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

Yuan, G.; Dhaynaut, M.; Guehl, N. J.; Afshar, S.; Huynh, D.; Moon, S.-H.; Iyengar, S.; Kang, H. J.; Ondrechen, M. J.; El Fakhri, G.; Normandin, M. D.; Brownell, A.-L.

doi:10.1101/2021.06.29.450249

bioRxiv · 10.1101/2021.06.29.450249

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

Yuan, G.·Dhaynaut, M.·Guehl, N. J.·Afshar, S.·Huynh, D.·Moon, S.-H.·Iyengar, S.·Kang, H. J.·Ondrechen, M. J.·El Fakhri, G.·Normandin, M. D.·Brownell, A.-L.

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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 TRACERLabTM FXF-N platform. Both [18F]8 and [18F]9 were obtained with satisfactory radiochemical yields (> 5%, non-decay corrected), high molar activity (> 180 GBq/mol), and excellent chemical and radiochemical purities (> 98%). Preliminary characterization of [18F]8 and [18F]9 in rats confirmed their excellent brain permeability with [18F]9 showing better brain heterogeneity and favorable binding kinetics. Pretreatment with different classes of PAMs enhanced the radioactivity uptake for both [18F]8 and [18F]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 [18F]9 in a nonhuman primate confirmed its superior brain heterogeneity in mapping mGlu2 receptors and its higher specific binding than [18F]6. Pretreatment with 0.5 mg/kg BINA led (2) to an enhanced brain uptake of [18F]9 by 3% in high tracer uptake regions that was consistent with the rat studies. Therefore, [18F]9 has the potential to be translated for human studies.

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Yuan, G., Dhaynaut, M., Guehl, N. J., Afshar, S., Huynh, D., Moon, S.-H., Iyengar, S., Kang, H. J., Ondrechen, M. J., El Fakhri, G., Normandin, M. D., Brownell, A.-L.. 2021-07-01. Design, synthesis, and characterization of mG2P026 as a high contrast PET imaging ligand for metabotropic glutamate receptor 2. https://doi.org/10.1101/2021.06.29.450249

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