| Abstract
| - The synthesis and the structural properties of the lanthanide(III) complexes of the new heptadentate ligand tpaa are presented. Three types of crystal structures have been found for these complexes along the lanthanide series, which differ in their nuclearity and in coordination number of the metal ion. This flexible heptadentate podate leads to a Gd complex with a relaxivity remarkably higher than those of the currently clinically used contrast agents based on complexes of octacoordinate ligands. A very short metal−water bond distance associated with a water coordination equilibrium (between 10-coordinate tris(aqua) species and 9-coordinate bis(aqua) species) could be at the origin of the high relaxivity of the Gd(tpaa) complex. The rapid water exchange rate can be attributed to a low-energy barrier between 10-, 9-, and 8-coordinate geometries, as indicated by the structural data.
- The tripodal ligand (α,α‘,α‘ ‘nitrilotri(6-methyl-2-pyridinecarboxylic acid)) (H3tpaa) forms a Gd(III) complex whichhas a relaxivity (r1p = 13.3 mM-1 s-1 at 25 °C and at 60 MHz) remarkably higher than those of the currentlyclinically used contrast agents based on octacoordinate polyaminocarboxylate complexes (3.5−4.7 mM-1 s-1)and a reasonably good thermodynamic stability. The crystal structure of the ligand and of its La, Nd, Eu, Gd, Tb,Ho, Tm, Yb, and Lu complexes have been determined by X-ray crystallography. The neutral H3tpaa moleculeadopts, in the solid state, a preorganized tripodal conformation in which the three H3tpaa arms are located on thesame side of the molecule, ready to bind a metal ion in a heptadentate coordination mode. The structures of theLn(III) complexes vary along the series for their nuclearity and number of water molecules coordinated to themetal, and a tetrameric structure is observed for the La3+ ion (9- and 10-coordinate metal centers), dimeric structuresare formed from the Nd3+ ion through the Yb3+ ion (9-coordinate), and a monomeric structure results for Lu3+(8-coordinate). The relaxivity studies presented here suggest that the high relaxivity of the Gd(tpaa) complex ismainly the consequence of a shorter bound water proton−Gd(III) distance associated with a probable watercoordination equilibrium between tris(aqua) and bis(aqua) complexes, giving raise to a mean number of coordinatedwater molecules q> 2. Both effects are strongly related to the ligand flexibility, which allows for a large volumeavailable for water binding. The observed rapid water exchange rate is probably due to the presence of a low-energy barrier between 10-, 9-, and 8- coordinate geometries. Although the low solubility of the Gd complex oftpaa prevents its practical application as an MRI contrast agent, the straightforward introduction of substituentson the pyridine rings allows us to envisage ligands with a higher water solubility, containing functional groupsleading to macromolecular systems with very high relaxivity.
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