Synthesis and Evaluation of Pyridyloxypyridyl Indole Carboxamides as Potential PET Imaging Agents for 5-HT2C Receptors.,ACS Medicinal Chemistry Letters

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Synthesis and Evaluation of Pyridyloxypyridyl Indole Carboxamides as Potential PET Imaging Agents for 5-HT2C Receptors.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-02-05 , DOI: 10.1021/acsmedchemlett.7b00443
Fanxing Zeng ₁ , Jonathon A Nye ₁ , Ronald J Voll ₁ , Leonard Howell ₁ , Mark M Goodman ₁

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Nine pyridyloxypyridyl indole carboxamides were synthesized and displayed high affinities for 5-HT2C receptors and high selectivity over 5-HT2A and 5-HT2B. Among them, 6-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]1H-indole-3-carboxamide (8) exhibits the highest 5-HT2C binding affinity (Ki = 1.3 nM) and high selectivity over 5-HT2A (∼1000 times) and 5-HT2B (∼140 times). [11C]8 was synthesized by palladium-catalyzed coupling reaction between pinacolboranate 16 and [11C]CH3I with an average radiochemical yield of 27 ± 4% (n = 8, decay-corrected from end of [11C]CH3I synthesis). MicroPET imaging studies in rhesus monkeys showed regional uptake of [11C]8 in the choroid plexus, whereas the bindings in all other brain regions were low. The specific binding in the choroid plexus was confirmed by administration of a blocking dose of 0.1 mg/kg of the 5-HT2C antagonist SB-242084.

中文翻译：

吡啶氧基氧基吡啶基吲哚羧酰胺的合成和评估作为潜在的5-HT2C受体PET显像剂。

合成了九种吡啶氧基氧基吡啶基吲哚羧酰胺，它们显示出对5-HT2C受体的高亲和力和对5-HT2A和5-HT2B的高选择性。其中，6-甲基-N- [6-[（2-甲基-3-吡啶基）氧基] -3-吡啶基] 1H-吲哚-3-羧酰胺（8）表现出最高的5-HT2C结合亲和力（Ki = 1.3 nM）和对5-HT2A（〜1000倍）和5-HT2B（〜140倍）的高选择性。[11C] 8是通过频哪醇硼酸酯16与[11C] CH3I之间的钯催化偶联反应合成的，平均放射化学产率为27±4％（n = 8，从[11C] CH3I合成结束时进行衰减校正）。在恒河猴中的MicroPET成像研究显示脉络丛中[11C] 8的区域摄取，而在所有其他脑区域中的结合均很低。通过给予0的阻断剂量可以确认脉络丛中的特异性结合。

更新日期：2018-02-05

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