The Race for Hydroxamate-Based Zirconium-89 Chelators

SIMPLE SUMMARY: 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 ([(89)Zr]Zr(4+), denoted as (89)Zr in the following). The most common chelator used in this context is desferrioxamine (DFO). However, preclinical studies indicate that the (89)Zr-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. ABSTRACT: 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 (t(1/2) = 78.4 h, 22.6% β(+) decay) match well with the slow pharmacokinetics of antibodies (t(biol). = days to weeks) allowing for late time point imaging. The most commonly used chelator for (89)Zr in this context is desferrioxamine (DFO). However, it has been shown in preclinical studies that the hexadentate DFO ligand does not provide (89)Zr-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 (89)Zr 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.