MicroPET of tumor integrin αvβ3 expression using 18F-Labeled PEGylated tetrameric RGD peptide (18F-FPRGD4)

In vivo imaging of alpha(v)beta(3) expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin alpha(v)beta(3)-binding affinity due to the polyvalency effect. Here we report an example of F-18-labeled tetrameric RGD peptide for PET of alpha(v)beta(3) expression in both xenograft and spontaneous tumor models. Methods: The tetrameric RGD peptide E{E[c(RGDyK)](2)}(2) was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate a-amino group. NH2-mini-PEG-E{E[c(RGDyK)](2)}(2) (PRGD4) was labeled with F-18 via the N-succinimidyl-4-F-18-fluorobenzoate (F-18-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer F-18-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 F-18-FPRGD4 was about 15%, with a total reaction time of 180 min starting from F-18-F-. The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. F-18-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of F-18-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 (18)FFPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin alpha(v)beta(3) expression in cancer and other angiogenesis related diseases.