Mn²⁺ Complexes Containing Sulfonamide Groups with pH-Responsive Relaxivity

We present two ligands containing a N-ethyl-4-(trifluoromethyl)benzenesulfonamide group attached to either a 6,6'-(azanediylbis(methylene))dipicolinic acid unit (H₃DPASAm) or a 2,2'-(1,4,7-triazonane-1,4-diyl)diacetic acid macrocyclic platform (H₃NO2ASAm). These ligands were designed to provide a pH-dependent relaxivity response upon complexation with Mn²⁺ in aqueous solution. The protonation constants of the ligands and the stability constants of the Mn²⁺ complexes were determined using potentiometric titrations complemented by spectrophotometric experiments. The deprotonations of the sulfonamide groups of the ligands are characterized by protonation constants of log K_i^H = 10.36 and 10.59 for DPASAm^3- and HNO2ASAm^2-, respectively. These values decrease dramatically to log K_i^H = 6.43 and 5.42 in the presence of Mn²⁺, because of the coordination of the negatively charged sulfonamide groups to the metal ion. The higher log K_i^H value in [Mn(DPASAm)]^- is related to the formation of a seven-coordinate complex, while the metal ion in [Mn(NO2ASAm)]^- is six-coordinated. The X-ray crystal structure of Na[Mn(DPASAm)(H₂O)]·2H₂O confirms the formation of a seven-coordinate complex, where the coordination environment is fulfilled by the donor atoms of the two picolinate groups, the amine N atom, the N atom of the sulfonamide group, and a coordinated water molecule. The lower conditional stability of the [Mn(NO2ASAm)]^- complex and the lower protonation constant of the sulfonamide group results in complex dissociation at relatively high pH (<7.0). However, protonation of the sulfonamide group in [Mn(DPASAm)]^- falls into the physiologically relevant pH window and causes a significant increase in relaxivity from r_1p = 3.8 mM^-1 s^-1 at pH 9.0 to r_1p = 8.9 mM^-1 s^-1 at pH 4.0 (10 MHz, 25 °C).