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

Thorium-227 (Th-227) is an & alpha;-emittingradionuclidethat has shown preclinical and clinical promise for use in targeted & alpha;-therapy (TAT), a type of molecular radiopharmaceutical treatmentthat harnesses high energy & alpha; particles to eradicate cancerouslesions. Despite these initial successes, there still exists a needfor bifunctional chelators that can stably bind thorium in vivo. Towardthis goal, we have prepared two macrocyclic chelators bearing 1,2-hydroxypyridinonegroups.Both chelators can be synthesized in less than six steps from readilyavailable starting materials, which is an advantage over currentlyavailable platforms. The complex formation constants (log & beta;(mlh)) of these ligands with Zr4+ and Th4+, measured by spectrophotometric titrations, are greater than 34for both chelators, indicating the formation of exceedingly stablecomplexes. Radiolabeling studies were performed to show that theseligands can bind [Th-227]Th4+ at concentrationsas low as 10(-6) M, and serum stability experimentsdemonstrate the high kinetic stability of the formed complexes underbiological conditions. Identical experiments with zirconium-89 (Zr-89), a positron-emitting radioisotope used for positron emissiontomography (PET) imaging, demonstrate that these chelators can alsoeffectively bind Zr4+ with high thermodynamic and kineticstability. Collectively, the data reported herein highlight the suitabilityof these ligands for use in Zr-89/Th-227 pairedradioimmunotheranostics. Design, synthesis,characterization, and evaluation of newmacrocyclic hydroxypyridinone ligands for rapid, stable radiolabelingof tetravalent thorium and zirconium isotopes, with promising applicationto molecular imaging and therapy.

Automated summary

This study identified two macrocyclic chelators with high stability that can effectively bind thorium and zirconium, offering promising applications in molecular imaging and therapy.