Cu-4,11-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-cyclic-arginine-glycine-aspartic acid peptide

Cu-4,11-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-cyclic arginine-glycine-aspartic acid peptide [Cu-CD-TE2A-c(RGDyK)] is an integrin-targeted molecular imaging agent developed for positron emission tomography (PET) of tumor vasculature, tumor angiogenesis, and osteoclasts (1). Cellular survival, invasion, and migration control embryonic development, angiogenesis, tumor metastasis, and other physiologic processes (2, 3). Among the molecules that regulate angiogenesis are integrins, which comprise a superfamily of cell adhesion proteins that form heterodimeric receptors for extracellular matrix (ECM) molecules (4, 5). These transmembrane glycoproteins consist of two noncovalently associated subunits, α and β (18 α- and 8 β-subunits in mammals), which are assembled into at least 24 α/β pairs. Several integrins, such as integrin αβ, have affinity for the arginine-glycine-aspartic acid (RGD) tripeptide motif, which is found in many ECM proteins. Expression of integrin αβ receptors on endothelial cells is stimulated by angiogenic factors and environments. The integrin αβ receptor is generally not found in normal tissue, but it is strongly expressed in vessels with increased angiogenesis, such as tumor vasculature. It is significantly upregulated in certain types of tumor cells and in almost all tumor vasculature. Molecular imaging probes carrying the RGD motif that binds to the integrin αβ can be used to image tumor vasculature and evaluate angiogenic response to tumor therapy (6, 7). Various RGD peptides in both linear and cyclic forms have been developed for binding to integrin αβ (8). Chen et al. (9) evaluated a cyclic RGD peptide [c(RGDyK)] labeled with Cu or F in nude mice bearing breast tumor. They used 1,4,7,10-tetrazadodecane-,,,-tetraacetic acid (DOTA) for c(RGDyK) conjugation with Cu. Cu-DOTA-c(RGDyK) showed prolonged tumor radioactivity retention but persistent liver radioactivity. Osteoclasts express high levels of αβ (1, 10), and αβ ligands have also been shown to inhibit osteoclastic bone resorption (11). The skeleton is one of the most common organs of cancer metastasis. Osteolytic bone lesions are difficult to detect, and molecular imaging agents that target osteoclasts can be useful for imaging osteolytic bone metastases and monitoring their responses to therapy. Boswell et al. (12) showed that the Cu complex of the cross-bridged macrocyclic chelator 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A) had less transchelation and improved liver clearance in normal rats than other cyclen derivatives. Sprague et al. (1) prepared Cu-CB-TE2A-c(RGDyK)] and showed that this radioligand selectively bound to osteoclasts in mice with induced osteoclastogenesis.