Dissociation kinetics of Mn2+ complexes of NOTA and DOTA

Abstract

The kinetics of transmetallation of [Mn(nota)]⁻ and [Mn(dota)]²⁻ was investigated in the presence of Zn²⁺ (5–50-fold excess) at variable pH (3.5–5.6) by ¹H relaxometry. The dissociation is much faster for [Mn(nota)]⁻ than for [Mn(dota)]²⁻ under both experimental and physiologically relevant conditions (t_½ = 74 h and 1037 h for [Mn(nota)]⁻ and [Mn(dota)]²⁻, respectively, at pH 7.4, c(Zn²⁺) = 10⁻⁵ M, 25 °C). The dissociation of the complexes proceeds mainly via spontaneous ([Mn(nota)]⁻k₀ = (2.6 ± 0.5) × 10⁻⁶s⁻¹; [Mn(dota)]²⁻k₀ = (1.8 ± 0.6) × 10⁻⁷s⁻¹) and proton-assisted pathways ([Mn(nota)]⁻k₁ = (7.8 ± 0.1) × 10⁻¹ M⁻¹s⁻¹; [Mn(dota)]²⁻k₁ = (4.0 ± 0.6) × 10⁻² M⁻¹s⁻¹, k₂ = (1.6 ± 0.1) × 10³M⁻² s⁻¹). The observed suppression of the reaction rates with increasing Zn²⁺ concentration is explained by the formation of a dinuclear Mn²⁺–L–Zn²⁺ complex which is about 20-times more stable for [Mn(dota)]²⁻ than for [Mn(nota)]⁻ (K_MnLZn = 68 and 3.6, respectively), and which dissociates very slowly (k₃ ∼10⁻⁵ M⁻¹s⁻¹). These data provide the first experimental proof that not all Mn²⁺ complexes are kinetically labile. The absence of coordinated water makes both [Mn(nota)]⁻ and [Mn(dota)]²⁻ complexes inefficient for MRI applications. Nevertheless, the higher kinetic inertness of [Mn(dota)]²⁻ indicates a promising direction in designing ligands for Mn²⁺ complexation.