Tuning the Kinetic Inertness of Bi3+Complexes: The Impact of Donor Atoms on Diaza-18-Crown-6 Ligands as Chelators for 213Bi Targeted Alpha Therapy

David J. Fiszbein; Victoria Brown; Nikki A. Thiele; Joshua J. Woods; Luke Wharton; Samantha N. Macmillan; Valery Radchenko; Caterina F. Ramogida; Justin J. Wilson

doi:10.1021/acs.inorgchem.1c01269

Tuning the Kinetic Inertness of Bi³⁺Complexes: The Impact of Donor Atoms on Diaza-18-Crown-6 Ligands as Chelators for ²¹³Bi Targeted Alpha Therapy

David J. Fiszbein, Victoria Brown, Nikki A. Thiele, Joshua J. Woods, Luke Wharton, Samantha N. Macmillan, Valery Radchenko, Caterina F. Ramogida, Justin J. Wilson

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

The radionuclide 213Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi3+ center arising from the stereochemically active 6s2 lone pair. The kinetic properties of the Bi3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s2 lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of 213Bi (30-210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10-7 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in 213Bi TAT.

Original language	English
Pages (from-to)	9199-9211
Number of pages	13
Journal	Inorganic Chemistry
Volume	60
Issue number	12
DOIs	https://doi.org/10.1021/acs.inorgchem.1c01269
State	Published - Jun 21 2021
Externally published	Yes

Funding

This research was supported by funding from the College of Arts and Sciences at Cornell University, by the National Institute for Biomedical Imaging and Bioengineering of the National Institutes of Health under award number R01 EB029259, and by the Research Corporation for Science Advancement in the form of a Cottrell Scholar Award to J. J. Wilson. J. J. Woods thanks the American Heart Association for a predoctoral fellowship (20PRE35120390). This research also made use of the NMR Facility at Cornell University, which is supported, in part, by the United States National Science Foundation under Award CHE-1531632. We gratefully acknowledge the Natural Sciences and Engineering Research Council (NSERC) of Canada for a CREATE IsoSiM at TRIUMF research stipend (L. Wharton), financial support via NSERC Discovery Grants (V. Radchenko), and support via a Master’s Canada Graduate Scholarship (V. Brown). TRIUMF receives federal funding via a contribution agreement with the National Research Council of Canada. This research was supported by funding from the College of Arts and Sciences at Cornell University, by the National Institute for Biomedical Imaging and Bioengineering of the National Institutes of Health under award number R01 EB029259, and by the Research Corporation for Science Advancement in the form of a Cottrell Scholar Award to J. J. Wilson. J. J. Woods thanks the American Heart Association for a predoctoral fellowship (20PRE35120390). This research also made use of the NMR Facility at Cornell University, which is supported, in part, by the United States National Science Foundation under Award CHE-1531632. We gratefully acknowledge the Natural Sciences and Engineering Research Council (NSERC) of Canada for a CREATE IsoSiM at TRIUMF research stipend (L. Wharton), financial support via NSERC Discovery Grants (V. Radchenko) and support via a Master?s Canada Graduate Scholarship (V. Brown). TRIUMF receives federal funding via a contribution agreement with the National Research Council of Canada.

Funders	Funder number
National Science Foundation	CHE-1531632
National Institutes of Health
National Institute of Biomedical Imaging and Bioengineering	R01EB029259
American Heart Association	20PRE35120390
Research Corporation for Science Advancement
College of Arts and Sciences, Cornell University
Natural Sciences and Engineering Research Council of Canada
National Research Council Canada

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Access to Document

10.1021/acs.inorgchem.1c01269

Cite this

Fiszbein, D. J., Brown, V., Thiele, N. A., Woods, J. J., Wharton, L., Macmillan, S. N., Radchenko, V., Ramogida, C. F., & Wilson, J. J. (2021). Tuning the Kinetic Inertness of Bi³⁺Complexes: The Impact of Donor Atoms on Diaza-18-Crown-6 Ligands as Chelators for ²¹³Bi Targeted Alpha Therapy. Inorganic Chemistry, 60(12), 9199-9211. https://doi.org/10.1021/acs.inorgchem.1c01269

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title = "Tuning the Kinetic Inertness of Bi3+Complexes: The Impact of Donor Atoms on Diaza-18-Crown-6 Ligands as Chelators for 213Bi Targeted Alpha Therapy",

abstract = "The radionuclide 213Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi3+ center arising from the stereochemically active 6s2 lone pair. The kinetic properties of the Bi3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s2 lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of 213Bi (30-210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10-7 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in 213Bi TAT.",

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AU - Brown, Victoria

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