Structural, stability and relaxation features of lanthanide-complexes designed for multimodal imaging detection of enzyme activities

Lanthanide complexes of DO3A-derivative ligands bearing a pyridine-carbamate (L1) or pyridine-amine (L2) arm have potential interest in the design of enzymatically activated imaging probes. Solid-state X-ray structures for CeL1 and YbL2 both demonstrate twisted square antiprismatic geometry, with the metal ion in a nine- or an eight-coordinate environment, respectively. As assessed by pH-potentiometry, in solution lanthanide ions form more stable complexes with the nonadentate L1 than with the octadentate L2 ligand (logK(ML)=18.7-21.1 vs. 16.7-18.6, respectively), while stability constants are similar for L1 and L2 chelates of Mg2+, Ca2+, Zn2+ or Cu2+. The kinetic inertness of GdL1 is exceptionally high, with an estimated dissociation half-life of similar to 10(8) h at pH 7.4, while LnL2 (Ln=Ce, Gd, Yb) complexes have 3-4 orders of magnitude faster dissociation, related to the presence of the protonatable, non-coordinating amine function. The water exchange rate determined for the monohydrated GdL2 (k(ex)(298)=1.3x10(6) s(-1)) shows a threefold decrease with respect to GdDOTA, as a consequence of a reduction in the negative charge and in the steric crowding around the water binding site, both important in dissociatively activated water exchange processes.