Improving the Stability and Kinetic Inertness of Mn(II) Complexes by Increasing the Bridge Length in Bicyclic CDTA-Like Ligands

Kinetic inertness of Mn(II)-based MRI contrast agents can be improved by increasing the rigidity of the polydentate ligand that tightly coordinate the metal ion. Taking inspiration from the remarkable increase in kinetic inertness of [Mn(CDTA)](2-) compared to [Mn(EDTA)](2-) due to the cyclohexyl backbone rigidity, we devised that bicyclic ligands would further improve the kinetic inertness of the Mn(II) complexes. The length of the alkyl bridge on the cyclohexane ring was varied from methylene (BCH-DTA), ethylene (BCO-DTA) to propylene (BCN-DTA) to evaluate the influence of the different trans-diaminotetraacetate ligands on relaxometric, thermodynamic and kinetic properties of the Mn(II) complexes. H-1 and O-17 NMR relaxometric studies showed a slight increase in relaxivity and a faster water exchange rate in these Mn(II)-complexes with respect to [Mn(CDTA)](2-). Solution studies revealed that the conditional stability (pMn) and dissociation half-life (t(1/2)) at pH 7.4 follow the order [Mn(BCH-DTA)](2-)<[Mn(BCO-DTA)](2-)<[Mn(BCN-DTA)](2-) highlighting the effect of the bridge length on the overall stability of the Mn(II) complexes. Remarkably, [Mn(BCN-DTA)](2-) shows an improved pMn value and a 7-times higher kinetic inertness than [Mn(CDTA)](2-). NMR studies on the Zn(II) analogues confirm the rigidity of the bicyclic complexes with an isomerization process at >313 K for the smaller bridged complex [Zn(BCH-DTA)](2-).