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 (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.
Highlights
IntroductionNuclearimaging imagingis is a medical radionuclides for diagnosis, to therapy predictNuclear a medical tool tool usingusing radionuclides for diagnosis, to predict therapy outcome anddisease followprogression.disease progression.One field distinct field ofimaging, nuclear imaging, outcome and followOne distinct of nuclear namely namely immunoPET, has become increasingly important over the last decade [1].immunoPET, has become increasingly important over the last decade [1]
When 89 Zr was first investigated for PET imaging, common universal metal chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were used to explore the coordination chemistry and complex formation [11]
Even though good radiolabeling results could be obtained, in vivo experiments (C57B1/6j mice) showed significantly lower complex stability compared to DFO (accumulation in bones 3 d post injection (p.i.), 5% ID/g vs. 29% ID/g for 89 Zr-DFO-trastuzumab and 89 Zr-YM103trastuzumab, respectively) [14]
Summary
Nuclearimaging imagingis is a medical radionuclides for diagnosis, to therapy predict. Nuclear a medical tool tool usingusing radionuclides for diagnosis, to predict therapy outcome anddisease followprogression. One distinct of nuclear namely namely immunoPET, has become increasingly important over the last decade [1]. ImmunoPET, has become increasingly important over the last decade [1]. It combines theIt combines the high target specificity of monoclonal antibodies (mAbs) with the high high target specificity of monoclonal antibodies (mAbs) with the high sensitivity of positron sensitivitytomography of positron(PET). The choice of an appropriate radioisotope labeling radioisotope for the labeling of mAbs relates to the following aspects. Besides the of mAbs relates to the following aspects. Y(p,n) and be obtained commercially in rather via 89 Y(p,n) reaction and be obtained commercially in sufficient
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