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

Wang, Xuejuan ; Fani, Melpomeni ; Schulz, Stefan ; Rivier, Jean ; Reubi, Jean ; Maecke, Helmut

In: European Journal of Nuclear Medicine and Molecular Imaging, 2012, vol. 39, no. 12, p. 1876-1885

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    Titel
    • Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy
    Autor
    • Wang, Xuejuan. Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland
    • Fani, Melpomeni. Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland
    • Schulz, Stefan. Department of Pharmacology and Toxicology, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany
    • Rivier, Jean. The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA, USA
    • Reubi, Jean. Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Bern, Bern, Switzerland
    • Maecke, Helmut. Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • European Journal of Nuclear Medicine and Molecular Imaging, 2012, vol. 39, no. 12, p. 1876-1885. Springer-Verlag
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:322467
    Summary
    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 4h), 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 4h after injection) and surprisingly long-lasting (about 20-23 %IA/g 24h 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