44Sc: An Attractive Isotope for Peptide-Based PET Imaging

The overexpression of integrin alpha(v)beta(3) has been linked to tumor aggressiveness and metastasis in several cancer types. Because of its high affinity, peptides containing the arginine glycine aspartic acid (RGD) motif have been proven valuable vectors for noninvasive imaging of integrin alpha(v)beta(3) expression and for targeted radionuclide therapy. In this study, we aim to develop a Sc-44-labeled RGD-based peptide for in vivo positron emission tomography (PET) imaging of integrin alpha(v)beta(3) expression in a preclinical cancer model. High quality Sc-44 (t(1/2), 3.97 h; beta(+) branching ratio, 94.3%) was produced inexpensively in a cyclotron, via proton irradiation of natural Ca metal targets, and separated by extraction chromatography. A dimeric cyclic-RGD peptide, (cRGD), was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with Sc-44 in high yield (>90%) and specific activity (7.4 MBq/nmol). Serial PET imaging of mice bearing U87MG tumor xenografts showed elevated Sc-44-DOTA-(cRGD), uptake in the tumor tissue of 3.93 +/- 1.19, 3.07 +/- 1.17, and 3.00 +/- 1.25 %ID/g at 0.5, 2, and 4 h postinjection, respectively (n = 3), which were validated by ex vivo biodistribution experiments. The integrin alpha(v)beta(3) specificity of the tracer was corroborated, both in vitro and in vivo, by competitive cell binding and receptor blocking assays. These results parallel previously reported studies showing similar tumor targeting and pharmacokinetic profiles for dimeric cRGD peptides labeled with Cu or 68Ga. Our findings, together with the advantageous radionuclidic properties of Sc-44, capitalize on the relevance of this isotope as an attractive alternative isotope to more established radiometals for small molecule-based PET imaging, and as imaging surrogate of Sc-47 in theranostic applications.