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⁶⁴Cu-Labeled Tetrameric and Octameric RGD Peptides for Small-Animal PET of Tumor _vß₃ Integrin Expression

Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California

Correspondence: For correspondence or reprints contact: Xiaoyuan Chen, PhD, Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd., P095, Stanford, CA 94305-5484. E-mail: shawchen{at}stanford.edu

Integrin _vß₃ plays a critical role in tumor angiogenesis and metastasis. Suitably radiolabeled cyclic arginine-glycine-aspartic (RGD) peptides can be used for noninvasive imaging of _vß₃ expression and targeted radionuclide therapy. In this study, we developed ⁶⁴Cu-labeled multimeric RGD peptides, E{E[c(RGDyK)]₂}₂ (RGD tetramer) and E(E{E[c(RGDyK)]₂}₂)₂ (RGD octamer), for PET imaging of tumor integrin _vß₃ expression. Methods: Both RGD tetramer and RGD octamer were synthesized with glutamate as the linker. After conjugation with 1,4,7,10-tetra-azacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), the peptides were labeled with ⁶⁴Cu for biodistribution and small-animal PET imaging studies (U87MG human glioblastoma xenograft model and c-neu oncomouse model). A cell adhesion assay, a cell-binding assay, receptor blocking experiments, and immunohistochemistry were also performed to evaluate the _vß₃-binding affinity/specificity of the RGD peptide-based conjugates in vitro and in vivo. Results: RGD octamer had significantly higher integrin _vß₃-binding affinity and specificity than RGD tetramer analog (inhibitory concentration of 50% was 10 nM for octamer vs. 35 nM for tetramer). ⁶⁴Cu-DOTA-RGD octamer had higher tumor uptake and longer tumor retention than ⁶⁴Cu-DOTA-RGD tetramer in both tumor models tested. The integrin _vß₃ specificity of both tracers was confirmed by successful receptor-blocking experiments. The high uptake and slow clearance of ⁶⁴Cu-DOTA-RGD octamer in the kidneys was attributed mainly to the integrin positivity of the kidneys, significantly higher integrin _vß₃-binding affinity, and the larger molecular size of the octamer, as compared with the other RGD analogs. Conclusion: Polyvalency has a profound effect on the receptor-binding affinity and in vivo kinetics of radiolabeled RGD multimers. The information obtained here may guide the future development of RGD peptide-based imaging and internal radiotherapeutic agents targeting integrin _vß₃.

Key Words: integrin _vß₃ • RGD multimer • tumor angiogenesis • positron emission tomography (PET) • ⁶⁴Cu

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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