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Predicting the Thermodynamic Stability of Zirconium Radiotracers


Holland, Jason P (2020). Predicting the Thermodynamic Stability of Zirconium Radiotracers. Inorganic Chemistry, 59(3):2070-2082.

Abstract

The thermodynamic stability of a metal−ligand complex, as measured by the formation constant (logβ), is one of themost important parameters that determines metal ion selectivity and potential applications in, for example, radiopharmaceuticalscience. The stable coordination chemistry of radioactive89Zr4+in an aqueous environment is of paramount importance whendeveloping positron-emitting radiotracers based on proteins (usually antibodies) for use with positron emission tomography.Desferrioxamine B (DFO) remains the chelate of choice for clinical applications of89Zr-labeled proteins, but the coordination ofDFO to Zr4+ions is suboptimal. Many alternative ligands have been reported, but the challenges in measuring very high logβvalueswith metal ions such as Zr4+that tend to hydrolyze mean that accurate thermodynamic data are scarce. In this work, densityfunctional theory (DFT) calculations were used to predict the reaction energetics for metal ion complexation. Computed values ofpseudoformation constants (logβ′) are correlated with experimental data and showed an excellent linear relationship (R2= 0.97).The model was then used to estimate the absolute and relative formation constants of 23 different Zr4+complexes using a total of 17different ligands, including many of the alternative bifunctional chelates that have been reported recently for use in89Zr4+radiochemistry. In addition, detailed computational studies were performed on the geometric isomerism and hydration state of Zr-desferrioxamine. Collectively, the results offer new insights into Zr4+coordination chemistry that will help guide the synthesis offuture ligands. The computational model developed here is straightforward and reproducible and can be readily applied in the designof other metal coordination compounds.

Abstract

The thermodynamic stability of a metal−ligand complex, as measured by the formation constant (logβ), is one of themost important parameters that determines metal ion selectivity and potential applications in, for example, radiopharmaceuticalscience. The stable coordination chemistry of radioactive89Zr4+in an aqueous environment is of paramount importance whendeveloping positron-emitting radiotracers based on proteins (usually antibodies) for use with positron emission tomography.Desferrioxamine B (DFO) remains the chelate of choice for clinical applications of89Zr-labeled proteins, but the coordination ofDFO to Zr4+ions is suboptimal. Many alternative ligands have been reported, but the challenges in measuring very high logβvalueswith metal ions such as Zr4+that tend to hydrolyze mean that accurate thermodynamic data are scarce. In this work, densityfunctional theory (DFT) calculations were used to predict the reaction energetics for metal ion complexation. Computed values ofpseudoformation constants (logβ′) are correlated with experimental data and showed an excellent linear relationship (R2= 0.97).The model was then used to estimate the absolute and relative formation constants of 23 different Zr4+complexes using a total of 17different ligands, including many of the alternative bifunctional chelates that have been reported recently for use in89Zr4+radiochemistry. In addition, detailed computational studies were performed on the geometric isomerism and hydration state of Zr-desferrioxamine. Collectively, the results offer new insights into Zr4+coordination chemistry that will help guide the synthesis offuture ligands. The computational model developed here is straightforward and reproducible and can be readily applied in the designof other metal coordination compounds.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Physical Sciences > Physical and Theoretical Chemistry
Physical Sciences > Inorganic Chemistry
Uncontrolled Keywords:Physical and Theoretical Chemistry, Inorganic Chemistry
Language:English
Date:3 February 2020
Deposited On:17 Apr 2020 09:39
Last Modified:22 Apr 2020 23:24
Publisher:American Chemical Society (ACS)
ISSN:0020-1669
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.inorgchem.9b03515
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P2_163683
  • : Project TitleAdvanced radiochemical methods for multi-modal imaging with nanomedicines
  • : FunderSNSF
  • : Grant IDPP00P2_190093
  • : Project Title
  • : FunderKrebsliga
  • : Grant IDKLS-4257-08-2017
  • : Project Title

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Content: Accepted Version
Language: English
Filetype: PDF - Registered users only until 15 January 2021
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Embargo till: 2021-01-15