Lanthanide Chelates Containing Pyridine Units with Potential Application as Contrast Agents in Magnetic Resonance Imaging

Abstract

A new pyridine‐containing ligand, N,N′‐bis(6‐carboxy‐2‐pyridylmethyl)ethylenediamine‐N,N′‐diacetic acid (H₄L), has been designed for the complexation of lanthanide ions. ¹H and ¹³C NMR studies in D₂O solutions show octadentate binding of the ligand to the Ln^III ions through the nitrogen atoms of two amine groups, the oxygen atoms of four carboxylates, and the two nitrogen atoms of the pyridine rings. Luminescence measurements demonstrate that both Eu^III and Tb^III complexes are nine‐coordinate, whereby a water molecule completes the Ln^III coordination sphere. Ligand L can sensitize both the Eu^III and Tb^III luminescence; however, the quantum yields of the Eu^III‐ and Tb^III‐centered luminescence remain modest. This is explained in terms of energy differences between the singlet and triplet states on the one hand, and between the 0‐phonon transition of the triplet state and the excited metal ion states on the other. The anionic [Ln(L)(H₂O)]⁻ complexes (Ln=La, Pr, and Gd) were also characterized by theoretical calculations both in vacuo and in aqueous solution (PCM model) at the HF level by means of the 3–21G* basis set for the ligand atoms and a 46+4 fⁿ effective core potential for the lanthanides. The structures obtained from these theoretical calculations are in very good agreement with the experimental solution structures, as demonstrated by paramagnetic NMR measurements (lanthanide‐induced shifts and relaxation‐rate enhancements). Data sets obtained from variable‐temperature ¹⁷O NMR at 7.05 T and variable‐temperature ¹H nuclear magnetic relaxation dispersion (NMRD) on the Gd^III complex were fitted simultaneously to give insight into the parameters that govern the water ¹H relaxivity. The water exchange rate (k =5.0×10⁶ s⁻¹) is slightly faster than in [Gd(dota)(H₂O)]⁻ (DOTA=1,4,7,10‐tetrakis(carboxymethyl)‐1,4,7,10‐tetraazacyclododecane). Fast rotation limits the relaxivity under the usual MRI conditions.