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

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Synthesis and Characterization of 5-(2-Fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-01-28 , DOI: 10.1021/acs.jmedchem.1c02004
Gengyang Yuan ₁ , Maeva Dhaynaut ₁ , Yu Lan ₂ , Nicolas J Guehl ₁ , Dalena Huynh ₁ , Suhasini M Iyengar ₃ , Sepideh Afshar ₁ , Manish Kumar Jain ₄ , Julie E Pickett ₄ , Hye Jin Kang ₄ , Hao Wang ₂ , Sung-Hyun Moon ₁ , Mary Jo Ondrechen ₃ , Changning Wang ₂ , Timothy M Shoup ₁ , Georges El Fakhri ₁ , Marc D Normandin ₁ , Anna-Liisa Brownell ₁

Affiliation

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.

中文翻译：

5-(2-氟-4-[11C]甲氧基苯基)-2,2-二甲基-3,4-二氢-2H-吡喃并[2,3-b]吡啶-7-甲酰胺的合成和PET成像表征代谢型谷氨酸受体 2 的配体

代谢型谷氨酸受体 2 (mGluR2) 是多种神经精神疾病的治疗靶点。正电子发射断层扫描 (PET) 可以揭示 mGluR2 在病因学中的功能。在这方面，5-(2-氟-4-[ ¹¹ C]甲氧基苯基)-2,2-二甲基-3,4-二氢-2 H-吡喃并[2,3 -b ]吡啶-7-甲酰胺([ ¹¹ C] 13 ，[ ¹¹ C]mG2N001），一种有效的负变构调节剂（NAM），是为了支持这一努力而开发的。 [ ¹¹ C] 13通过苯酚24的O -[ ¹¹ C]甲基化合成，具有 212 ± 76 GBq/μmol ( n = 5) 的高摩尔活性和优异的放射化学纯度 (>99%)。大鼠体内 [ ¹¹ C] 13的 PET 成像显示其卓越的脑异质性，并通过 mGluR2 NAM、VU6001966 ( 9 ) 和 MNI-137 ( 26 ) 预处理减少了积累，其程度揭示了阻断的时间依赖性药物效应代理。在非人类灵长类动物中，[ ¹¹ C] 13选择性地积累在 mGluR2 丰富的区域，并产生高对比度的大脑图像。因此，[ ¹¹ C] 13是 mGluR2 功能平移 PET 成像的潜在候选者。

更新日期：2022-02-10

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