Thorium chelators for targeted alpha therapy: Rapid chelation of thorium-226

One of the main challenges in targeted alpha therapy is assuring delivery of the α-particle dose to the targeted cells. Thus, it is critical to identify ligands for α-emitting radiometals that will form complexes that are very stable, both in vitro and in vivo. In this investigation, thorium-227 (t_1/2 = 18.70 days) chelation of ligands containing hydroxypyridinonate (HOPO) or picolinic acid (pa) moieties and the stability of the resultant complexes were studied. Chelation reactions were followed by reversed-phased HPLC and gamma spectroscopy. Studies revealed that high ²²⁷ Th chelation yields could be obtained within 2.5 h or less with ligands containing four Me-3,2-HOPO moieties, 1 (83%) and 2 (65%), and also with ligands containing pa moieties, H₄ octapa 3 (65%) and H₄ py4pa 6 (87%). No reaction occurred with H₄ neunpa-p-Bn-NO₂ 4, and the chelation reaction with another pa ligand H₄ pypa 5 gave inconsistent yields with a very broad radio-HPLC peak. The ligands spermine-(Me-3,2-HOPO)₄ 1, H₄ octapa 3, and H₄ py4pa 6 had high stability (i.e., 87% of ²²⁷ Th still bound to the ligand) in phosphate-buffered saline at room temperature over a 6-day period. Preliminary studies with ligand 6 demonstrated efficient chelation of thorium-226 (t_1/2 = 30.57 min) when heated to 80°C for 5 min.