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

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 (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.

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

“…A comparative study of chelating agents containing HOPO or picolinic acid (pa) moieties was recently reported for possible complexation of 226 Th. Chelation properties of octadentate HOPO ligands were confirmed and octadentate or undecadentate pa ligands appeared as potential chelators for thorium by demonstrating high radiolabeling yields and interesting stability of the corresponding complexes [ 293 ].…”

Fusion-Based Neutron Generator Production of Tc-99m and Tc-101: A Prospective Avenue to Technetium Theranostics

“…A few such examples of these are 226 Th (t 1/2 = 30.57 min), which decays by multiple successive alpha emissions to long-lived 210 Pb [82], and the beta-minus emitter 214 Pb (t 1/2 = 27.06 min) and its succession of beta and alpha emitting daughter isotopes [83]. For both radionuclides, integration of the parent isotope, i.e., 230 U (t 1/2 = 20.23 d) for 226 Th and 222 Rn (t 1/2 = 3.82 d) for 214 Pb, into a generator form is a key feature that makes dispensation, tagging, and administering of the end drug possible despite the shorter than usual half-lives [84].…”

Hydroxypyridinones as a Very Promising Platform for Targeted Diagnostic and Therapeutic Radiopharmaceuticals

“…They found that these chelators could retain high chelation yields with thorium-227 within 2.5 h or less. The thorium complexes possess high stability in phosphate-buffered saline at ambient condition over a 6-dayperiod [143].…”