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

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Abstract
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 αvβ3 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 αvβ3 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 αvβ3-positive tumors and may have the potential for noninvasive monitoring of tumor growth or shrinkage during antiangiogenic treatment.