Identification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[11C]methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu2)

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-1 H -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 .