Identification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[C]methoxyphenyl)-5-((1-methyl-1-pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu).

Metabotropic glutamate receptor 2 (mGlu) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu, we identified new candidates - that are potent negative allosteric modulators (NAMs) of mGlu. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1-pyrazol-3-yl)methoxy)picolinamide (, also named as [C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound was labeled with positron-emitting carbon-11 (C) to obtain [C] in high radiochemical yield and high molar activity by -[C]methylation of the phenol precursor with [C]CHI. autoradiography with [C] showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [C] indicated specific binding of mGlu in the rat brain. Based on the [C] scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu.