Tc-Diamine dioxime-Lys-Cys-Arg-Gly-Asp-Cyc-Phe-Cys-polyethylene glycol

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 on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues (6, 8, 9). The peptide sequence 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. Various cyclic RGD peptides exhibit selective inhibition of binding to αβ integrin (50% inhibition concentration (IC), 7–40 nM) but no inhibition of binding to αβ (IC, 600–4,000 nM) or αβ (IC, 700–5,000 nM) integrins (11). Various radiolabeled cyclic RGD peptides and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Of these developments, [F]galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of αβ integrin in cancer patients (14-19). Both αβ and αβ integrins bind to vitronectin (20). However, while the αβ integrin is required for basic fibroblast growth factor–mediated angiogenesis, the αβ integrin is required for vascular endothelial growth factor–induced angiogenesis (21, 22). The peptide Lys-Cys-Arg-Gly-Asp-Cyc-Phe-Cys (NC100717) was identified with phage display screening to be a potent and selective binder to both αβ and αβ integrins (23). A new peptide, NC100692, was derived from NC100717 with addition of diamine dioxime to the ε-amine of Lys and the N-terminal end modified with a short polyethylene glycol unit. Hua et al. (24) reported the development of Tc-NC100692 for single-photon emission computed tomography (SPECT) imaging of αβ and αβ integrins in mice with hindlimb ischemia. Bach-Gansmo et al. (25) has performed a preliminary study in patients with breast cancer.