A europium complex capable of selectively binding zinc (see picture) has been developed as a new paramagnetic chemical exchange saturation transfer (PARACEST) imaging agent for use in magnetic resonance imaging (MRI). A hydroxide group on the bound Zn ion increases the rate of water exchange on the Eu ion.

Smart/intelligent contrast agent candidates for MRI based on Mn­(II) ion are rare, as it usually forms labile complexes with polyaminocarboxylate-type ligands. Here, we report the first example of a Mn­(II) complex that can be activated by changing the pH of its local environment. The PC2A-EA ligand with an ethylamine pendant arm was found to form a thermodynamically stable (log K MnL = 19.01, pMn = 9.27) and kinetically inert complex with Mn­(II) with respect to trans-chelation with a metal ion such as Cu­(II). The [MnH­(PCA2-EA)] complex displays a relatively slow water exchange rate ((4.0 ± 0.2) × 107 s–1), but the pH-dependent coordination of the ethylamine moiety occurs in the pH range of 6–8 (log K MnL H = 6.88), enabling the complex to exhibit pH-sensitive relaxivity in the biologically relevant pH range.

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.