MicroPET imaging of breast cancer αv-integrin expression with 64Cu-labeled dimeric RGD peptides

PURPOSE: Alpha(v)beta(3) and alpha(v)beta(5) integrins are cell adhesion molecules that play a vital role in tumor angiogenesis and metastasis.-The ability to visualize and quantify integin expression in vivo will foster our understanding of the role of integrins alpha(v)beta(3) and alpha(v)beta(5) in tumor angiogenesis and allow for direct assessment of anti-angiogenic treatment efficacy based on integrin antagonists. This study compared the tumor targeting characteristics of two dimeric Cu-64-labeled RGD peptide agonists of alpha(v)beta(3) integrin. PROCEDURES: Dimeric RGD peptides E[c(RGDyK)](2) and E[c(RGDfK)](2) were conjugated with 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) and labeled with positron emitter Cu-64(t(1/2) = 12.8 h, beta(+) = 19%). Both Cu-64-DOTA-E[c(RGDyK)](2) and Cu-64-DOTA-E[c(RGDfK)](2) were used in biodistribution, microPET imaging and whole-body autoradiography studies in athymic female nude mice with orthotopically growing MDA-MB-435 breast carcinoma xenografts. RESULTS: At all time points, activity accumulation of Cu-64-DOTA-E [c(RGDyK)](2) in tumors was significantly higher compared to the D-Phe analog. Liver uptake of the D-Tyr derivative was lower than the D-Phe derivative at early time points but the difference became marginal with time. Overall, Cu-64-DOTA-E[c(RGDyK)](2) yielded better position emission tomography (PET) images in orthotopic MDA-MB-435 bearing mice than did Cu-64-DOTA-E[c(RGDfK)](2). Both radiotracers had alpha(v)-integrin specific tumor activity accumulation, as demonstrated by significant reduction of uptake with a coinjected blocking dose of c(RGDyK). CONCLUSIONS: The radiolabeled dimeric RGD peptides Cu-64-DOTA-E[c(RGDyK)](2) and Cu-64-DOTA-E[c(RGDfK)](2) have high and specific tumor uptake in a human breast cancer tumor xenograft, with the D-Tyr derivative showing better in vivo kinetics than the D-Phe derivative, most likely due to the increased hydrophilicity of the D-Tyr. Both dimeric peptides showed better tumor retention than the previously tested monomeric RGD counterparts, presumably because of bivalency and increase in apparent molecular size. (C) 2004 Elsevier Inc. All rights reserved.