Synthesis and structure-affinity relationships of selective high-affinity 5-HT(4) receptor antagonists: application to the design of new potential single photon emission computed tomography tracers.
Synthesis and structure-affinity relationships of selective high-affinity 5-HT(4) receptor antagonists: application to the design of new potential single photon emission computed tomography tracers.
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DOI：
10.1021/jm300943r
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发表时间：
2012-11-26
影响因子：
7.3
通讯作者：
Fabis, Frederic
中科院分区：
文献类型：
--
作者：
Dubost, Emmanuelle;Dumas, Noe;Fossey, Christine;Magnelli, Rosa;Butt-Gueulle, Sabrina;Ballandonne, Celine;Caignard, Daniel H.;Dulin, Fabienne;Santos, Jana Sopkova de-Oliveira;Millet, Philippe;Charnay, Yves;Rault, Sylvain;Cailly, Thomas;Fabis, Frederic
本文描述的工作旨在寻找新的潜在配体，用于使用单光子发射计算机断层扫描(SPECT)进行5-HT4受体的脑成像。从5-HT4R上显示KI值为51 nm的非取代菲啶化合物4a开始，我们探索了该系列化合物的结构亲和性。我们发现，用氟原子在三轮车的第四位进行取代效果最好。在三环骨架中引入一个额外的氮原子，提高了5-HT4R的亲和力和选择性，表明拮抗剂4V的设计具有0.04 nM的高亲和力。然后合成了几个碘化类似物作为潜在的SPECT示踪剂。碘化合物11d在体外和体内均能取代参比的放射性5-HT4R拮抗剂(1-butylpiperidin-4-yl)methyl-8-amino-7-iodo[123I]-2，3-dihydrobenzo[b][1，4]dioxine-5-carboxylate([123I]1，[123I]Sb 207710)。化合物11d被放射性标记了[125I]碘，为5-HT4R的脑显像提供了潜在的候选SPECT。
The work described herein aims at finding new potential ligands for the brain imaging of 5-HT4 receptors using single-photon emission computed tomography (SPECT). Starting from the non-substituted phenanthridine compound 4a exhibiting a Ki value of 51 nM on 5-HT4R, we explored structure-affinity in this series. We found that substitution in position 4 of the tricycle with a fluorine atom gave the best result. Introduction of an additional nitrogen atom inside the tricyclic framework led to increase both the affinity and the selectivity for 5-HT4R suggesting the design of the antagonist 4v exhibiting a high affinity of 0.04 nM. Several iodinated analogues were then synthesized as potential SPECT tracers. The iodinated compound 11d was able to displace the reference radioiodinated 5-HT4R antagonist (1-butylpiperidin-4-yl)methyl-8-amino-7-iodo[123I]-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate ([123I]1, [123I]SB 207710) both in vitro and in vivo in brain. Compound 11d was radiolabeled with [125I]iodine, providing a potential SPECT candidate for brain imaging of 5-HT4R.
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