Identification And Development Of A New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[C-11]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 [C-11]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 (C-11) to obtain [C-11]5i in high radiochemical yield and high molar activity by O-[C-11]methylation of the phenol precursor 12 with [C-11]CH3I. In vitro autoradiography with [C-11]5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum >> thalamus > pons. PET study of [C-11]5i indicated in vivo specific binding of mGlu(2) in the rat brain. Based on the [C-11]5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu(2).