Mn²⁺ Complexes Containing Sulfonamide Groups with pH-Responsive Relaxivity

Abstract

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 DPASAm3– and HNO2ASAm2–, 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).

Understanding the Effect of the Electron Spin Relaxation on the Relaxivities of Mn(II) Complexes with Triazacyclononane Derivatives

“…The synthesis of the ligand H 3 NO2ASAm was reported in a previous work. 40 Ligand H 2 NO2AM was prepared by alkylation of commercially available NO2A(O t Bu) 2 with 2-chloroacetamide by using acetonitrile as a solvent and K 2 CO 3 as a base. Subsequent hydrolysis of the tert -butyl esters under acidic conditions provided the ligand as the trifluoroacetate salt with 91% overall yield.…”

“…The synthesis of the ligand H 3 NO2ASAm was reported in a previous work . Ligand H 2 NO2AM was prepared by alkylation of commercially available NO2A­(O t Bu) 2 with 2-chloroacetamide by using acetonitrile as a solvent and K 2 CO 3 as a base.…”

“…To this end, we decided to analyze the 1 H nuclear relaxation dispersion (NMRD) profiles of a series of structurally related complexes derived from a tetraazacyclononane (TACN) macrocyclic platform. The complexes investigated include the well-known symmetric [Mn(NOTA)] − complex 39 and three derivatives in which one of the acetate pendant arms is replaced by a charged sulfonamide donor group (H 3 NO2ASAm) 40 or neutral acetamide (H 2 NO2AM) or methylenepyridine (H 2 NO2APy) groups ( Scheme 1 ). Furthermore, we also studied the complex with the propionic acid derivative H 3 NOTPrA, 41 which maintains an identical donor set with respect to H 3 NOTA, but it is expected to modify the metal coordination environment.…”

Bioimaging agents based on redox-active transition metal complexes

“…This proton binding process of sulfonamide group is reversible. 92 Some metal ion-sensitive MRI studies have also been reported. Sherry's group prepared a Mn(II)-based zinc-sensitive MRI CA (41, Fig.…”

Not only manganese, but fruit component effects dictate the efficiency of fruit juice as an oral magnetic resonance imaging contrast agent

“…Fruit juices that are rich in manganese ions fulfill most of the above requirements, and therefore they are conveniently used in magnetic resonance cholangiopancreatography 3–7 . Similar to gadolinium(III), whose complexes with multidentate ligands are used as intravenous MRI contrast agents, manganese(II) is a paramagnetic ion that can increase the longitudinal relaxation rate ( R 1 ) of the neighboring water protons, thus increasing their signal intensity in T1‐weighted MRI images 3,8–10 . This causes a higher contrast between tissues where the paramagnetic ions are absorbed and those where they are not present.…”