title: Improving tumor uptake and excretion kinetics of 99mTc-labeled cyclic arginine-glycine-aspartic (RGD) dimers with triglycine linkers.
abstract: 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.
authors.affiliation: School of Health Sciences, Purdue University, 550 Stadium Mall Drive, Indiana 47907, USA.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Shi
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.forename: Young-Seung
authors.initials: YS
authors.lastname: Kim
authors.forename: Shizhen
authors.initials: S
authors.lastname: Zhai
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Liu
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019281:Dimerization; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D013667:Technetium / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; D013667:Technetium; C035647:glycyl-glycyl-glycine