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Radiolabelling of the octadentate chelators DFO* and oxoDFO* with zirconium-89 and gallium-68

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Abstract

In recent years, clinical imaging with zirconium-89 (89Zr)-labelled monoclonal antibodies (Ab) by positron emission tomography (immunoPET) has been gaining significant importance in nuclear medicine for the diagnosis of different types of cancer. For complexation of the radiometal 89Zr and its attachment to the Ab, chelating agents are required. To date, only the hexadentate chelator desferrioxamine (DFO) is applied in the clinic for this purpose. However, there is increasing preclinical evidence that the [89Zr]Zr-DFO complex is not sufficiently stable and partly releases the radiometal in vivo due to the incomplete coordination sphere of the metal. This leads to unfavourable unspecific uptake of the osteophilic radiometal in bones, hence decreasing the signal-to-noise-ratio and leading to an increased dose to the patient. In the past, several new chelators with denticities > 6 have been published, notably the octadentate DFO derivative DFO*. DFO*, however, shows limited water solubility, wherefore an oxygen containing analogue, termed oxoDFO*, was developed in 2017. However, no data on the suitability of oxoDFO* for radiolabelling with 89Zr has yet been reported. In this proof-of-concept study, we present the first radiolabelling results of the octadentate, water-soluble chelator oxoDFO*, as well as the in vitro stability of the resulting complex [89Zr]Zr-oxoDFO* in comparison to the analogous octadentate, but less water-soluble derivative DFO* and the current “standard” chelator DFO. In addition, the suitability of DFO* and oxoDFO* for radiolabeling with the short-lived PET metal gallium-68 is discussed.

Graphic abstract

The water-soluble, octadentate chelator oxoDFO* provides stable complexes with the positron emitter Zirconium-89. The radiolabelling can be performed at room temperature and neutral pH and thus, oxoDFO* represents a promising chelator for applications in immunoPET.

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Acknowledgements

This work was funded by the Swiss National Science Foundation (Grant no. SNSF 205321_157216 to G.G. and T.L.M). The authors thank Katarina Benčurová (Ludwig Boltzmann Institute Applied Diagnostics) and Jonas Aronow (Medical University of Vienna) for technical assistance.

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Authors and Affiliations

  1. Ludwig Boltzmann Institute Applied Diagnostics, General Hospital of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria

    Marie Brandt & Thomas L. Mindt

  2. Department of Biomedical Imaging and Image Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria

    Marie Brandt & Thomas L. Mindt

  3. Laboratory for Inorganic Chemical Biology, Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, 75005, Paris, France

    Joseph Cowell, Margaret L. Aulsebrook & Gilles Gasser

  4. Department of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Währinger Straße 42, 1090, Vienna, Austria

    Thomas L. Mindt

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Correspondence to Gilles Gasser or Thomas L. Mindt.

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Thomas Mindt and Gilles Gasser are co-inventors on pending patent applications describing DFO* and its derivatives. These patent applications are owned by the University of Zurich and the University of Basel. The patent owners have granted an exclusive license to the company ABX Advanced Biochemicals Compounds. The inventors are unrelated to this company.

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Brandt, M., Cowell, J., Aulsebrook, M.L. et al. Radiolabelling of the octadentate chelators DFO* and oxoDFO* with zirconium-89 and gallium-68. J Biol Inorg Chem 25, 789–796 (2020). https://doi.org/10.1007/s00775-020-01800-4

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