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Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

Reubi, Jean ; Erchegyi, Judit ; Cescato, Renzo ; Waser, Beatrice ; Rivier, Jean

In: European Journal of Nuclear Medicine and Molecular Imaging, 2010, vol. 37, no. 8, p. 1551-1558

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    Titre
    • Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog
    Auteur
    • Reubi, Jean. Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, PO Box62, 3010, Berne, Switzerland
    • Erchegyi, Judit. The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, 92037, La Jolla, CA, USA
    • Cescato, Renzo. Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, PO Box62, 3010, Berne, Switzerland
    • Waser, Beatrice. Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, PO Box62, 3010, Berne, Switzerland
    • Rivier, Jean. The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, 92037, La Jolla, CA, USA
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • European Journal of Nuclear Medicine and Molecular Imaging, 2010, vol. 37, no. 8, p. 1551-1558. Springer-Verlag
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:319191
    Summary
    Purpose: Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Methods: Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst1-sst5) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst2 and sst3 internalization in vitro in HEK293 cells stably expressing the human sst2 or sst3 receptor, using an immunofluorescence microscopy-based internalization assay. Results: All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst2 internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Conclusion: Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added