Remarkable differences and similarities between the isomeric Mn(II)- cis - and trans- 1,2-diaminocyclohexane- N , N , N ′, N ′-tetraacetate complexes

Enikő Molnár (1) , Balázs Váradi (1) , Zoltán Garda (1) , Richárd Botár (1) , Ferenc Kálmán (2, 3) , Éva Tóth (2) , Imre Toth (1) , Ernő Brücher (1) , Gyula Tircsó (1)

1 University of Debrecen Egyetem [Debrecen]
2 CBM - Centre de biophysique moléculaire
3 Le Studium Loire Valley Institute for Advanced Studies, 45000 Orléans, France

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. Graphical abstract M(II) complexes formed with c-cdta (cis-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid) chelator have been investigated by pH-potentiometry, UV–vis spectrophotometry, DFT calculations,1H- and 17O-NMR relaxometry. pMn as well as the inertness of the Mn(II) complex formed with c-cdta ligand were found to differ substantially form those found for the trans-derivative while the water exchange rate and the relaxivity do not differ remarkably. Our results confirm, that the t-cdta platform has better potential for further ligand development owing to better dissociation kinetic parameters of its Mn(II) complex.

Mots clés: Magnetic resonance Imaging (MRI); Contrast Agents (CAs); Manganese(II) complexes; Stability; Inertness; Solvent exchange; Relaxivity

Domaines: Chimie

Enikő Molnár, Balázs Váradi, Zoltán Garda, Richárd Botár, Ferenc Kálmán, et al.. Remarkable differences and similarities between the isomeric Mn(II)- cis - and trans- 1,2-diaminocyclohexane- N , N , N ′, N ′-tetraacetate complexes. Inorganica Chimica Acta, 2018, 472, pp.254-263. ⟨hal-02572224⟩