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首页> 外文期刊>Journal of Medicinal Chemistry >Toward stable N-4-modified neurotensins for NTS1-receptor-targeted tumor imaging with Tc-99m
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Toward stable N-4-modified neurotensins for NTS1-receptor-targeted tumor imaging with Tc-99m

机译：寻求稳定的N-4-修饰神经降压素，用于Tc-99m靶向NTS1受体的肿瘤成像

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摘要

A series of Gly-neurotensin(8-13) analogues modified at the N-terminus by acyclic tetraamines (Demotensin 1-4) were obtained by solid-phase peptide synthesis techniques. Strategic replacement of amino acids and/or reduction of sensitive peptide bonds were performed to enhance conjugate resistance against proteolytic enzymes. During Tc-99m-labeling, single species radiopeptides, [Tc-99m] Demotensin 1-4, were easily obtained in high yields and typical specific activities of 1 Ci/mu mol. Peptide conjugates displayed a high affinity binding to the human neurotensin subtype 1 receptor (NTS1-R) expressed in colon adenocarcinoma HT-29 or WiDr cells and/or in human tumor sections. [Tc-99m] Demotensin 1-4 internalized very rapidly in HT-29 or WiDr cells by a NTS1-R-mediated process. [Tc-99m] Demotensin 3 and 4, which remained stable during 1 h incubation in murine plasma, were selectively studied in nude mice bearing human HT-29 and WiDr xenografts. After injection, [Tc-99m] Demotensin 3 and 4 effectively and specifically localized in the experimental tumors and were rapidly excreted via the kidneys into the urine, exhibiting overall biodistribution patterns favorable for NTS1-R-targeted tumor imaging in man.
机译：通过固相肽合成技术，获得了一系列由无环四胺（Demotensin 1-4）在N端修饰的Gly-神经降压素（8-13）类似物。进行了战略性的氨基酸替换和/或敏感肽键的还原，以增强对蛋白水解酶的共轭抗性。在Tc-99m标记过程中，很容易以高收率和1 Ci / mu mol的典型比活轻松获得单种放射性肽[Tc-99m] Demotensin 1-4。肽结合物显示出与结肠腺癌HT-29或WiDr细胞和/或人肿瘤切片中表达的人神经降压素亚型1受体（NTS1-R）的高亲和力结合。 [Tc-99m]降压素1-4通过NTS1-R介导的过程在HT-29或WiDr细胞中快速内化。 [Tc-99m]在携带人HT-29和WiDr异种移植物的裸鼠中选择性地研究了在鼠血浆中孵育1 h时保持稳定的降压素3和4。注射后，[Tc-99m]降压素3和4有效地且特异性地定位在实验性肿瘤中，并通过肾脏迅速排泄到尿液中，表现出有利于人类NTS1-R靶向肿瘤成像的总体生物分布模式。

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