Thorium chelators for targeted alpha therapy: Rapid chelation of thorium‐226
Maryline G. Ferrier, Yawen Li, Ming‐Kuan Chyan, Roger Wong, Lily Li, Sarah Spreckelmeyer, Donald K. Hamlin, Tara Mastren, Michael E. Fassbender, Chris Orvig, D. Scott Wilbur
Abstract
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, H 4 octapa 3 (65%) and H 4 py4pa 6 (87%). No reaction occurred with H 4 neunpa‐ p ‐Bn‐NO 2 4 , and the chelation reaction with another pa ligand H 4 pypa 5 gave inconsistent yields with a very broad radio‐HPLC peak. The ligands spermine‐(Me‐3,2‐HOPO) 4 1 , H 4 octapa 3 , and H 4 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.