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

Abstract

Mn 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, H relaxometry, UV-vis spectrophotometry and cyclic voltammetry. The physico-chemical characteristics of Mn complexes of these structure isomers do not differ dramatically, however the cis-DO2A platform has better potential for further development. Manganese (Mn) is a promising alternative to gadolinium (Gd) 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 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 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=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 +705mV versus Ag/AgCl, respectively. These values indicate that the Mn ion in these complexes is more stabilized against the oxidation than in [Mn(EDTA)]. The kinetic inertness of the complexes has been studied in transmetallation reactions with Cu or Zn ions. Kinetic measurements indicate that both Mn 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)] (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 complexes as alternatives to Gd-based MRI agents.

A Bisamide Derivative of [Mn(1,4‐DO2A)] – Solution Thermodynamic, Kinetic, and NMR Relaxometric Studies

“…[12] [b] Ref. [13] shift changes over well-defined pH ranges, which are associated with the various protonation steps of the ligand.…”

“…[13] [b] Ref. [12] Notably, the metal complexes of 1,4-DO2AM show significantly lower stabilities compared with those of the corresponding complexes with 1,4-DO2A and 1,7-DO2A (Δlog K ML = 2.5-3.0). The difference with the DO3A or DOTA complexes is even larger.…”

“…[4] Typically, the dissociation of MnDOTA-like complexes is very slow and occurs by proton-assisted pathways, whereas the presence of endogenous metal ions such as Zn 2+ and Cu 2+ has a minor influence on the dissociation rates. [5,12] Although the rates of the metal exchange reactions between [Mn(1,4-DO2A)] and [Mn(1,7-DO2A)] and Zn 2+ and Cu 2+ ions were investigated previously, [2] we studied the kinetic inertness of [Mn(1,4-DO2AM)] by focusing on the metal exchange reactions with high Zn 2+ concentrations (10-40 fold excess) to guarantee pseudo-first-order conditions, see Equation (6). These reactions were followed by relaxometry at 20 MHz and 25°C in the pH range 4.5-6.5.…”

“…By considering all of the possible pathways and the rate of transmetallation of [Mn(1,4- [a] Ref. [12] [b] Ref. [5] DO2AM)] 2+ [Equation (7)], the pseudo-first-order rate constant (k d ) can be expressed by Equation (10).…”

Nyíltláncú és makrociklusos aminokarboxilát ligandumok szintézise és fémkomplexeik vizsgálata: koordinációs kémia az orvosi képalkotás szolgálatában

“…Koordinált vízmolekula csak a cisz-származékban található, amely redoxi szempontból is stabilabb, így a további fejlesztések alapját is ebben a ligandumban láttuk. 39 Ezen információkat az elõzõekben bemutatott szisztematikus vizsgálatok eredményeivel "összefésülve" megterveztük, elõállítottuk és vizsgáltuk az oldalláncok alfa szénatomján metilcsoportot tartalmazó ciszDO2MA, ill. az amidszármazék ciszDO2AM Me2 , és a ciszDO2AM Pip ligandumokat. 40,41 A ciszDO2MA ligandummal kapott eredményeinket a [Mn(ciszDO2A)]-komplexre jellemzõ adatokkal összehasonlítva a ciszDO2MA komplex nagyobb termodinamikai, de kisebb redoxi stabilitását tapasztaltuk.…”