Synthesis and characterization of DOTA-(amide)₄ derivatives: Equilibrium and kinetic behavior of their lanthanide(III) complexes

Lanthanide complexes of tetraamide derivatives of DOTA are of interest today because of their application as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI). The protonation constants of some simple tetraamide derivatives of DOTA and the stability constants of the complexes formed with some endogenous metal ions, namely Mg²⁺, Ca²⁺, Cu²⁺, Zn²⁺, and lanthanide(III) ions, have been studied. These complexes were found to be considerably less stable than the corresponding [M(DOTA)]^2- complexes, largely due to the lower basicity of the tetraamide ligands. The Mg²⁺ and Ca ²⁺ complexes are well described by formation of only ML species at equilibrium while the Zn²⁺ and Cu²⁺ complexes exhibit one and two additional deprotonation steps above a pH of around 6, respectively. The extra deprotonation that occurs at high pH for the [Zn{DOTA-(amide) ₄}]²⁺ complexes has been assigned to an amide deprotonation by ¹H NMR spectroscopy. The first deprotonation step for the Cu²⁺ complexes was traced to formation of the ternary hydroxo complexes ML(OH) (by UV/Vis spectrophotometry) while the second step corresponds to deprotonation of an amide group to form ML(OH)H_-1-type complexes. The trends in the stability constants of the [Ln{DOTA-(amide) ₄}]³⁺ complexes follow similar trends with respect to ion size as those reported previously for the corresponding [Ln(DOTA)]^- complexes, but again, the stability constants are about 10-11 orders of magnitude lower. A kinetic analysis of complex formation has shown that complexes are directly formed between a Ln³⁺ cation and fully deprotonated L without formation of a protonated intermediate. [Ln{DOTA-(MeAm)₄}]³⁺ complex formation occurs at a rate that is two to three orders of magnitude slower than those of the corresponding [Ln(DOTA)]^- complexes, while the variation in complex formation rates with Ln³⁺ ion size is opposite to that observed for the corresponding [Ln(DOTA)]^- complexes. The Ce³⁺ and Eu ³⁺ complexes of DOTA-(MeAm)₄ are kinetically inert with respect to acid-catalyzed dissociation, which suggests that these complexes may potentially be safe for use in vivo.