microPET of Tumor Integrin avb3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4)

In vivo imaging of avb3 expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin avb3–binding affinity due to the polyvalency effect. Here we report an example of 18F-labeled tetrameric RGD peptide for PET of avb3 expression in both xenograft and spontaneous tumor models. Methods: The tetrameric RGD peptide EfE[c(RGDyK)]2g2 was derived with amino3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate a-amino group. NH2-miniPEG-EfE[c(RGDyK)]2g2 (PRGD4) was labeled with 18F via the N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer 18F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies. Results: The decay-corrected radiochemical yield for 18FFPRGD4 was about 15%, with a total reaction time of 180 min starting from 18F-F2. The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. 18F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of 18F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK). Conclusion: The tetrameric RGD peptide tracer 18FFPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin avb3 expression in cancer and other angiogenesis related diseases.