Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for ²³⁰U Targeted α-Therapy

Abstract

Uranium-230 is an α-emitting radionuclide with favorable properties for use in targeted α-therapy (TAT), a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To successfully implement this radionuclide for TAT, a bifunctional chelator that can stably bind uranium in vivo is required. To address this need, we investigated the acyclic ligands H 2 dedpa, H 2 CHXdedpa, H 2 hox, and H 2 CHXhox as uranium chelators. The stability constants of these ligands with UO 2 2+ were measured via spectrophotometric titrations, revealing log β ML values that are greater than 18 and 26 for the "pa" and "hox" chelators, respectively, signifying that the resulting complexes are exceedingly stable. In addition, the UO 2 2+ complexes were structurally characterized by NMR spectroscopy and X-ray crystallography. Crystallographic studies reveal that all six donor atoms of the four ligands span the equatorial plane of the UO 2 2+ ion, giving rise to coordinatively saturated complexes that exclude solvent molecules. To further understand the enhanced thermodynamic stabilities of the "hox" chelators over the "pa" chelators, density functional theory (DFT) calculations were employed. The use of the quantum theory of atoms in molecules revealed that the extent of covalency between all four ligands and UO 2 2+ was similar. Analysis of the DFT-computed ligand strain energy suggested that this factor was the major driving force for the higher thermodynamic stability of the "hox" ligands. To assess the suitability of these ligands for use with 230 U TAT in vivo, their kinetic stabilities were probed by challenging the UO 2 2+ complexes with the bone model hydroxyapatite (HAP) and human plasma. All four complexes were >95% stable in human plasma for 14 days, whereas in the presence of HAP, only the complexes of H 2 CHXdedpa and H 2 hox remained >80% intact over the same period. As a final validation of the suitability of these ligands for radiotherapy applications, the in vivo biodistribution of their UO 2 2+ complexes was determined in mice in comparison to unchelated [UO 2 (NO 3 ) 2 ]. In contrast to [UO 2 (NO 3 ) 2 ], which displays significant bone uptake, all four ligand complexes do not accumulate in the skeletal system, indicating that they remain stable in vivo. Collectively, these studies suggest that the equatorial-spanning ligands H 2 dedpa, H 2 CHXdedpa, H 2 hox, and H 2 CHXhox are highly promising candidates for use in 230 U TAT.

Rigidified Derivative of the Non-macrocyclic Ligand H4OCTAPA for Stable Lanthanide(III) Complexation

“…The stability constants determined for the Ln 3+ complexes of CHX OCTAPA 4– by different methods (pH-potentiometry and 1 H-relaxometry) are in excellent agreement, being comparable with those reported for the analogues with OCTAPA 4– (Table ). , This indicates that the replacement of the ethylenediamine spacer by a more rigid cyclohexyl group does not have a significant impact on complex stability, as observed recently for uranyl complexes . The stability constants characterizing the Ln 3+ complexes of CHX OCTAPA 4– are similar to those of DO3A 3– , , but remain lower than those reported for the analogous DOTA 4– complexes. , We note that the stability constants determined in 0.1 M KCl and 0.15 M NaCl for the Gd 3+ complex of DTPA 5– are in good agreement, while there is a significant difference in the case of DO3A 3– .…”

Hybrids of 1,4-Quinone with Quinoline Derivatives: Synthesis, Biological Activity, and Molecular Docking with DT-Diaphorase (NQO1)

“…The 8-hydroxyquinoline-2-carbaldehyde 3 and 2-chloroquinolin-8-ol 4 were prepared according to the method described in the literature [ 26 , 42 ].…”

Medicinal inorganic chemistry – challenges, opportunities and guidelines to develop the next generation of radioactive, photoactivated and active site inhibiting metal-based medicines

“…Evidently, while UO 2 2+ coordination chemistry in anhydrous solvents has been subject to long-standing interest in the f-element community, stabilization of chelation in biological media is to date widely lacking yet an attractive emerging challenge with importance for nuclear medicine applications. 4 Another significant challenge for the development of f-elements as radiopharmaceuticals is the lack of available diagnostic congeners. Small ions with PET isotopes, such as Sc 3+ , Y 3+ and Zr 4+ cannot accurately capture the chemical behavior, and as a result, biological properties of the large triand tetravalent f-elements.…”

“…Evidently, while UO 2 2+ coordination chemistry in anhydrous solvents has been subject to long-standing interest in the f-element community, stabilization of chelation in biological media is to date widely lacking yet an attractive emerging challenge with importance for nuclear medicine applications. 4…”