Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2,ACS Chemical Neuroscience

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Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-06-13 00:00:00 , DOI: 10.1021/acschemneuro.7b00098
Xiaofei Zhang _{1,

2,

3} , Katsushi Kumata ₄ , Tomoteru Yamasaki ₄ , Ran Cheng _{1,

2} , Akiko Hatori ₄ , Longle Ma _{1,

2} , Yiding Zhang ₄ , Lin Xie ₄ , Lu Wang _{1,

2} , Hye Jin Kang ₅ , Douglas J Sheffler ₆ , Nicholas D P Cosford ₆ , Ming-Rong Zhang ₄ , Steven H Liang _{1,

2}

Affiliation

Metabotropic glutamate 2 receptors (mGlu₂) are involved in the pathogenesis of several CNS disorders and neurodegenerative diseases. Pharmacological modulation of this target represents a potential disease-modifying approach for the treatment of substance abuse, depression, schizophrenia, and dementias. While quantification of mGlu₂ receptors in the living brain by positron emission tomography (PET) would help us better understand signaling pathways relevant to these conditions, few successful examples have been demonstrated to image mGlu₂ in vivo, and a suitable PET tracer is yet to be identified. Herein we report the design and synthesis of a radiolabeled negative allosteric modulator (NAM) for mGlu₂ PET tracer development based on a quinoline 2-carboxamide scaffold. The most promising candidate, 7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[¹¹C]methoxyphenyl) quinoline-2-carboxamide ([¹¹C]QCA) was prepared in 13% radiochemical yield (non-decay-corrected at the end of synthesis) with >99% radiochemical purity and >74 GBq/μmol (2 Ci/μmol) specific activity. While the tracer showed limited brain uptake (0.3 SUV), probably attributable to effects on PgP/Bcrp efflux pump, in vitro autoradiography studies demonstrated heterogeneous brain distribution and specific binding. Thus, [¹¹C]QCA is a chemical probe that provides the basis for the development of a new generation mGlu₂ PET tracers.

中文翻译：

新型负变构调节剂 7-（（2,5-二氧代吡咯烷-1-基）甲基）-4-（2-氟-4-[11C]甲氧基苯基）喹啉-2-甲酰胺的合成和初步研究，用于代谢型谷氨酸受体 2 的成像

代谢型谷氨酸 2 受体（mGlu₂）参与多种 CNS 疾病和神经退行性疾病的发病机制。该靶点的药理学调节代表了治疗药物滥用、抑郁症、精神分裂症和痴呆症的潜在疾病缓解方法。虽然通过正电子发射断层扫描（PET）定量活脑中的 mGlu₂ 受体有助于我们更好地了解与这些情况相关的信号通路，但很少有成功的例子被证明可以在体内对 mGlu₂ 进行成像，并且尚未确定合适的 PET 示踪剂。在此，我们报道了基于喹啉 2-羧酰胺支架的放射性标记负变构调节剂（NAM）的设计和合成，用于 mGlu₂ PET 示踪剂开发。最有希望的候选者 7-（（2,5-二氧代吡咯烷-1-基）甲基）-4-（2-氟-4-[¹¹C]甲氧基苯基）喹啉-2-甲酰胺（[¹¹C]QCA）以 13% 的放射化学产率（合成结束时未衰减校正）制备，放射化学纯度为 >99%，比活性为 >74 GBq/μmol （2 Ci/μmol）。虽然示踪剂显示脑摄取有限（0.3 SUV），可能归因于对 PgP/Bcrp 外排泵的影响，但体外放射自显影研究表明脑分布异质性和特异性结合。因此，[¹¹C]QCA 是一种化学探针，为开发新一代 mGlu₂ PET 示踪剂提供了基础。

更新日期：2017-06-13

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