (2) to an enhanced brain uptake of [ 18 F] 9 by 3% in high tracer uptake regions that was consistent with the rat studies. Therefore, [ 18 F] 9 has the potential to be translated for human studies.