In-Tetraazacyclododecane--tetraacetic 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. 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). 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 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). Dijkgraaf et al. (13) reported the development of In-tetraazacyclododecane--tetraacetic acid-Glu-{Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)]} (In-DOTA-E-{E-[c(RGDfK)]}) for imaging αβ receptors in nude mice bearing ovarian carcinoma tumors.