Oxyaapa: A Picolinate-Based Ligand with Five Oxygen Donors that Strongly Chelates Lanthanides

Coordination compounds of the lanthanide ions (Ln³⁺) have important applications in medicine due to their photophysical, magnetic, and nuclear properties. To effectively use the Ln³⁺ ions for these applications, chelators that stably bind them in vivo are required to prevent toxic side effects that arise from localization of these ions in off-target tissue. In this study, two new picolinate-containing chelators, a heptadentate ligand OxyMepa and a nonadentate ligand Oxyaapa, were prepared, and their coordination chemistries with Ln³⁺ ions were thoroughly investigated to evaluate their suitability for use in medicine. Protonation constants of these chelators and stability constants for their Ln³⁺ complexes were evaluated. Both ligands exhibit a thermodynamic preference for small Ln³⁺ ions. The log K_LuL = 12.21 and 21.49 for OxyMepa and Oxyaapa, respectively, indicating that the nonadentate Oxyaapa forms complexes of significantly higher stability than the heptadentate OxyMepa. X-ray crystal structures of the Lu³⁺ complexes were obtained, revealing that Oxyaapa saturates the coordination sphere of Lu³⁺, whereas OxyMepa leaves an additional open coordination site for a bound water ligand. Solution structural studies carried out with NMR spectroscopy revealed the presence of two possible conformations for these ligands upon Ln³⁺ binding. Density functional theory (DFT) calculations were applied to probe the geometries and energies of these conformations. Energy differences obtained by DFT are small but consistent with experimental data. The photophysical properties of the Eu³⁺ and Tb³⁺ complexes were characterized, revealing modest photoluminescent quantum yields of <2%. Luminescence lifetime measurements were carried out in H₂O and D₂O, showing that the Eu³⁺ and Tb³⁺ complexes of OxyMepa have two inner-sphere water ligands, whereas the Eu³⁺ and Tb³⁺ complexes of Oxyaapa have zero. Lastly, variable-temperature ¹⁷O NMR spectroscopy was performed for the Gd-OxyMepa complex to determine its water exchange rate constant of k_ex²⁹⁸ = (2.8 ± 0.1) × 10⁶ s^-1. Collectively, this comprehensive characterization of these Ln³⁺ chelators provides valuable insight for their potential use in medicine and garners additional understanding of ligand design strategies.