Noninvasive imaging of tumor integrin expression using 18F-labeled RGD dimer peptide with PEG4 linkers

PurposeVarious radiolabeled Arg-Gly-Asp (RGD) peptides have been previously investigated for tumor integrin αvβ3 imaging. To further develop RGD radiotracers with enhanced tumor-targeting efficacy and improved in vivo pharmacokinetics, we designed a new RGD homodimeric peptide with two PEG4 spacers (PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) between the two monomeric RGD motifs and one PEG4 linker on the glutamate α-amino group (18F-labeled PEG4-E[PEG4-c(RGDfK)]2, P-PRGD2), as a promising agent for noninvasive imaging of integrin expression in mouse models.MethodsP-PRGD2 was labeled with 18F via 4-nitrophenyl 2-18F-fluoropropionate (18F-FP) prosthetic group. In vitro and in vivo characteristics of the new dimeric RGD peptide tracer 18F-FP-P-PRGD2 were investigated and compared with those of 18F-FP-P-RGD2 (18F-labeled RGD dimer without two PEG4 spacers between the two RGD motifs). The ability of 18F-FP-P-PRGD2 to image tumor vascular integrin expression was evaluated in a 4T1 murine breast tumor model.ResultsWith the insertion of two PEG4 spacers between the two RGD motifs, 18F-FP-P-PRGD2 showed enhanced integrin αvβ3-binding affinity, increased tumor uptake and tumor-to-nontumor background ratios compared with 18F-FP-P-RGD2 in U87MG tumors. MicroPET imaging with 18F-FP-P-PRGD2 revealed high tumor contrast and low background in tumor-bearing nude mice. Biodistribution studies confirmed the in vivo integrin αvβ3-binding specificity of 18F-FP-P-RGD2. 18F-FP-P-PRGD2 can specifically image integrin αvβ3 on the activated endothelial cells of tumor neovasculature.Conclusion18F-FP-P-PRGD2 can provide important information on integrin expression on the tumor vasculature. The high integrin binding affinity and specificity, excellent pharmacokinetic properties and metabolic stability make the new RGD dimeric tracer 18F-FP-P-PRGD2 a promising agent for PET imaging of tumor angiogenesis and for monitoring the efficacy of antiangiogenic treatment.

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