Advancing Chelation Chemistry for Actinium and Other +3 f-Elements, Am, Cm, and la

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.