Macrocyclic 1,2-Hydroxypyridinone-Based Chelators as Potential Ligands for Thorium-227 and Zirconium-89 Radiopharmaceuticals

Thorium-227 (227Th) is an α-emitting radionuclide that has shown preclinical and clinical promise for use in targeted α-therapy (TAT), a type of molecular radiopharmaceutical treatment that harnesses high energy α particles to eradicate cancerous lesions. Despite these initial successes, there still exists a need for bifunctional chelators that can stably bind thorium in vivo. Toward this goal, we have prepared two macrocyclic chelators bearing 1,2-hydroxypyridinone groups. Both chelators can be synthesized in less than six steps from readily available starting materials, which is an advantage over currently available platforms. The complex formation constants (log βmlh) of these ligands with Zr4+ and Th4+, measured by spectrophotometric titrations, are greater than 34 for both chelators, indicating the formation of exceedingly stable complexes. Radiolabeling studies were performed to show that these ligands can bind [227Th]Th4+ at concentrations as low as 10–6 M, and serum stability experiments demonstrate the high kinetic stability of the formed complexes under biological conditions. Identical experiments with zirconium-89 (89Zr), a positron-emitting radioisotope used for positron emission tomography (PET) imaging, demonstrate that these chelators can also effectively bind Zr4+ with high thermodynamic and kinetic stability. Collectively, the data reported herein highlight the suitability of these ligands for use in 89Zr/227Th paired radioimmunotheranostics

Uranium(IV) Chloride Complexes: UCl₆^2– and an Unprecedented U(H₂O)₄Cl₄ Structural Unit

The room temperature synthesis and structural characterization of two U­(IV) compounds isolated from acidic aqueous solution is reported. Evaporation of a U­(IV)/HCl solution containing pyridinium (HPy) yielded (HPy)₂UCl₆ (<b>1</b>), yet in the presence of an organic carboxylate U­(H₂O)₄Cl₄­·(HPy·Cl)₂ (<b>2</b>) is obtained. The structures have been determined by single crystal X-ray diffraction and characterized by Raman, IR, and optical spectroscopies. The magnetism of both compounds was also investigated. The structure of <b>1</b> is built from UCl₆^2– anionic units, pervasive in descriptions of the aqueous chemistry of tetravalent uranium, and is found to undergo a phase transition from <i>C</i>2/<i>m</i> to <i>P</i>1̅ upon cooling. By comparison, the structure of <b>2</b> contains a neutral U­(IV)-aquo-chloro complex, U­(H₂O)₄Cl₄, for which there is no literature precedence. Density functional theory calculations were performed to predict the geometries, vibrational frequencies, and relative energetics of the UCl₆^2– and U­(H₂O)₄Cl₄ units. The energetics of the reaction of U­(H₂O)₄Cl₄ to form the dianion are predicted to be exothermic in the gas phase and in aqueous solution. The predicted energetics coupled with no previous solid state reports of a U­(IV)-aquo-chloro complex may point toward the importance of hydrogen bonding and other supramolecular interactions, prevalent in the structures of <b>1</b> and <b>2</b>, on the stabilization and/or crystallization of the U­(H₂O)₄Cl₄ structural unit

Solution and Solid State Structural Chemistry of Th(IV) and U(IV) 4‑Hydroxybenzoates

Organic ligands with carboxylate functionalities have been shown to affect the solubility, speciation, and overall chemical behavior of tetravalent metal ions. While many reports have focused on actinide complexation by relatively simple monocarboxylates such as amino acids, in this work we examined Th­(IV) and U­(IV) complexation by 4-hydroxybenzoic acid in water with the aim of understanding the impact that the organic backbone has on the solution and solid state structural chemistry of thorium­(IV) and uranium­(IV) complexes. Two compounds of the general formula [An₆O₄(OH)₄(H₂O)₆(4-HB)₁₂]·<i>n</i>H₂O [An = Th (<b>Th-1</b>) and U (<b>U-1</b>); 4-HB = 4-hydroxybenzoate] were synthesized via room-temperature reactions of AnCl₄ and 4-hydroxybenzoic acid in water. Solid state structures were determined by single-crystal X-ray diffraction, and the compounds were further characterized by Raman, infrared, and optical spectroscopies and thermogravimetry. The magnetism of <b>U-1</b> was also examined. The structures of the Th and U compounds are isomorphous and are built from ligand-decorated oxo/hydroxo-bridged hexanuclear units. The relationship between the building units observed in the solid state structure of <b>U-1</b> and those that exist in solution prior to crystallization as well as upon dissolution of <b>U-1</b> in nonaqueous solvents was investigated using small-angle X-ray scattering, ultraviolet–visible optical spectroscopy, and dynamic light scattering. The evolution of U solution speciation as a function of reaction time and temperature was examined. Such effects as well as the impact of the ligand on the formation and evolution of hexanuclear U­(IV) clusters to UO₂ nanoparticles compared to prior reported monocarboxylate ligand systems are discussed. Unlike prior reported syntheses of Th and U­(IV) hexamers where the pH was adjusted to ∼2 and 3, respectively, to drive hydrolysis, hexamer formation with the HB ligand appears to be promoted only by the ligand