Improving tumor uptake and excretion kinetics of 99mTc-labeled cyclic arginine-glycine-aspartic (RGD) dimers with triglycine linkers.

This report describes the synthesis of two new cyclic RGD (Arg-Gly-Asp) dimers, 3 (E[G(3)-c(RGDfK)](2)) and 4 (G(3)-E[G(3)-c(RGDfK)](2)), and their corresponding conjugates 5 (HYNIC-E[G(3)-c(RGDfK)](2): HYNIC = 6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinyl) and 6 (HYNIC-G(3)-E[G(3)-c(RGDfK)](2)). Integrin alpha(v)beta(3) binding affinities of 5 and 6 were determined by displacement of (125)I-echistatin bound to U87MG glioma cells. (99)(m)Tc complexes 7 ([(99m)Tc(5)(tricine)(TPPTS)]: TPPTS = trisodium triphenylphosphine-3,3',3''-trisulfonate) and 8 ([(99m)Tc(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 G(3) linkers are particularly useful for increasing integrin alpha(v)beta(3) binding affinity of cyclic RGD dimers and improving the tumor uptake and clearance kinetic of their (99)(m)Tc radiotracers. Complex 8 is a very promising radiotracer for the early detection of integrin alpha(v)beta(3)-positive tumors and may have the potential for noninvasive monitoring of tumor growth or shrinkage during antiangiogenic treatment.