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选择性高亲和力 5-HT(4) 受体拮抗剂的合成与结构亲和力关系：在新型单光子发射计算机断层扫描示踪剂设计中的应用。

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.

机构信息

UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie, EA 4258 CERMN, FR CNRS 3038 INC3M, SF-4206 ICORE, Boulevard Becquerel, F-14032 Caen, France.

出版信息

J Med Chem. 2012 Nov 26;55(22):9693-707. doi: 10.1021/jm300943r. Epub 2012 Nov 9.

DOI:10.1021/jm300943r
PMID:23102207
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3509320/
Abstract

The work described herein aims at finding new potential ligands for the brain imaging of 5-HT(4) receptors (5-HT(4)Rs) using single-photon emission computed tomography (SPECT). Starting from the nonsubstituted phenanthridine compound 4a, exhibiting a K(i) value of 51 nM on the 5-HT(4)R, we explored the 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 an increase of both the affinity and selectivity for 5-HT(4)R, 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-HT(4)R antagonist (1-butylpiperidin-4-yl)methyl-8-amino-7-iodo[(123)I]-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate {[(123)I]1, [(123)I]SB 207710} both in vitro and in vivo in brain. Compound 11d was radiolabeled with [(125)I]iodine, providing a potential SPECT candidate for brain imaging of 5-HT(4)R.

摘要

本文旨在通过单光子发射计算机断层扫描（SPECT）寻找新的潜在配体，用于脑成像 5-HT(4)受体（5-HT(4)Rs）。从非取代的菲啶化合物 4a 开始，其对 5-HT(4)R 的 K(i)值为 51 nM，我们在此系列中探索了结构-亲和力。我们发现三环中 4 位的取代氟原子效果最佳。在三环骨架内引入额外的氮原子会导致对 5-HT(4)R 的亲和力和选择性增加，这表明设计出的拮抗剂 4v 具有高亲和力，为 0.04 nM。然后合成了几种碘化类似物作为潜在的 SPECT 示踪剂。碘化化合物 11d 能够在体外和体内脑中置换参考放射性碘标记的 5-HT(4)R 拮抗剂[(123)I]1-丁基哌啶-4-基甲基-8-氨基-7-碘-[(123)I]-2,3-二氢苯并[b][1,4]二恶嗪-5-羧酸酯{[(123)I]1, [(123)I]SB 207710}。化合物 11d 用 [(125)I]碘标记，为脑成像 5-HT(4)R 提供了潜在的 SPECT 候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/e489d1d219a0/nihms420889f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/9ab7739a4a3e/nihms420889f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/b0543dbbad97/nihms420889f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/e8000dc846c3/nihms420889f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/ab9a4791afb4/nihms420889f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/0e75b5f6fe88/nihms420889f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/2f0156119c06/nihms420889f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/e489d1d219a0/nihms420889f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/9ab7739a4a3e/nihms420889f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/b0543dbbad97/nihms420889f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/e8000dc846c3/nihms420889f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/ab9a4791afb4/nihms420889f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/0e75b5f6fe88/nihms420889f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/2f0156119c06/nihms420889f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f31f/3509320/e489d1d219a0/nihms420889f7.jpg

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