Synthesis and Characterization of 5-(2-Fluoro-4-11Cmethoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano2,3-bpyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2

• Published in: Journal of medicinal chemistry 2022-02, Vol.65 (3), p.2593
• Main Authors: Yuan, Gengyang, Dhaynaut, Maeva, Lan, Yu, Guehl, Nicolas J, Huynh, Dalena, Iyengar, Suhasini M, Afshar, Sepideh, Jain, Manish Kumar, Pickett, Julie E, Kang, Hye Jin, Wang, Hao, Moon, Sung-Hyun, Ondrechen, Mary Jo, Wang, Changning, Shoup, Timothy M, El Fakhri, Georges, Normandin, Marc D, Brownell, Anna-Liisa
• Format: Article
• Language: English
• ISSN: 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c02004

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-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]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, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.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-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]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, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.