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The Race for Hydroxamate-Based Zirconium-89 Chelators

Ludwig Boltzmann Institute Applied Diagnostics, General Hospital of Vienna, 1090 Vienna, Austria
Division of Nuclear Medicine, Department of Biomedical Imaging and Imaging Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria
Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, Chimie ParisTech, PSL University, CNRS, 75005 Paris, France
TU Wien, Institut für Angewandte Synthesechemie, Getreidemarkt 9, 1060 Wien, Austria
TU Wien, Center for Labeling and Isotope Production, Stadionallee 2, 1020 Wien, Austria
Department of Radiology and Nuclear Medicine, Amsterdam UMC, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
Department of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria
Author to whom correspondence should be addressed.
Academic Editors: Vladimir Tolmachev and Anzhelika Vorobyeva
Cancers 2021, 13(17), 4466;
Received: 17 August 2021 / Revised: 30 August 2021 / Accepted: 31 August 2021 / Published: 4 September 2021
Chelators are small molecules that can form a complex with a metal ion by coordinating electron rich atoms from the chelator to the electron-poor cation. Bifunctionalization of the chelator allows for the coupling of the chelator to a vector, such as a biomolecule. Using this approach, radiolabeling of biomolecules with metallic radionuclides can be performed, enabling nuclear imaging studies for diagnosis and radiotherapy of diseases. In the case of positron emission tomography (PET) of radiolabeled antibodies, this approach is called immunoPET. In this review we focus on chelators using hydroxamate groups to coordinate the radionuclide zirconium-89 ([89Zr]Zr4+, denoted as 89Zr in the following). The most common chelator used in this context is desferrioxamine (DFO). However, preclinical studies indicate that the 89Zr-DFO complex is not stable enough in vivo, in particular when combined with biomolecules with slow pharmacokinetics (e.g., antibodies). Subsequently, new chelators with improved properties have been developed, of which some show promising potential. The progress is summarized in this review.
Metallic radionuclides conjugated to biological vectors via an appropriate chelator are employed in nuclear medicine for the diagnosis (imaging) and radiotherapy of diseases. For the application of radiolabeled antibodies using positron emission tomography (immunoPET), zirconium-89 has gained increasing interest over the last decades as its physical properties (t1/2 = 78.4 h, 22.6% β+ decay) match well with the slow pharmacokinetics of antibodies (tbiol. = days to weeks) allowing for late time point imaging. The most commonly used chelator for 89Zr in this context is desferrioxamine (DFO). However, it has been shown in preclinical studies that the hexadentate DFO ligand does not provide 89Zr-complexes of sufficient stability in vivo and unspecific uptake of the osteophilic radiometal in bones is observed. For clinical applications, this might be of concern not only because of an unnecessary dose to the patient but also an increased background signal. As a consequence, next generation chelators based on hydroxamate scaffolds for more stable coordination of 89Zr have been developed by different research groups. In this review, we describe the progress in this research field until end of 2020, including promising examples of new candidates of chelators currently in advanced stages for clinical translation that outrun the performance of the current gold standard DFO. View Full-Text
Keywords: hydroxamate chelators; zirconium-89; immunoPET; desferrioxamine; DFO hydroxamate chelators; zirconium-89; immunoPET; desferrioxamine; DFO
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MDPI and ACS Style

Feiner, I.V.J.; Brandt, M.; Cowell, J.; Demuth, T.; Vugts, D.; Gasser, G.; Mindt, T.L. The Race for Hydroxamate-Based Zirconium-89 Chelators. Cancers 2021, 13, 4466.

AMA Style

Feiner IVJ, Brandt M, Cowell J, Demuth T, Vugts D, Gasser G, Mindt TL. The Race for Hydroxamate-Based Zirconium-89 Chelators. Cancers. 2021; 13(17):4466.

Chicago/Turabian Style

Feiner, Irene V. J., Marie Brandt, Joseph Cowell, Tori Demuth, Daniëlle Vugts, Gilles Gasser, and Thomas L. Mindt. 2021. "The Race for Hydroxamate-Based Zirconium-89 Chelators" Cancers 13, no. 17: 4466.

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