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The Race for Hydroxamate-Based Zirconium-89 Chelators

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The Race for Hydroxamate-Based Zirconium-89 Chelators cancers Review The Race for Hydroxamate-Based Zirconium-89 Chelators Irene V. J. Feiner 1,2, Marie Brandt 1,2, Joseph Cowell 3 , Tori Demuth 4,5, Daniëlle Vugts 6, Gilles Gasser 3 and Thomas L. Mindt 1,2,7,* 1 Ludwig Boltzmann Institute Applied Diagnostics, General Hospital of Vienna, 1090 Vienna, Austria; [email protected] (I.V.J.F.); [email protected] (M.B.) 2 Division of Nuclear Medicine, Department of Biomedical Imaging and Imaging Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria 3 Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, Chimie ParisTech, PSL University, CNRS, 75005 Paris, France; [email protected] (J.C.); [email protected] (G.G.) 4 TU Wien, Institut für Angewandte Synthesechemie, Getreidemarkt 9, 1060 Wien, Austria; [email protected] 5 TU Wien, Center for Labeling and Isotope Production, Stadionallee 2, 1020 Wien, Austria 6 Department of Radiology and Nuclear Medicine, Amsterdam UMC, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected] 7 Department of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria * Correspondence: [email protected]; Tel.: +43-1-40400-25350 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 Citation: Feiner, I.V.J.; Brandt, M.; Cowell, J.; Demuth, T.; Vugts, D.; approach, radiolabeling of biomolecules with metallic radionuclides can be performed, enabling Gasser, G.; Mindt, T.L. The Race for nuclear imaging studies for diagnosis and radiotherapy of diseases. In the case of positron emission Hydroxamate-Based Zirconium-89 tomography (PET) of radiolabeled antibodies, this approach is called immunoPET. In this review Chelators. Cancers 2021, 13, 4466. we focus on chelators using hydroxamate groups to coordinate the radionuclide zirconium-89 https://doi.org/10.3390/ ([89Zr]Zr4+, denoted as 89Zr in the following). The most common chelator used in this context is cancers13174466 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., Academic Editors: antibodies). Subsequently, new chelators with improved properties have been developed, of which Vladimir Tolmachev and some show promising potential. The progress is summarized in this review. Anzhelika Vorobyeva Abstract: Metallic radionuclides conjugated to biological vectors via an appropriate chelator are Received: 17 August 2021 employed in nuclear medicine for the diagnosis (imaging) and radiotherapy of diseases. For the Accepted: 31 August 2021 application of radiolabeled antibodies using positron emission tomography (immunoPET), zirconium- Published: 4 September 2021 + 89 has gained increasing interest over the last decades as its physical properties (t1/2 = 78.4 h, 22.6% β Publisher’s Note: MDPI stays neutral decay) match well with the slow pharmacokinetics of antibodies (tbiol. = days to weeks) allowing for 89 with regard to jurisdictional claims in late time point imaging. The most commonly used chelator for Zr in this context is desferrioxamine published maps and institutional affil- (DFO). However, it has been shown in preclinical studies that the hexadentate DFO ligand does 89 iations. not provide 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 89Zr have been Copyright: © 2021 by the authors. developed by different research groups. In this review, we describe the progress in this research field Licensee MDPI, Basel, Switzerland. until end of 2020, including promising examples of new candidates of chelators currently in advanced This article is an open access article stages for clinical translation that outrun the performance of the current gold standard DFO. distributed under the terms and conditions of the Creative Commons Keywords: hydroxamate chelators; zirconium-89; immunoPET; desferrioxamine; DFO Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Cancers 2021, 13, 4466. https://doi.org/10.3390/cancers13174466 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 23 Cancers 2021, 13, 4466 2 of 23 1.1. IntroductionIntroduction NuclearNuclear imagingimaging is is a medicala medical tool tool using using radionuclides radionuclides for diagnosis, for diagnosis, to predict to therapypredict outcometherapy outcome and follow and disease follow progression. disease progressio One distinctn. One fielddistinct of nuclearfield of imaging,nuclear imaging, namely