Abstract
A major chemical challenge facing implementation of 225Ac in targeted alpha therapy - an emerging technology that has potential for treatment of disease - is identifying an 225Ac chelator that is compatible with in vivo applications. It is unclear how to tailor a chelator for Ac binding because Ac coordination chemistry is poorly defined. Most Ac chemistry is inferred from radiochemical experiments carried out on microscopic scales. Of the few Ac compounds that have been characterized spectroscopically, success has only been reported for simple inorganic ligands. Toward advancing understanding in Ac chelation chemistry, we have developed a method for characterizing Ac complexes that contain highly complex chelating agents using small quantities (μg) of 227Ac. We successfully characterized the chelation of Ac3+ by DOTP8- using EXAFS, NMR, and DFT techniques. To develop confidence and credibility in the Ac results, comparisons with +3 cations (Am, Cm, and La) that could be handled on the mg scale were carried out. We discovered that all M3+ cations (M = Ac, Am, Cm, La) were completely encapsulated within the binding pocket of the DOTP8- macrocycle. The computational results highlighted the stability of the M(DOTP)5- complexes.
| Original language | English |
|---|---|
| Pages (from-to) | 19404-19414 |
| Number of pages | 11 |
| Journal | Journal of the American Chemical Society |
| Volume | 141 |
| Issue number | 49 |
| DOIs | |
| State | Published - Dec 11 2019 |
Funding
We thank the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, heavy element chemistry program (Am, Cm, La; 2020LANLE372) and LANL’s LDRD-ER (201505575ER, method development), and LDRD-DR (20180005DR, Ac). Postdoctoral support was provided in part by the Glenn T. Seaborg Institute (B.W.S., M.G.F.) and named fellowship programs: Hoffman Distinguished Postdoctoral Fellowship (S.K.C.) and the Agnew National Security Fellowship (S.E.B.). We acknowledge the U.S. Department of Energy, Office of Science, Isotope Development and Production for Research and Application subprogram within Office of Nuclear Physics for providing the 227 Ac and 243 Am isotopes. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). LANL, an affirmative action/equal opportunity employer, is managed by Triad National Security, LLC, for the NNSA of the U.S. Department of Energy (contract 89233218CNA000001).