microPET of Tumor Integrin _v3 Expression Using ¹⁸F-Labeled PEGylated Tetrameric RGD Peptide (¹⁸F-FPRGD4)

¹ The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California; Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
² The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California
³ Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China

^* To whom correspondence should be addressed. E-mail: shawchen{at}stanford.edu.

	Abstract

In vivo imaging of _v3 expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin _v3–binding affinity due to the polyvalency effect. Here we report an example of ¹⁸F-labeled tetrameric RGD peptide for PET of _v3 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 -amino group. NH₂-mini-PEG-E{E[c(RGDyK)]₂}₂ (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 ¹⁸F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from ¹⁸F-F^-. 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 ¹⁸F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin _v3 expression in cancer and other angiogenesis related diseases.

Key Words: microPET, integrin _v3, tetrameric RGD peptide, PEGylation, ¹⁸F

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