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.

We have reported here a series of ligands containing pentadentate 6,6'-(azanediylbis(methylene))dipicolinic acid units that differ in the substituent present at the amine nitrogen atom (acetate: HDPAAA; phenyl: HDPAPhA; dodecyl: HDPAC12A; 4-hexylphenyl: HDPAC6PhA). The protonation constants of the hexadentate DPAAA and pentadentate DPAPhA ligands and the stability constants of their Mn complexes were determined using pH-potentiometry (25 °C, 0.15 M NaCl). The mono-hydrated [Mn(DPAAA)] complex (log K = 13.19(5)) was found to be considerably more stable than the bis-hydrated [Mn(DPAPhA)] analogue (log K = 9.55(1)). A detailed H andO NMR relaxometric study was carried out to determine the parameters that govern the proton relaxivities of these complexes. The [Mn(DPAC12A)] complex, which contains a dodecyl lipophilic chain, forms micelles in solution characterized by a critical micellar concentration (cmc) of 96(9) μM. The lipophilic [Mn(DPAC6PhA)] and [Mn(DPAC12A)] derivatives form rather strong adducts with Human Serum Albumin (HSA) with association constants of 7.1 ± 0.1 × 10 and 1.3 ± 0.4 × 10 M, respectively. The X-ray structure of the complex {K(HO)}{[Mn(DPAAA)(HO)]} shows that the Mn ion in [Mn(DPAAA)] is coordinated to the six donor atoms of the ligand, a coordinated water molecule completing the pentagonal bipyramidal coordination environment.

Abstract:A new 1,4-DO2A-bisamide [1, 1,4,7,

We report two novel macrocyclic ligands based on the 1,4-DO2AM platform (1,4-DO2AM = 2,2'-(1,4,7,10-tetraazacyclododecane-1,4-diyl)diacetamide) and containing two benzyl groups attached either to the nitrogen atoms of the macrocyclic unit (1,4-BzDO2AM) or to the amide pendant arms (1,4-DO2AMBz). The protonation constants of the ligands and the stability constants of their Mn complexes were determined using pH potentiometry. The introduction of benzyl groups results in a slight decrease of the stability constants of the Mn complexes and a slight increase of their acid-catalysed dissociation reactions. A detailed relaxometric characterisation of the complexes using nuclear magnetic dispersion relaxation (NMRD) and O NMR studies indicated that the increase in molecular weight associated with the presence of benzyl groups results in a remarkable increase of proton relaxivities r, which take values of 3.8, 3.5 and 2.5 mM s for [Mn(1,4-BzDO2AM)], [Mn(1,4-DO2AMBz)] and [Mn(1,4-DO2AM)] (at 25 °C and 20 MHz). The [Mn(1,4-BzDO2AM)] and [Mn(1,4-DO2AMBz)] complexes form relatively strong adducts with Human Serum Albumin (HSA) with association constants of (3.9 ± 0.6) × 10 and (2.0 ± 0.3) × 10 M, respectively. The interaction with the protein slows down the rotational tumbling of the complex in solution, which results in adducts endowed with remarkably high proton relaxivities (r = 18.5 ± 0.7 and 27.4 ± 1.4 mM s for [Mn(1,4-BzDO2AM)] and [Mn(1,4-DO2AMBz)], respectively).