Tc-Hydrazinonicotinic acid-Glu-{Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)]}

Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell-cell and cell-matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. αβ integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of αβ integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. αβ antagonists are being studied as antitumor and antiangiogenic agents and the agonists as angiogenic agents for coronary angiogenesis (6, 8, 9). Extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) contain a tripeptide sequence consisting of Arg-Gly-Asp (RGD), which binds to a variety of integrins, including αβ. Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most of the cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to αβ (IC, 7-40 nM) but not to αβ (IC, 600-4,000 nM) or αβ (IC, 700-5,000 nM) integrins. Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Hydrazinonicotinic acid (HYNIC) is a coupling agent for Tc labeling of peptides that can achieve high specific activities without affecting receptor-binding ability of the amino acid sequence. Liu et al. (13) reported the success of radiolabeling cylco(Arg-Gly-Asp-D-Phe-Lys) (c(RGDfK)) tetramer linked by glutamic acid that was conjugated with HYNIC. Trisodium triphenylphosphine-3,3’,3’’-trisulfonate (TPPTS) and tris(hydroxymethyl)-methylglycine (tricine) were used as coligands. Tc-HYNIC-E{E[c(RGDfK)]}(tricine)(TPPTS) showed high tumor accumulation in nude mice bearing human tumor xenografts.