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Preclinical Evaluation of Radiolabeled DOTA-Derivatized Cyclic Minigastrin Analogs for Targeting Cholecystokinin Receptor Expressing Malignancies

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Abstract

Purpose

Targeting of cholecystokinin receptor expressing malignancies such as medullary thyroid carcinoma is currently limited by low in vivo stability of radioligands. To increase the stability, we have developed and preclinically evaluated two cyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-minigastrin analogs radiolabeled with 111In and 68Ga.

Procedures

Radiolabeling efficiency, in vitro characterization, cholecystokinin receptor subtype 2 (CCK-2) binding in human tumor tissues, and cell internalization on CCK-2 receptor expressing AR42J cells, as well as biodistribution and small animal imaging in two different mouse xenograft models were studied.

Results

High receptor affinity and receptor-mediated uptake of the radioligands in AR42J cells was confirmed in vitro. 111In-labeled cyclic DOTA-peptides showed a specific tumor uptake of ~1% ID/g in vivo, 68Ga-labeled analogs of ~3% ID/g. Small animal SPECT imaging resulted to be superior with 111In-DOTA-cyclo-MG2 in comparison with 111In-DOTA-cyclo-MG1.

Conclusions

Cyclic DOTA-minigastrin analogs are promising candidates for gastrin receptor scintigraphy and targeted radionuclide therapy.

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Acknowledgments

We would like to thank Werner Sallegger from piCHEM Research and Development (Graz, Austria) for synthesizing the peptide derivatives used in this study. Lieke Joosten (Radboud University Nijmegen Medical Centre) is acknowledged for expert help in radiolabeling. Ciara Finucane, Jerome Burnet, and Julie Foster assisted in the imaging studies carried out at Barts and the London, Queen Mary's School of Medicine and Dentistry. Collaboration within the COST Action BM0607 “Targeted Radionuclide Therapy (TRNT)” is greatly acknowledged. This work was supported by grants from the Austrian Nano Initiative (Nano-Health consortium, Project N208-NAN) and was partly performed within the PhD program Image Guided Diagnosis and Therapy (IGDT) of the Medical University Innsbruck, Austria.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Innsbruck Medical University, Anichstrasse 35, 6020, Innsbruck, Austria

    Elisabeth von Guggenberg, Christine Rangger, Irene Johanna Virgolini & Clemens Decristoforo

  2. Centre for Molecular Oncology and Imaging, Barts and the London, Queen Mary’s School of Medicine and Dentistry, London, UK

    Jane Sosabowski

  3. Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Peter Laverman

  4. Department of Pathology, University of Berne, Berne, Switzerland

    Jean-Claude Reubi

Authors
  1. Elisabeth von Guggenberg
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  2. Christine Rangger
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  3. Jane Sosabowski
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  4. Peter Laverman
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  5. Jean-Claude Reubi
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  6. Irene Johanna Virgolini
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  7. Clemens Decristoforo
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Correspondence to Elisabeth von Guggenberg.

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von Guggenberg, E., Rangger, C., Sosabowski, J. et al. Preclinical Evaluation of Radiolabeled DOTA-Derivatized Cyclic Minigastrin Analogs for Targeting Cholecystokinin Receptor Expressing Malignancies. Mol Imaging Biol 14, 366–375 (2012). https://doi.org/10.1007/s11307-011-0506-2

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