Abstract
(1) Background: Deferoxamine B (DFO) is the most widely used chelator for labeling of zirconium-89 (89Zr) to monoclonal antibody (mAb). Despite the remarkable developments of the clinical 89Zr-immuno-PET, chemical species and stability constants of the Zr-DFO complexes remain controversial. The aim of this study was to re-evaluate their stability constants by identifying species of Zr-DFO complexes and demonstrate that the stability constants can estimate radiochemical yield (RCY) and chelator-to-antibody ratio (CAR). (2) Methods: Zr-DFO species were determined by UV and ESI-MS spectroscopy. Stability constants and speciation of the Zr-DFO complex were redetermined by potentiometric titration. Complexation inhibition of Zr-DFO by residual impurities was investigated by competition titration. (3) Results: Unknown species, ZrHqDFO2, were successfully detected by nano-ESI-Q-MS analysis. We revealed that a dominant specie under radiolabeling condition (pH 7) was ZrHDFO, and its stability constant (logβ111) was 49.1 ± 0.3. Competition titration revealed that residual oxalate inhibits Zr-DFO complex formation. RCYs in different oxalate concentration (0.1 and 0.04 mol/L) were estimated to be 86% and >99%, which was in good agreement with reported results (87%, 97%). (4) Conclusion: This study succeeded in obtaining accurate stability constants of Zr-DFO complexes and estimating RCY and CAR from accurate stability constants established in this study.
Highlights
Coordination chemistry has played an important role in evaluating the functions of radiometal-labeled radiopharmaceuticals for both diagnostic and therapeutic applications.Especially, stability constants between radiometals and bifunctional chelators (BFC) have been key parameters for the evaluation of metal ion selectivity, in-vivo stability, and the pharmacokinetics of radiopharmaceuticals
Interest in zirconium-89 (89 Zr) for immunopositron emission tomography has been accelerating in recent years due to its favorable decay characteristics: a suitable half-life (78.4 h) for antibodies that take a few days to reach the tumor and a low positron (β+ ) energy (395 keV), which results in recent years due to its favorable decay characteristics: a suitable half-life (78.4 h) bodies that take a few days to reach the tumor and a low positron (β+) energy
The chelator-to-antibody ratio (CAR) with the same radiochemical yield (RCY) is lower (0.3) when the oxalate concentration is 0.05 mol/L. These results demonstrated that a lower concentration of oxalate is desirable to minimize the CAR when meeting the RCY criteria since a low CAR is generally preferable to maintain the immunoreactivity of the desired radiolabeled antibodies, as described above
Summary
Coordination chemistry has played an important role in evaluating the functions of radiometal-labeled radiopharmaceuticals for both diagnostic and therapeutic applications.Especially, stability constants between radiometals and bifunctional chelators (BFC) have been key parameters for the evaluation of metal ion selectivity, in-vivo stability, and the pharmacokinetics of radiopharmaceuticals. Interest in zirconium-89 (89 Zr) for immunopositron emission tomography (immuno-PET) has been accelerating in recent years due to its favorable decay characteristics: a suitable half-life (78.4 h) for antibodies that take a few days to reach the tumor and a low positron (β+ ) energy (395 keV), which results in recent years due to its favorable decay characteristics: a suitable half-life (78.4 h) bodies that take a few days to reach the tumor and a low positron (β+) energy These characteristics enc 2 of have the development of Zr-labeled monoclonal antibodies (mAb) as Zr-immune gents for theranostic applications to therapeutic radiometal-labeled antibodies, 177Lu
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