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

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 β_mlh) 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.