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

Abstract

Metabotropic glutamate receptor 2 (mGlu₂) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu₂, we identified new candidates 5a-i that are potent negative allosteric modulators (NAMs) of mGlu₂. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide (5i, also named as [¹¹C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 (¹¹C) to obtain [¹¹C]5i in high radiochemical yield and high molar activity by O-[¹¹C]methylation of the phenol precursor 12 with [¹¹C]CH₃I. In vitro autoradiography with [¹¹C]5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [¹¹C]5i indicated in vivo specific binding of mGlu₂ in the rat brain. Based on the [¹¹C]5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu₂.