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 βML 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.