一种用于肽和蛋白质酪氨酸特异性放射性标记的新型双功能螯合剂
A Novel Bifunctional Chelating Agent for Tyrosine-Specific Radiolabeling of Peptides and Proteins
影响因子:3.90000
分区:化学2区 / 生化研究方法2区 有机化学2区 生化与分子生物学3区 化学：综合3区
发表日期:2024 Oct 07
作者:
Daiki Nakano, Hiroyuki Watanabe, Saito Kosuke, Masahiro Ono
摘要
位点特异性放射性标记用于开发基于抗体或肽的放射性抑制剂。尽管酪氨酸可以被用作肽和蛋白质位点特异性放射性标记的靶标之一，但尚未建立酪氨酸特异性放射性标记方法。在这项研究中，我们新设计和合成了一种新型的双功能螯合剂TBD-DO3A，由三氮杂二烯（TBD）支架和金属螯合剂组成，1,4,7,7,10-TetraazacyClododecane 1,4,7-7-7-7-7-三乙酸酸（DO3A）。 TBD-DO3A与AC-TYR-NHME的结合，其次是111in标记的[111in] In-Tyr-Do3a，在小鼠等离子体中显示出高水平的稳定性。然后，我们选择了含酪氨酸的环状肽C（RGDYK）作为模型配体，并合成[111in] In-ryd。 [111/NATIN] IN-RYD显示了整合素αVβ3的体外结合特性，等于[111/natin] In-RKD（一种赖氨酸残基标记的对照化合物）。在体内生物分布和SPECT/CT成像研究中，使用U87MG/PC-3肿瘤的小鼠，[111in] In-ryd和[111in] In-RKD在24小时注射后24小时选择性地积累，并促进U87MG肿瘤可视化。这些结果表明，TBD-DO3A具有基本特性，是肽和蛋白质酪氨酸特异性放射性标记的双功能螯合剂。
Abstract
Site-specific radiolabeling is utilized for the development of antibody- or peptide-based radiotheranostic agents. Although tyrosine can be exploited as one of the target residues for site-specific radiolabeling of peptides and proteins, a tyrosine-specific radiolabeling method has not been established. In this study, we newly designed and synthesized a novel bifunctional chelating agent, TBD-DO3A, consisting of a triazabutadiene (TBD) scaffold and metal chelator, 1,4,7,10-tetraazacyclododecane 1,4,7-triacetic acid (DO3A). Conjugation of TBD-DO3A with Ac-Tyr-NHMe followed by 111In-labeling afforded [111In]In-Tyr-DO3A, which showed high-level stability in mouse plasma. Then, we selected the tyrosine-containing cyclic peptide c(RGDyK) as a model ligand and synthesized [111In]In-RYD. [111/natIn]In-RYD showed in vitro binding properties for integrin αvβ3 equivalent to those of [111/natIn]In-RKD, a lysine residue-labeled control compound. In in vivo biodistribution and SPECT/CT imaging studies using U87MG/PC-3 tumor-bearing mice, [111In]In-RYD and [111In]In-RKD were selectively accumulated and facilitated U87MG tumor visualization at 24 h postinjection. These results indicate that TBD-DO3A has fundamental properties as a bifunctional chelator for tyrosine-specific radiolabeling of peptides and proteins.