Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes

Wilson, Justin J.; Ferrier, Maryline G.; Radchenko, Valery; Maassen, Joel R.; Engle, Jonathan W.; Batista, Enrique R.; Martin, Richard L.; Nortier, F.M.; Fassbender, Michael E.; John, Kevin D.; Birnbaum, Eva R.

doi:10.1016/j.nucmedbio.2014.12.007

Cited by 43 publications

(42 citation statements)

References 81 publications

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“…70 The 225 Ac isotope was purified from a clean 229 Th source, which had been achieved in the LANL isotope inventory many years ago. 71 Trifluoromethanesulfonic acid and sodium hydroxide were obtained commercially (Fisher Scientific). Water was purified to 18.2 MΩ/cm resistivity using Thermo-Scientific Barnstead Nanopure or Millipore Nanopure water purification systems.…”

Section: Experimental Sectionmentioning

confidence: 99%

Synthesis and Characterization of the Actinium Aquo Ion

et al. 2017

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Metal aquo ions occupy central roles in all equilibria that define metal complexation in natural environments. These complexes are used to establish thermodynamic metrics (i.e., stability constants) for predicting metal binding, which are essential for defining critical parameters associated with aqueous speciation, metal chelation, in vivo transport, and so on. As such, establishing the fundamental chemistry of the actinium(III) aquo ion (Ac-aquo ion, Ac(H2O)x3+) is critical for current efforts to develop 225Ac [t1/2 = 10.0(1) d] as a targeted anticancer therapeutic agent. However, given the limited amount of actinium available for study and its high radioactivity, many aspects of actinium chemistry remain poorly defined. We overcame these challenges using the longer-lived 227Ac [t1/2 = 21.772(3) y] isotope and report the first characterization of this fundamentally important Ac-aquo coordination complex. Our X-ray absorption fine structure study revealed 10.9 ± 0.5 water molecules directly coordinated to the AcIII cation with an Ac–OH2O distance of 2.63(1) Å. This experimentally determined distance was consistent with molecular dynamics density functional theory results that showed (over the course of 8 ps) that AcIII was coordinated by 9 water molecules with Ac–OH2O distances ranging from 2.61 to 2.76 Å. The data is presented in the context of other actinide(III) and lanthanide(III) aquo ions characterized by XAFS and highlights the uniqueness of the large AcIII coordination numbers and long Ac–OH2O bond distances.

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Section: Experimental Sectionmentioning

confidence: 99%

Synthesis and Characterization of the Actinium Aquo Ion

et al. 2017

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“…While there is great interest in using 225 Ac for targeted alpha therapy 27,28 , the development of 225 Ac-based pharmaceuticals is still hindered by low isotope availability relative to potential market needs 1 . Furthermore, Ac chemistry is largely unexplored since (i) Ac 3+ being the biggest trivalent ion of the periodic table 28,29 , there is no adequate surrogate to study its chemistry, and (ii) its highly-radioactive longest-lived isotope ( 227 Ac, t 1/2 = 21.8 year) is available in only μg amounts.…”

Section: Resultsmentioning

confidence: 99%

Ultra-selective ligand-driven separation of strategic actinides

2019

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Metal ion separations are critical to numerous fields, including nuclear medicine, waste recycling, space exploration, and fundamental research. Nonetheless, operational conditions and performance are limited, imposing compromises between recovery, purity, and cost. Siderophore-inspired ligands show unprecedented charge-based selectivity and compatibility with harsh industry conditions, affording excellent separation efficiency, robustness and process control. Here, we successfully demonstrate a general separation strategy on three distinct systems, for Ac, Pu, and Bk purification. Separation factors (SF) obtained with model compound 3,4,3-LI(1,2-HOPO) are orders of magnitude higher than with any other ligand currently employed: 10 6 between Ac and relevant metal impurities, and over 10 8 for redox-free Pu purification against uranyl ions and trivalent actinides or fission products. Finally, a one-step separation method (SF > 3 × 10 6 and radiopurity > 99.999%) enables the isolation of Bk from adjacent actinides and fission products. The proposed approach offers a paradigm change for the production of strategic elements.

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“…The small frozen-core approximation was applied. This level of theory has been used in several recent studies on TAT-related complexes [43][44][45][46]. An auxiliary set of s, p, d, f and g STOs was used to fit the molecular density and to represent the Coulomb and exchange potentials accurately in each SCF cycle.…”

Section: Computational Detailsmentioning

confidence: 99%

Metal–ligand interactions in complexes of cyclen-based ligands with Bi and Ac

Kovács

Varga

2021

Struct Chem

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The structural and bonding properties of Bi and Ac complexes with cyclen-based chelating ligands have been studied using relativistic DFT calculations in conjunction with TZ2P all-electron basis sets. Besides the parent cyclen ligand, the study has covered its extensions with pyridine-type (Lpy), carboxylate (DOTA, DOTPA), picolinate (MeDO2PA) and phosphonate (DOTMP) pendant arms. The effect of the cyclen ring size has been probed by increasing it from [12]aneN4 to [16]aneN4. Additional extensions in the DOTA complexes included the H2O ligand at the 9th coordination site as well as the p-SCN-Bn substituent (a popular linker to the targeting vector). The study focuses on the complex stability, the nature of bonding and the differences between Ac and Bi in the complexes. The metal–ligand interactions have been analysed by the Extended Transition State method combined with Natural Orbitals of Chemical Valence theory and Quantum Theory of Atoms in Molecules models.

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Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes

Abstract: Taken together, these data implicate L(py) as a valuable chelating agent for the delivery of (213)Bi. Its selectivity for Bi(3+) and rapid and stable labeling properties warrant further investigation and biological studies.

Cited by 43 publications

References 81 publications

Synthesis and Characterization of the Actinium Aquo Ion

Synthesis and Characterization of the Actinium Aquo Ion

Ultra-selective ligand-driven separation of strategic actinides

Metal–ligand interactions in complexes of cyclen-based ligands with Bi and Ac

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