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Evaluation of two novel 64Cu-labeled RGD peptide radiotracers for enhanced PET imaging of tumor integrin αvβ3

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Our goal was to demonstrate that suitably derivatized monomeric RGD peptide-based PET tracers, targeting integrin αvβ3, may offer advantages in image contrast, time for imaging, and low uptake in nontarget tissues.

Methods

Two cyclic RGDfK derivatives, (PEG)2-c(RGDfK) and PEG4-SAA4-c(RGDfK), were constructed and conjugated to NOTA for 64Cu labeling. Their integrin αvβ3-binding properties were determined via a competitive cell binding assay. Mice bearing U87MG tumors were intravenously injected with each of the 64Cu-labeled peptides, and PET scans were acquired during the first 30 min, and 2 and 4 h after injection. Blocking and ex vivo biodistribution studies were carried out to validate the PET data and confirm the specificity of the tracers.

Results

The IC50 values of NOTA-(PEG)2-c(RGDfK) and NOTA-PEG4-SAA4-c(RGDfK) were 444 ± 41 nM and 288 ± 66 nM, respectively. Dynamic PET data of 64Cu-NOTA-(PEG)2-c(RGDfK) and 64Cu-NOTA-PEG4-SAA4-c(RGDfK) showed similar circulation t 1/2 and peak tumor uptake of about 4 %ID/g for both tracers. Due to its marked hydrophilicity, 64Cu-NOTA-PEG4-SAA4-c(RGDfK) provided faster clearance from tumor and normal tissues yet maintained excellent tumor-to-background ratios. Static PET scans at later time-points corroborated the enhanced excretion of the tracer, especially from abdominal organs. Ex vivo biodistribution and receptor blocking studies confirmed the accuracy of the PET data and the integrin αvβ3-specificity of the peptides.

Conclusion

Our two novel RGD-based radiotracers with optimized pharmacokinetic properties allowed fast, high-contrast PET imaging of tumor-associated integrin αvβ3. These tracers may facilitate the imaging of abdominal malignancies, normally precluded by high background uptake.

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Compliance with ethical standards

Funding

This study was funded by the University of Wisconsin–Madison, the Department of Defense (W81XWH-11-1-0644 & W81XWH-11-1-0648), the National Science Foundation (DGE-1256259), the National Institutes of Health (NIBIB/NCI 1R01CA169365, P30CA014520, T32CA009206, and 5T32GM08349), the US Department of States sponsored Fulbright Scholar Program (1831/FNPDR/2013), and the American Cancer Society (125246-RSG-13-099-01-CCE).

Conflicts of interest

Andrzej Czerwinski and Francisco Valenzuela are employees of Peptides International, Inc. The other authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Wisconsin Institutional Animal Care and Use Committee.

This article does not describe any studies with human participants performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Medical Physics, University of Wisconsin, Madison, WI, 53705, USA

    Reinier Hernandez, Stephen A. Graves, Robert J. Nickles & Weibo Cai

  2. Peptides International, Inc., Louisville, KY, 40299, USA

    Andrzej Czerwinski & Francisco Valenzuela

  3. Department of Radiology, University of Wisconsin, Madison, WI, 53705, USA

    Rubel Chakravarty, Yunan Yang, Christopher G. England & Weibo Cai

  4. University of Wisconsin Carbone Cancer Center, Madison, WI, 53705, USA

    Weibo Cai

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  1. Reinier Hernandez
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Correspondence to Weibo Cai.

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Hernandez, R., Czerwinski, A., Chakravarty, R. et al. Evaluation of two novel 64Cu-labeled RGD peptide radiotracers for enhanced PET imaging of tumor integrin αvβ3 . Eur J Nucl Med Mol Imaging 42, 1859–1868 (2015). https://doi.org/10.1007/s00259-015-3085-7

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  • DOI: https://doi.org/10.1007/s00259-015-3085-7

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