immunoPET,namely immunoPET, has become has increasingly become increasingly important overimportant the last over decade the[ 1last]. It decade combines [1]. the It highcombines target the specificity high target of monoclonal specificity antibodies of monoclonal (mAbs) withantibodies the high (mAbs) sensitivity with of the positron high emissionsensitivity tomography of positron (PET). emission The choicetomography of an appropriate (PET). The radioisotope choice of foran theappropriate labeling ofradioisotope mAbs relates for the to the labeling following of mAbs aspects. relates Besides to the following the required aspects. positron Besides decay the required for PET imaging,positron availabilitydecay for PET of theimaging, radionuclide availability and itsof physicalthe radionuclide half-life playand aits crucial physical role. half-life Some 1/2 ofplay the a mostcrucial common role. Some PET of isotopes, the most such common as fluorine-18 PET isotopes, (t1/2 such= 109.7 as fluorine-18 min) and gallium-68 (t = 109.7 (tmin)1/2 = and 67.6 gallium-68 min), are not (t1/2 appropriate = 67.6 min), for are immunoPET not appropriate due to for their immunoPET short physical due half-lifeto their whichshort physical does not half-life match the which slow does biodistribution not match the of mAbs.slow biodistribution Therefore, the of use mAbs. of long Therefore, half-life 89 89 124 radioisotopes,the use of long such half-life as zirconium-89 radioisotopes, ( Zr, such t1/2 as= zirconium-89 78.4 h) [2], iodine-124 ( Zr, t1/2 ( = 78.4I, t1/2 h) =[2], 4.2 iodine- d) [3], 124 64 64 90 90 copper-64124 ( I, t1/2 ( = Cu,4.2 d) t1/2 [3],= copper-64 12.7 h) [4], ( niobium-90Cu, t1/2 = 12.7 ( h)Nb, [4], t 1/2niobium-90= 14.6 h) ( [5Nb,] and t1/2 manganese- = 14.6 h) [5] 52g 52g 52gand (manganese-52gMn, t1/2 = 5.6 ( d)Mn, [6 ],t1/2 is = more 5.6 d) reasonable [6], is more for reasonable radiolabeling for radiolabeling of mAbs. However, of mAbs. whileHowever, the availabilitywhile the availability of some of of these some radioisotopesof these radioisotopes is low, the is low, production the production of 89Zr isof rather89Zr is straightforwardrather straightforward via 89Y(p,n) via 8989ZrY(p,n) reaction89Zr reaction and be obtained and be obtained commercially commercially in sufficient in puritysufficient [7,8 ].purity That convenience[7,8]. That makesconvenience89Zr preferred makes and89Zr has preferred led to a progressivelyand has led larger to a setprogressively of data and larger publications. set of Thisdata riseand of publications. research related This to rise89Zr of highlights research therelated importance to 89Zr ofhighlights finding anthe effective importance chelator of finding for the stablean effective complexation chelator offor the the radiometal, stable complexation since such isof requiredthe radiometal, for clinical since applications such is of required biomolecules for radiolabeledclinical applications with metallic of radionuclidesbiomolecules (Figureradiolabeled1). with metallic radionuclides (Figure 1). FigureFigure 1.1.Schematic Schematic representation representation of aof biological a biological vector vect (antibody)or (antibody) conjugated conjugated via a linker via toa linker a hydroxa- to a 89 matehydroxamate chelator andchelator radiolabeled and radiolabeled with Zr. Thewith enlargement 89Zr. The enlargement shows the O show,O-coordinations the O,O-coordination between the electronbetween rich the oxygen electron atoms rich and oxygen the radiometal atoms and cation the 89radiometalZr forming cation a stable 89 five-member-ring.Zr forming a stable five- member-ring. The use of chelators in radiolabeling approaches can be challenging as the vector usuallyThe undergoes use of chelators bigger changesin radiolabeling in its structure, approaches compared can be to challenging other labelling as strategies,the vector 124 e.g.,usually with undergoes a covalent biggerI radiolabeling. changes in its However, structure, when compared working to withother largerlabelling biomolecules strategies, (e.g.,e.g., with Abs) a as covalent in the case 124I ofradiolabeling. immunoPET, However, the coupling when of wo a chelatorrking with does larger usually biomolecules not affect the(e.g., bioactivity Abs) as in asthe long case asof theimmunoPET, number of the chelators coupling per of a mAb chelator molecule does usually is
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