ADF reveals the origin of La–F bond stability in new radiotheranostic complexes

Designing stable fluoride complexes for radiopharmaceutical applications remains a major challenge, particularly for lanthanum and actinium systems used in targeted alpha therapy. In a recent Dalton Transactions study, Behe et al. combine synthesis, spectroscopy, crystallography, radiochemistry, and ADF calculations to uncover why some La–F complexes remain intact while others rapidly decompose.

Using ADF 2021, the authors optimized structures with PBE-D3(BJ), ZORA, TZ2P, and COSMO, and calculated solution-phase thermodynamics for competing fluoride, hydroxide, and water coordination. The computed free-energy differences accurately reproduce the experimentally observed stability trend, explaining why the DOTpy ligand forms a water-stable La–F complex while DOTA and macropa do not.

To uncover the electronic origin of this behavior, the authors performed Energy Decomposition Analysis (EDA) together with Voronoi Deformation Density (VDD) charge analysis. The calculations reveal that stronger electrostatic interactions and greater charge transfer stabilize the La–F bond, leading to a practical design rule: neutral, nitrogen-rich ligands maximize fluoride retention in aqueous solution.

These computational insights support the experimental discovery of the first lanthanum–¹⁸F coordination complex and provide a framework for developing future lanthanum/actinium theranostic agents.