Improving Tumor Uptake and Pharmacokinetics of 64Cu-Labeled Cyclic RGD Peptide Dimers with Gly3 and PEG4 Linkers

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Abstract
Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides represent a new class of radiotracers with potential for early tumor detection and noninvasive monitoring of tumor metastasis and therapeutic response in cancer patients. This article describes the synthesis of two cyclic RGD peptide dimer conjugates, DOTA-PEG4-E[PEG4-c(RGDfK)]2 (DOTA-3PEG4-dimer: DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and DOTA-G3-E[G3-c(RGDfK)]2 (DOTA-3G3-dimer: G3 = Gly-Gly-Gly). Integrin αvβ3 binding affinities of cyclic RGD peptides were determined by competitive displacement of 125I-echistatin bound to U87MG human glioma cells and follow the order of DOTA-E{E[c(RGDfK)]2}2 (DOTA-tetramer: IC50 = 10 ± 2 nM) > DOTA-3G3-dimer (IC50 = 62 ± 6 nM) ∼ DOTA-3PEG4-dimer (IC50 = 74 ± 3 nM) > DOTA-E[c(RGDfK)]2 (DOTA-dimer: IC50 = 102 ± 5 nM). The addition of PEG4 and G3 linkers between two cyclic RGD motifs in DOTA-3G3-dimer and DOTA-3PEG4-dimer makes it possible for them to achieve the simultaneous integrin αvβ3 binding in a bivalent fashion. Both 64Cu(DOTA-3PEG4-dimer) and 64Cu(DOTA-3G3-dimer) were prepared in high yield with specific activity being >50 Ci/mmol. Biodistribution and imaging studies were performed in athymic nude mice bearing U87MG human glioma xenografts. The results from those studies show that PEG4 and G3 linkers are particularly useful for improving tumor uptake and clearance kinetics of 64Cu radiotracers from the nontumor organs, such as kidneys, liver, and lungs. There is a linear relationship between the tumor size and %ID tumor uptake, suggesting that 64Cu(DOTA-3PEG4-dimer) and 64Cu(DOTA-3PEG4-dimer) might be useful for noninvasive monitoring of tumor growth or shrinkage during antiangiogenic therapy. MicroPET imaging data clearly demonstrate the utility of 64Cu(DOTA-3G3-dimer) as a new PET radiotracer for imaging integrin αvβ3-positive tumors.