Abstract
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Objectives 44Sc has desirable decay characteristics for PET imaging, such as high positron-branching ratio (94%), relatively clean emission spectrum, and suitable half-life (3.97 h) for labeling of small molecules and peptides. The goal of this study is to develop 44Sc-based tracers for PET imaging, using a cyclic arginine-glycine-aspartic acid (RGD) peptide as the model compound. RGD peptides are potent antagonists of integrin αvβ3, which plays a pivotal role in tumor angiogenesis and metastasis.
Methods 44Sc was produced in a cyclotron via the 44Ca(p,n)44Sc reaction and separated using extraction chromatography. A dimeric cyclic RGD peptide, E[c(RGDyK)]2 (abbreviated as RGD2), was conjugated to DOTA for 44Sc-labeling, which was carried out at 90 oC under slightly acidic condition. Serial PET imaging and biodistribution studies were performed and tumor uptake values were calculated. Blocking studies and cell-binding assay were also performed to confirm the affinity and specificity of 44Sc-DOTA-RGD2 for integrin αvβ3.
Results DOTA-RGD2 was synthesized and purified by HPLC. 44Sc-labeling of DOTA-RGD2 was achieved with high radiolabeling yield (~90%) and specific activity. PET imaging of integrin αvβ3 expression in the xenograft U87MG model (integrin αvβ3 positive) was performed at multiple time points post-injection (p.i.), and 44Sc-DOTA-RGD2 exhibited prominent and specific tumor uptake of 4.4±0.4, 3.5±0.5, 3.4±0.5 %ID/g at 0.5, 2, and 4 h p.i. (n=3). The quantitative data from PET were validated by ex vivo biodistribution studies. Tumor uptake of the tracer was significantly reduced with co-injection of unlabeled RGD2 which, together with cell-binding assay, confirmed the specificity of 44Sc-DOTA-RGD2 for integrin αvβ3. The results obtained here are comparable to the previously reported RGD peptide-based tracers using other radiometals such as 68Ga and 64Cu, which exhibited primarily renal clearance.
Conclusions We have shown that 44Sc is a suitable isotope to label peptides for PET imaging of tumor biomarker expression, which warrants further investigation of 44Sc for PET applications.