Physico-chemical properties of Mn^II complexes formed with cis- and trans-DO2A: thermodynamic, electrochemical and kinetic studies

Synopsis: Mn^II complexes formed with cis- and trans-DO2A (DO2A = 1,4,7,10-tetraazacyclododecane-1,4 (or 1,7) -diacetic acid) chelators were investigated by pH-potentiometry, ¹H relaxometry, UV-vis spectrophotometry and cyclic voltammetry. The physico-chemical characteristics of Mn^II complexes of these structure isomers do not differ dramatically, however the cis-DO2A platform has better potential for further development. Manganese (Mn^II) is a promising alternative to gadolinium (Gd^III) as a magnetic resonance imaging (MRI) agent. Unlike gadolinium, this biogenic metal might be better tolerated by the body, reducing the risk of toxicity associated with dissociation of the complex. Herein we report detailed equilibrium and kinetic studies performed with Mn^II complexes of 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid (1,4-DO2A or cis-DO2A) and 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (1,7-DO2A or trans-DO2A). The protonation constants of the ligands as well as stability constants of their Mn^II complexes have been determined by pH-potentiometry. The stability constants of [Mn(cis-DO2A)] are slightly higher than those of [Mn(trans-DO2A)] (log K_MnL = 15.68 and 15.22, respectively). Cyclic voltammetric (CV) experiments performed on [Mn(cis-DO2A)] and [Mn(trans-DO2A)] revealed quasireversible systems with a half-wave potential of + 636 and + 705 mV versus Ag/AgCl, respectively. These values indicate that the Mn^II ion in these complexes is more stabilized against the oxidation than in [Mn(EDTA)]^2 −. The kinetic inertness of the complexes has been studied in transmetallation reactions with Cu^II or Zn^II ions. Kinetic measurements indicate that both Mn^II complexes primarily undergo acid catalyzed dissociation and positions of the acetate pendant arms do not influence kinetic inertness. The inertness of these complexes is comparable to that of [Mn(NOTA)]⁻ (NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid) and about twenty times lower than that of [Mn(DOTA)]^2 − (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). In conclusion, [Mn(cis-DO2A)] displays some very interesting features (thermodynamic and redox stability as well as kinetic inertness) which makes this complex a promising platform for the development of more efficient Mn^II complexes as alternatives to Gd-based MRI agents.