Synthesis and Characterization of 5-(2-Fluoro-4-[ 11 C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2 H -pyrano[2,3- b ]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[ 11 C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2 H -pyrano[2,3- b ]pyridine-7-carboxamide ([ 11 C] 13 , [ 11 C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [ 11 C] 13 was synthesized via the O -[ 11 C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol ( n = 5) and excellent radiochemical purity (>99%). PET imaging of [ 11 C] 13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 ( 9 ) and MNI-137 ( 26 ), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [ 11 C] 13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [ 11 C] 13 is a potential candidate for translational PET imaging of the mGluR2 function.