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

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 H₂dedpa, H₂CHXdedpa, H₂hox, and H₂CHXhox as uranium chelators. The stability constants of these ligands with UO₂²⁺ 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 UO₂²⁺ 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 UO₂²⁺ 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 UO₂²⁺ 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 ²³⁰U TAT in vivo, their kinetic stabilities were probed by challenging the UO₂²⁺ 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 H₂CHXdedpa and H₂hox 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 UO₂²⁺ complexes was determined in mice in comparison to unchelated [UO₂(NO₃)₂]. In contrast to [UO₂(NO₃)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 H₂dedpa, H₂CHXdedpa, H₂hox, and H₂CHXhox are highly promising candidates for use in ²³⁰U TAT.