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Improved PET Imaging of Tumors in Mice Using a Novel 18 F-Folate Conjugate with an Albumin-Binding Entity

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Abstract

Purpose

The folate receptor (FR) is a promising target for nuclear imaging due to its overexpression in many different cancer types. A drawback of using folate radioconjugates is the high accumulation of radioactivity in the kidneys. Therefore, the aim of this study was to develop a 18 F-labeled folate conjugate with an albumin-binding entity to enhance the blood circulation time and hence improve the tumor-to-kidney ratio.

Procedures

The novel 18 F-folate was prepared by conjugation of a 18 F-labeled glucose azide to an alkyne-functionalized folate precursor containing an albumin-binding entity via Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radioconjugate was tested in vitro on FR-positive KB tumor cells and by biodistribution and positron emission tomography (PET) imaging studies using KB tumor-bearing mice.

Results

The radiosynthesis of the albumin-binding [18 F]fluorodeoxyglucose–folate ([18 F]3) resulted in a radiochemical yield of 1–2 % decay corrected (d.c.) and a radiochemical purity of ≥95 %. The specific activity of [18 F]3 ranged from 20 to 50 GBq/μmol. In vitro experiments revealed FR-specific binding of [18 F]3 to KB tumor cells. In vivo we found an increasing uptake of [18 F]3 into tumor xenografts over time reaching a value of ∼ 15 % injected dose (ID)/g at 4 h post-injection (p.i.). Uptake in the kidneys (∼ 13 % ID/g; 1 h p.i.) was approximately fourfold reduced compared to previously published 18 F-labeled folic acid derivatives. An excellent visualization of tumor xenografts with an unprecedentedly high tumor-to-kidney ratio (∼ 1) was obtained by PET imaging.

Conclusions

[18 F]3 showed a favorable accumulation in tumor xenografts compared to the same folate conjugate without albumin-binding properties. Moreover, the increased tumor-to-kidney ratios improved the PET imaging quality significantly, in spite of a somewhat higher background radioactivity which was a consequence of the slower blood clearance of [18 F]3.

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Acknowledgments

We thank Dr. Thomas Betzel, Nadja Romano, and Martin Hungerbühler for their support and technical assistance. The project was financially supported by the Swiss National Science Foundation (Ambizione grants PZ00P3_121772 and PZ00P3_138834), COST-BM0607 (C08.0026), and the Swiss Cancer League (KLS-02762-02-2011).

Conflict of Interest

There are no conflicts of interest to declare.

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Authors and Affiliations

  1. Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, 8093, Zurich, Switzerland

    Cindy R. Fischer, Roger Schibli & Simon M. Ametamey

  2. Merck & Cie, 8200, Schaffhausen, Switzerland

    Viola Groehn

  3. Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Paul Scherrer Institute, 5232, Villigen-PSI, Switzerland

    Josefine Reber, Roger Schibli & Cristina Müller

Authors
  1. Cindy R. Fischer
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  2. Viola Groehn
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  3. Josefine Reber
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  4. Roger Schibli
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  5. Simon M. Ametamey
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  6. Cristina Müller
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Corresponding author

Correspondence to Cristina Müller.

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Fischer, C.R., Groehn, V., Reber, J. et al. Improved PET Imaging of Tumors in Mice Using a Novel 18 F-Folate Conjugate with an Albumin-Binding Entity. Mol Imaging Biol 15, 649–654 (2013). https://doi.org/10.1007/s11307-013-0651-x

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  • DOI: https://doi.org/10.1007/s11307-013-0651-x

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