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Assessing p-Glycoprotein (Pgp) Activity In Vivo Utilizing 68Ga–Schiff Base Complexes

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Abstract

Purpose

The p-glycoprotein (Pgp) is the most prominent member of active drug transporters leading to a multidrug-resistant phenotype. For identification of tumors functionally overexpressing Pgp in vivo, non-invasive imaging techniques are needed.

Procedures

Six Schiff base compounds were synthesized and labeled with 68Ge/68Ga generator-derived 68Ga. The compounds were studied in vitro in Pgp-positive tumor cells. The property of being a Pgp substrate was tested by comparison of the tracers uptake in R-3327 Dunning prostate carcinoma AT1 cells in presence and absence of the Pgp-inhibitor verapamil. In vivo investigations were performed with tumor-bearing rats imaged with micro-positron emission tomography.

Results

All ligands were labeled with 68Ga in yields of >92% beside one (~55%). The tracers showed different accumulation within the cells in vitro (4–60%). In blocking experiments, the ratio (blocked to unblocked) varied from 1.8 to 1.0. For in vivo experiments, 68Ga–ENBDMPI and 68Ga–MFL6.MZ were selected. The tumors showed specific uptake of the tracer. Direct intratumoral injection of verapamil increased the tracer concentration by ~25% reflecting the functional Pgp activity.

Conclusions

Two 68Ga-labeled ligands appear to be valuable for imaging non-invasively the intratumoral Pgp activity. On a long term, patients with multidrug-resistant tumors pre-therapeutically may be identified prior to treatment.

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Abbreviations

Pgp:

p-glycoprotein

VPL:

verapamil

MDR:

multidrug resistance

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Acknowledgments

The study was supported by the European Union (project COST D38 and BM0607) and the Deutsche Krebshilfe (grant 109136).

Conflict of Interest Disclosure

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Nuclear Chemistry, University of Mainz, Fritz Strassmann-Weg 2, 55128, Mainz, Germany

    Marco Fellner & Frank Rösch

  2. Institute of Physiology and Pathophysiology, University Medicine Mainz, 55128, Mainz, Germany

    Wolfgang Dillenburg & Oliver Thews

  3. Department of Nuclear Medicine, University Hospital, 55101, Mainz, Germany

    Hans-Georg Buchholz, Nicole Bausbacher & Mathias Schreckenberger

  4. Institute of Inorganic Chemistry, University of Hannover, 30167, Hannover, Germany

    Franz Renz

Authors
  1. Marco Fellner
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  2. Wolfgang Dillenburg
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  3. Hans-Georg Buchholz
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  4. Nicole Bausbacher
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  5. Mathias Schreckenberger
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  6. Franz Renz
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  7. Frank Rösch
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  8. Oliver Thews
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Correspondence to Frank Rösch.

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Fellner, M., Dillenburg, W., Buchholz, HG. et al. Assessing p-Glycoprotein (Pgp) Activity In Vivo Utilizing 68Ga–Schiff Base Complexes. Mol Imaging Biol 13, 985–994 (2011). https://doi.org/10.1007/s11307-010-0410-1

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  • DOI: https://doi.org/10.1007/s11307-010-0410-1

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