Concise site-specific synthesis of DTPA-peptide conjugates: Application to imaging probes for the chemokine receptor CXCR4
Concise site-specific synthesis of DTPA-peptide conjugates: Application to imaging probes for the chemokine receptor CXCR4
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DOI：
10.1016/j.bmc.2011.03.059
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发表时间：
2011-05-15
影响因子：
3.5
通讯作者：
Fujii, Nobutaka
中科院分区：
文献类型：
--
作者：
Masuda, Ryo;Oishi, Shinya;Fujii, Nobutaka
二乙烯三胺五乙酸（DTPA）是一种用于核医学显像的放射性核素（68）Ga、（99 m）Tc和（111）In的螯合剂。在这项研究中，我们建立了一个简单的合成协议生产单DTPA共轭肽探针。利用邻硝基苯磺酰基（Ns）保护基的化学作用，分两步合成了一种新型的单活性DTPA前体试剂，并在温和的条件下将该DTPA前体掺入到受保护肽树脂的N（N）-溴乙酰化赖氨酸上。通过在固相合成过程中使用高度酸不稳定的4-甲基三苯甲基（Mtt）保护基团来促进生物活性肽的靶位点的位点特异性DTPA缀合。两种技术的组合产生具有二硫键的肽，例如奥曲肽和多菌霉素II衍生的CXCR 4拮抗剂。DTPA-肽缀合物在从树脂裂解和二硫键形成后的单个步骤中纯化。这种位点特异性的树脂上构建策略被用于设计和合成一种新的In-DTPA标记的CXCR 4拮抗剂，其对SDF-1-CXCR 4结合表现出高度有效的抑制活性。(C)2011爱思唯尔有限公司保留所有权利。
Diethylenetriaminepentaacetic acid (DTPA) is a useful chelating agent for radionuclides such as (68)Ga, (99m)Tc and (111)In, which are applicable to nuclear medicine imaging. In this study, we established a facile synthetic protocol for the production of mono-DTPA-conjugated peptide probes. A novel monoreactive DTPA precursor reagent was synthesized in two steps using the chemistry of the o-nitrobenzenesulfonyl (Ns) protecting group, and under mild conditions this DTPA precursor was incorporated onto an N(epsilon)-bromoacetylated Lys of a protected peptide resin. The site-specific DTPA conjugation was facilitated by using a highly acid-labile 4-methyltrityl (Mtt) protecting group for the target site of the bioactive peptide during the solid-phase synthesis. A combination of both techniques yielded peptides with disulfide bonds, such as octreotide and polyphemusin II-derived CXCR4 antagonists. DTPA-peptide conjugates were purified in a single step following cleavage from the resin and disulfide bond formation. This site-specific on-resin construction strategy was used for the design and synthesis of a novel In-DTPA-labeled CXCR4 antagonist, which exhibited highly potent inhibitory activity against SDF-1-CXCR4 binding. (C) 2011 Elsevier Ltd. All rights reserved.