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

Dalton Transactions Pub Date: 2009-04-22 DOI: 10.1039/B823402G

Abstract

A novel bis-hydroxymethyl-substituted DTTA chelatorN′-Bz-C4,4′-(CH2OH)2-DTTA (1) and its DTPA analogue C4,4′-(CH2OH)2-DTPA (2) were synthesized and characterized. A variable-temperature 1H NMR spectroscopy study of the solution dynamics of their diamagnetic (La) and paramagnetic (Sm, Eu) Ln3+ complexes showed them to be rigid when compared with analogous Ln3+-DTTA and Ln3+-DTPA complexes, as a result of their C4,4′-(CH2OH)2 ligand backbone substitution. The parameters that govern the water1H relaxivity of the [Gd(1)(H2O)2]? and [Gd(2)(H2O)]2? complexes were obtained by 17O and 1H 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 1H 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 153Sm3+-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.

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