Lanthanide(III) Complexes of Novel Mixed Carboxylic‐Phosphorus Acid Derivatives of Diethylenetriamine: A Step towards More Efficient MRI Contrast Agents

Abstract

Three novel phosphorus-containing analogues of H(5)DTPA (DTPA = diethylenetriaminepentaacetate) were synthesised (H6L1, H5L2, H5L3). These compounds have a -CH2-P(O)(OH)-R function (R = OH, Ph, CH2NBn2) attached to the central nitrogen atom of the diethylenetriamine backbone. An NMR study reveals that these ligands bind to lanthanide(III) ions in an octadentate fashion through the three nitrogen atoms, a P-O oxygen atom and four carboxylate oxygen atoms. The complexed ligand occurs in several enantiomeric forms due to the chirality of the central nitrogen atom and the phosphorus atom upon coordination. All lanthanide complexes studied have one coordinated water molecule. The residence times (tau(M)298) of the coordinated water molecules in the gadolinium(III) complexes of H6L1 and H5L2 are 88 and 92 ns, respectively, which are close to the optimum. This is particularly important upon covalent and noncovalent attachment of these Gd(3+) chelates to polymers. The relaxivity of the complexes studied is further enhanced by the presence of at least two water molecules in the second coordination sphere of the Gd(3+) ion, which are probably bound to the phosphonate/phosphinate moiety by hydrogen bonds. The complex [Gd(L3)(H2O)](2-) shows strong binding ability to HSA, and the adduct has a relaxivity comparable to MS-325 (40 s(-1) mM(-1) at 40 MHz, 37 degrees C) even though it has a less favourable tau(M) value (685 ns). Transmetallation experiments with Zn(2+) indicate that the complexes have a kinetic stability that is comparable to-or better than-those of [Gd(dtpa)(H2O)](2-) and [Gd(dtpa-bma)(H2O)].

Study of Thermodynamic and Kinetic Stability of Transition Metal and Lanthanide Complexes of DTPA Analogues with a Phosphorus Acid Pendant Arm

“…As polydentate aminocarboxylic acids can form relatively strong complexes with alkali metal ions, the potentiometric studies were performed using tetramethylammonium chloride (TMAC) as a background electrolyte. Indeed, the determined values of the highest protonation constants are systematically higher than those reported previously, [16] which were obtained by NMR and are lower as a consequence of sodium()-induced deprotonation (Table 2). A similar trend was observed also for H 5 dtpa, where constant log β 1 determined with NaCl as the supporting electrolyte is about one order of magnitude lower (9.45 [22] ) than that measured in TMAC (10.41, [22] Table 2).…”

“…The corresponding lanthanide() complexes of the linear ligands H 6 L 1 and H 5 L 2 (Scheme 1) have been studied by NMR and relaxometry. [16] It was shown, that the water-exchange rate is much higher for the complexes with phosphorus-containing ligands than what was reported for the complexes of H 5 dtpa and its amides. Noticeable acceleration of water exchange was observed also for macrocyclic ligands with one phosphorus-based pendant arm (e.g.…”

“…A similar trend was observed also for H 5 dtpa, where constant log β 1 determined with NaCl as the supporting electrolyte is about one order of magnitude lower (9.45 [22] ) than that measured in TMAC (10.41, [22] Table 2). Accordingly to NMR-assigned sites of protonations [16] and well-known protonation Scheme of H 5 dtpa itself, [23] the first and second protonations take place on the nitrogen atoms of the ligand 6 35.23(8) …”

“…This coordination mode was also proved in the case of these phosphorus-containing ligands. [16] Therefore, protonations of their complexes occurs on non-coordinated oxygen atoms of the coordinated pendant moieties. In the case of the phosphonic ligand, first pK A 's are in range 5.70-6.48, which corresponds to the deprotonation of the coordinated …”

“…by hydrophobic interactions). [16] Here we report on the thermodynamic and kinetic stability studies of the complexes of two linear ligands -phosphonate and phenylphosphinate derivatives H 6 L 1 and Figure 1. Molecular structure of (H 7 L 1 ) + with atom numbering scheme.…”