⁶⁴Cu-Tetraazacyclododecane- N, N', N'', N'''-tetraacetic acid-MEDI-522

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 α_vβ₃ 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 α_vβ₃ integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α_vβ₃ are being studied as antitumor and antiangiogenic agents, and the agonists of α_vβ₃ 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 α_vβ₃. 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 α_vβ₃ (inhibition concentration (IC₅₀), 7–40 nM) but not to integrins α_vβ₅ (IC₅₀, 600–4,000 nM) or α_IIbβ₃ (IC₅₀, 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). In addition to RGD peptides, a humanized anti-human integrin α_vβ₃ monoclonal antibody (MEDI-522) was identified to be unique in that it recognizes either the human α_v or β₃ subunit. MEDI-522 cross-reacts with integrin α_vβ₃ from rabbits, chickens, and hamsters but not with integrin α_vβ₃ from mice or rats (13). MEDI-522 is being evaluated as an antiangiogenic agent for cancer therapy (14-16). Cai et al. (17) reported the development of ⁶⁴Cu-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-MEDI-522 (⁶⁴Cu-DOTA-MEDI-522) for positron emission tomography (PET) imaging of α_vβ₃ receptors in nude mice bearing tumors.