Improving Tumor Uptake and Excretion Kinetics of 99mTc-Labeled Cyclic Arginine-Glycine-Aspartic (RGD) Dimers with Triglycine Linkers

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• 作者：Jiyun Shi ; Lijun Wang ; Young-Seung Kim ; Shizhen Zhai ; Zhaofei Liu ; Xiaoyuan Chen ; Shuang Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 25, 2008
• 年：2008
• 卷：51
• 期：24
• 页码：7980-7990
• 全文大小：423K
• 年卷期：v.51,no.24(December 25, 2008)
• ISSN：1520-4804

文摘

This report describes the synthesis of two new cyclic RGD (Arg-Gly-Asp) dimers, 3 (E[G₃-c(RGDfK)]₂) and 4 (G₃-E[G₃-c(RGDfK)]₂), and their corresponding conjugates 5 (HYNIC-E[G₃-c(RGDfK)]₂: HYNIC = 6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinyl) and 6 (HYNIC-G₃-E[G₃-c(RGDfK)]₂). Integrin α_vβ₃ binding affinities of 5 and 6 were determined by displacement of ¹²⁵I-echistatin bound to U87MG glioma cells. ^99mTc complexes 7 ([^99mTc(5)(tricine)(TPPTS)]: TPPTS = trisodium triphenylphosphine-3,3′,3′′-trisulfonate) and 8 ([^99mTc(6)(tricine)(TPPTS)]) were prepared in high yield and high specific activity. Biodistribution and imaging studies were performed in athymic nude mice bearing U87MG glioma and MDA-MB-435 breast cancer xenografts. It was found that G₃ linkers are particularly useful for increasing integrin α_vβ₃ binding affinity of cyclic RGD dimers and improving the tumor uptake and clearance kinetic of their ^99mTc radiotracers. Complex 8 is a very promising radiotracer for the early detection of integrin α_vβ₃-positive tumors and may have the potential for noninvasive monitoring of tumor growth or shrinkage during antiangiogenic treatment.