1 research outputs found
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