|Title||Thorium chelators for targeted alpha therapy: Rapid chelation of thorium-226|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Ferrier, MG, Li, Y, Chyan, M-K, Wong, R, LI, LILY, Spreckelmeyer, S, Hamlin, DK, Mastren, T, Fassbender, ME, Orvig, C, D. Wilbur, S|
|Journal||J. Label. Compd. Radiopharm.|
|Keywords||hydroxypyridinonate (HOPO), metal chelates, octadentate, picolinic acid, TAT, thorium-226, thorium-227, undecadentate|
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 (t1/2 = 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 227Th 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, H4octapa 3 (65%) and H4py4pa 6 (87%). No reaction occurred with H4neunpa-p-Bn-NO2 4, and the chelation reaction with another pa ligand H4pypa 5 gave inconsistent yields with a very broad radio-HPLC peak. The ligands spermine-(Me-3,2-HOPO)4 1, H4octapa 3, and H4py4pa 6 had high stability (i.e., 87% of 227Th 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 (t1/2 = 30.57 min) when heated to 80°C for 5 min.