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Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy

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

Abstract

Purpose

Targeting of tumours positive for somatostatin receptors (sst) with radiolabelled peptides is of interest for tumour localization, staging, therapy follow-up and targeted radionuclide therapy. The peptides used clinically are exclusively agonists, but recently we have shown that the radiolabelled somatostatin-based antagonist 111In-DOTA-sst2-ANT may be preferable to agonists. However, a comprehensive study of this radiolabelled antagonist to determine its significance was lacking. The present report describes the evaluation of this novel antagonist labelled with 111In and 177Lu in three different tumour models.

Methods

Radiopeptide binding, internalization and dissociation studies were performed using cells expressing HEK293-rsst2. Biodistribution studies were performed in HEK293-rsst2, HEK293-hsst2 and HEK293-rsst3 xenografted mice.

Results

Saturation binding analysis confirmed earlier IC50 data for 111/natIn-DOTA-sst2-ANT and showed similar affinity of 177/natLu-DOTA-sst2-ANT for the sst2. Only low internalization was found in cell culture (6.68 ± 0.06 % at 4 h), which was not unexpected for an antagonist, and this could be further reduced by the addition of sucrose. No internalization was observed in HEK293 cells not expressing sst. Both results indicate that the internalization was specific. 111In-DOTA-sst2-ANT and 177Lu-DOTA-sst2-ANT were shown to target tumour xenografts expressing the rat and the human sst2 receptor with no differences in their uptake or pharmacokinetics. The uptake in rsst2 and hsst2 was high (about 30 %IA/g 4 h after injection) and surprisingly long-lasting (about 20–23 %IA/g 24 h after injection). Kidney uptake was blocked by approximately 50 % by lysine or Gelofusine.

Conclusion

These results indicate that radiolabelled somatostatin-based antagonists may be superior to corresponding agonists. The long tumour retention time of 177Lu-DOTA-sst2-ANT indicates that this new class of compounds is of relevance not only in diagnostic imaging but also in targeted radionuclide therapy of sst-positive tumours.

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Abbreviations

HEK:

Human embryonic kidney

DOTA:

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

CB-TE2A:

4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane

DMEM:

Dulbecco’s modified Eagle’s medium

BSA:

Bovine serum albumin

FBS:

Fetal bovine serum

PBS:

Phosphate-buffered saline

HEPES:

2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethanesulphonic acid

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Acknowledgments

We thank the Swiss National Science Foundation and the FP7 project TARCC for financial support, and also the COST action D38.

Conflicts of interest

None.

Author information

Author notes

  1. Helmut R. Maecke

    Present address: Department of Nuclear Medicine, University Hospital Freiburg, Hugstetterstrasse 55, 79106, Freiburg, Germany

Authors and Affiliations

  1. Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland

    Xuejuan Wang, Melpomeni Fani & Helmut R. Maecke

  2. Department of Pharmacology and Toxicology, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany

    Stefan Schulz

  3. The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA, USA

    Jean Rivier

  4. Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Bern, Bern, Switzerland

    Jean Claude Reubi

Authors
  1. Xuejuan Wang
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  2. Melpomeni Fani
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  4. Jean Rivier
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  5. Jean Claude Reubi
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Correspondence to Helmut R. Maecke.

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Wang, X., Fani, M., Schulz, S. et al. Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy. Eur J Nucl Med Mol Imaging 39, 1876–1885 (2012). https://doi.org/10.1007/s00259-012-2231-8

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  • DOI: https://doi.org/10.1007/s00259-012-2231-8

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