Search

Equilibrium, kinetic (solvent exchange and dissociation of the complex) and relaxometric studies (1H and 17O NMR) have been performed with the [M(II)(c-cdta)]2− complexes (c-cdta = cis-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid, M(II) = Mn(II), Zn(II), Cu(II),Ca(II), Mg(II)) and the physico-chemical data are compared to the isomeric complexes with trans-1,2-cdta (t-cdta) with the aim of searching appropriate ligands for Mn(II) complexation for safe MRI contrast agents. The total basicity (Σ log KiH) of the c-cdta ligand appears to be very similar to that of the trans-derivative under the conditions applied (I = 0.15 M NaCl and 25 °C), but the first two protonation constants notably differ. log K1H is 1.5 log units higher, while the log K2H is 0.8 log units lower than those determined for the trans-derivative. Similar basicity of the ligands results in similar complex stability (log K[Mn(L)] values are 14.19(2) and 14.32), whereas the conditional stabilities near to physiological pH are different (pMn values are 7.82 and 8.68) for the [Mn(c-cdta)]2− and the [Mn(t-cdta)]2− derivatives, respectively. Dissociation kinetic studies revealed that the [Mn(c-cdta)]2− dissociates 250 times faster than the [Mn(t-cdta)]2− complex. The water exchange rate (kex298) of [Mn(c-cdta)]2− is ca. 60% higher than that of [Mn(t-cdta)]2−. The differences can likely be attributed to the different distances between the individual donor atoms, and the arrangement of the donor atoms around the metal ions in the cis- and trans- isomers. Interestingly, the relaxivity values of the Mn(II) complexes are very close (r1p = 3.79 mM−1 s−1 and 3.62 mM−1 s−1; 20 MHz, 25 °C for the cis- and trans-isomers, respectively). DFT calculations were used to gain insight into the different properties of the [Mn(c-cdta)]2− and the [Mn(t-cdta)]2− complexes. The results gained in our studies confirm that the trans-1,2-cyclohexanediamine “building block” displays better features for further ligand development.

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, 1 H 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.

Stability constants of the complexes formed between the natural trihydroxamic acids desferrioxamine B (DFB) and desferricoprogen (DFC) with Nd(III), Gd(III) and Yb(III) ions were determined using pH-potentiometry. The equilibrium in these systems can be described by models containing mononuclear protonated (Ln(HL), Ln(H2L) and Ln(H3L)), deprotonated (LnL) and ternary hydroxo Ln(H-1L) complexes, but for both ligands dinuclear complexes of low stability were also detected. The stability constants for the Ln(HDFB)(+) complexes are 11.95 (Nd(III)), 13.16 (Gd(III)) and 14.67 (Yb(III)), while these values of the Ln(DFC) complexes are considerably higher (14.42 (Nd(III)), 15.14 (Gd(III)) and 16.49 (Yb(III))). The stability constants of the complexes of DFB and DFC are much lower than those of the Ln(L)3 complexes formed with some aromatic hydroxamic acids indicating that the relatively long spacer between the hydroxamic acid moieties in DFB and DFC is unfavorable for Ln(III) complexation. The relaxometric study conducted for the Gd(HDFB)(+) species revealed an interesting pH dependence of the relaxivity associated with a large hydration number (bishydrated complex) and fast water exchange (kex=(29.9±0.4)×10(6)s(-1)), which would be favorable for CA use. However the dissociation of Gd(HDFB)(+) is fairly fast (