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18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of αvβ3 integrin expression

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

Abstract

Purpose

We have previously reported that 18F-FB-E[c(RGDyK)]2 (18F-FRGD2) allows quantitative PET imaging of integrin αvβ3 expression. However, the potential clinical translation was hampered by the relatively low radiochemical yield. The goal of this study was to improve the radiolabeling yield, without compromising the tumor targeting efficiency and in vivo kinetics, by incorporating a hydrophilic bifunctional mini-PEG spacer.

Methods

18F-FB-mini-PEG-E[c(RGDyK)]2 (18F-FPRGD2) was synthesized by coupling N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) with NH2-mini-PEG-E[c(RGDyK)]2 (denoted as PRGD2). In vitro receptor binding affinity, metabolic stability, and integrin αvβ3 specificity of the new tracer 18F-FPRGD2 were assessed. The diagnostic value of 18F-FPRGD2 was evaluated in subcutaneous U87MG glioblastoma xenografted mice and in c-neu transgenic mice by quantitative microPET imaging studies.

Results

The decay-corrected radiochemical yield based on 18F-SFB was more than 60% with radiochemical purity of >99%. 18F-FPRGD2 had high receptor binding affinity, metabolic stability, and integrin αvβ3-specific tumor uptake in the U87MG glioma xenograft model comparable to those of 18F-FRGD2. The kidney uptake was appreciably lower for 18F-FPRGD2 compared with 18F-FRGD2 [2.0 ± 0.2%ID/g for 18F-FPRGD2 vs 3.0 ± 0.2%ID/g for 18F-FRGD2 at 1 h post injection (p.i.)]. The uptake in all the other organs except the urinary bladder was at background level. 18F-FPRGD2 also exhibited excellent tumor uptake in c-neu oncomice (3.6 ± 0.1%ID/g at 30 min p.i.).

Conclusion

Incorporation of a mini-PEG spacer significantly improved the overall radiolabeling yield of 18F-FPRGD2. 18F-FPRGD2 also had reduced renal uptake and similar tumor targeting efficacy as compared with 18F-FRGD2. Further testing and clinical translation of 18F-FPRGD2 are warranted.

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Acknowledgements

This work was supported in part by National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R21 EB001785), National Cancer Institute (NCI) (R21 CA102123, P50 CA114747, U54 CA119367, and R24 CA93862), Department of Defense (DOD) (W81XWH-04-1-0697, W81XWH-06-1-0665, W81XWH-06-1-0042, and DAMD17-03-1-0143), and a Benedict Cassen Postdoctoral Fellowship from the Education and Research Foundation of the Society of Nuclear Medicine (to W. Cai). We thank Dr. David W. Dick from the cyclotron facility for 18F-F− production.

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Authors and Affiliations

  1. The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd, P095, Stanford, CA, 94305-5484, USA

    Zhanhong Wu, Zi-Bo Li, Weibo Cai, Lina He, Frederick T. Chin & Xiaoyuan Chen

  2. Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, People’s Republic of China

    Zhanhong Wu & Fang Li

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  1. Zhanhong Wu
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Correspondence to Xiaoyuan Chen.

Additional information

Zhanhong Wu and Zi-Bo Li contributed equally to this work.

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Supplementary Fig. 1

Cell-binding assay of PRGD2, FPRGD2, RGD2, and FRGD2 using U87MG cells (integrin αvβ3-positive human glioblastoma) and 125I-echistatin as the radioligand. IC50 values for PRGD2, FPRGD2, RGD2, and FRGD2 were 70.1 ± 3.5, 40.6 ± 4.6, 26.1 ± 3.2, and 55.1 ± 6.5 nmol/l, respectively. Data points shown are means of triplicate samples (DOC 25 kb).

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Wu, Z., Li, ZB., Cai, W. et al. 18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of αvβ3 integrin expression. Eur J Nucl Med Mol Imaging 34, 1823–1831 (2007). https://doi.org/10.1007/s00259-007-0427-0

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