Lanthanide chelates of (bis)-hydroxymethyl-substituted DTTA with potential application as contrast agents in magnetic resonance imaging

A novel bis-hydroxymethyl-substituted DTTA chelator N'-Bz-C-4,C-4'-(CH2OH)(2)-DTTA (1) and its DTPA analogue C-4,C-4'-(CH2OH)(2)-DTPA (2) were synthesized and characterized. A variable-temperature H-1 NMR spectroscopy study of the solution dynamics of their diamagnetic (La) and paramagnetic (Sm, Eu) Ln(3+) complexes showed them to be rigid when compared with analogous Ln(3+)-DTTA and Ln(3+)-DTPA complexes, as a result of their C-4,C-4'-(CH2OH)(2) ligand backbone substitution. The parameters that govern the water H-1 relaxivity of the [Gd(1)(H2O)(2)](-) and [Gd(2)(H2O)](2-) complexes were obtained by O-17 and H-1 NMR relaxometry. While the relaxometric behaviour of the [Gd(2)(H2O)](2-) complex is very similar to the parent [Gd(DTPA)(H2O)](2-) system, the [Gd(1)(H2O)(2)](-) complex displays higher relaxivity, due to the presence of two inner sphere water molecules and an accelerated, near optimal water exchange rate. The [Gd(1)(H2O)(2)](-) complex interacts weakly with human serum albumin (HSA), and its fully bound relaxivity is limited by slow water exchange, as monitored by H-1 NMR relaxometry. This complex interacts weakly with phosphate, but does not form ternary complexes with bidentate bicarbonate and L-lactate anions, indicating that the two inner-sphere water molecules of the [Gd(1)(H2O)(2)](-) complex are not located in adjacent positions in the coordination sphere of the Gd3+ ion. The transmetallation reaction rate of [Gd(1)(H2O)(2)](-) with Zn2+ in phosphate buffer solution (pH 7.0) was measured to be similar to that of the backbone unsubstituted [Gd(DTTA-Me)(H2O)(2)](-), but twice faster than for [Gd(DTPA-BMA)(H2O)]. The in vivo biodistribution studies of the Sm-153(3+)-labelled ligand (1) in Wistar rats reveal slow blood elimination and short term fixation in various organs, indicating some dissociation. The bis-hydroxymethyl-substituted DTTA skeleton can be seen as a new lead for the synthesis of high relaxivity contrast agents, although its low thermodynamic and kinetic stability will limit its use to in vitro and animal studies.