Identification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[(11)C]methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu(2)).

Metabotropic glutamate receptor 2 (mGlu(2)) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu(2), we identified new candidates 5a-i that are potent negative allosteric modulators (NAMs) of mGlu(2). Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide (5i, also named as [(11)C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 ((11)C) to obtain [(11)C]5i in high radiochemical yield and high molar activity by O-[(11)C]methylation of the phenol precursor 12 with [(11)C]CH(3)I. In vitro autoradiography with [(11)C]5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [(11)C]5i indicated in vivo specific binding of mGlu(2) in the rat brain. Based on the [(11)C]5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu(2).