Tailoring an efficient computational methodology for studying ligand interactions with heavy radiometals in solution: the case of radium

Abstract

The availability of metallic radioelements, with only short-lived isotopes, at trace quantities, does not allow simple, straightforward evaluation of their chemical properties, although they represent societal issues of primary importance (environmental contamination, uses in nuclear medicine, etc.). A strategy is presented to establish a cost-effective computational methodology that is radiometal-specific and accurate to supplement the limited experimental data with a focus on complexation properties. With radium as application, the most suitable DFT methods have been selected by comparison with structures and interaction energies determined by state-of-the-art calculations. Scarce Ra²⁺ complexation constants are available, but combined through isodesmic-like reactions (e.g. transmetallation), they allow for error cancellation mechanisms. Then, a radiometal-specific cavity is fitted in an implicit solvent model to reproduce solvation effects. The equilibrium constants can finally be calculated accurately, i.e. with a precision of 1 logarithmic unit, provided that the relativistic spin–orbit interaction is taken into account. The relevance of this methodology is illustrated with macropa, an 18-membered macrocyclic ligand recently considered for developing ²²³Ra radiotherapeutics, highlighting that the design of an innovative chelator by assuming transferability of neighboring element chemistry can only be suboptimal.