Tc-Ethylenediaminediacetic acid/hydrazinonicotinic acid-cyclo(Arg-Gly-Asp-D-Try-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. The 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 the αβ integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of αβ are being studied as antitumor and antiangiogenic agents, and the agonists of αβ are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including αβ. Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most 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 (inhibition concentration (IC), 7–40 nM) but not to integrins αβ (IC, 600–4,000 nM) or αβ (IC, 700–5,000 nM). 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 the receptor-binding ability of the amino acid sequence. Decristoforo et al. (13) reported the success of radiolabeling cyclo(Arg-Gly-Asp-D-Tyr-Lys) (c(RGDyK)) by conjugation of HYNIC to the ε amino group of Lys with ethylenediaminediacetic acid (EDDA) and tris(hydroxymethyl)-methylglycine (tricine) as coligand. The Tc-EDDA/HYNIC-c(RGDyK) peptide showed high tumor accumulation in nude mice bearing M21 human melanoma tumors and A549 human lung carcinoma tumors.