NMR Studies of the Lanthanide(III) Complexes of 1,4,7,10-Tetraazacyclododecane-l,4,7,10-tetrakis(methanephosphonic acid mono(2',2',2'-trifluoroethyl) ester)

A new macrocyclic ligand 1,4.7.10,-tetraazacyclododecane-1.4,7,10-telrakis(methanephosphonic acid mono(2′,2′,2′trifluoroethyl) ester) (F-DOTPME) has been prepared and some of its metal binding properties examined. The ligand protonation constants (log K₁ = 10.5. log K₂ = 6.7) and its stability constant with Ca^II (log KCL = 8.4) were determined by pH potentiometry. The stability of the La complex could not be determined by potentiometry so it was evaluated in an EDTA competition experiment using ³¹P NMR to monitor the reaction. The dissociation kinetics of La(F-DOTPME)^- was slow, with a K of only 1.0 × 10^-7 s^-1 A series of Ln(F-DOTPME)^- complexes (Ln^III = La, Gd, Dy, Tm, and Yb) were examined by multinuclear NMR. The spectra show that these complexes exist in aqueous solution as a mixture of stereoisomers of nearly equal energy (energy differences of less than 1 kJ/mol). Several resolved ¹⁹F resonances in the NMR spectra of the Dy(F-DOTPME)-, Tm(F-DOTPMEF, and Yb(F-DOTPME)" complexes have been assigned to specific diastereomers by comparing resonance integrals, assuming an interaction model between neighboring pendant arms, and the magnitude and direction of the hyperfme |l!F NMR shifts induced by the paramagnetic lanthanide cation. Cationic detergents added to two different Ln(F-DOTPME)" complexes altered the distribution of isomers in favor of the symmetrical A-SSSS isomer, while neutral polyethylene glycol affected the |l'F chemical shifts of some isomers without altering their populations. Gd(F-DOTPME)^- displayed a water proton relaxivity (R₁) of 2.5 mM^- s^-1 at 25 °C and 40 MHz, typical of complexes lacking an inner-sphere-coordinated water molecule. ¹⁷O NMR was used to confirm that Dy(F-DOTPME)^- does not have an inner-sphere-coordinated water molecule. Addition of human serum albumin to aqueous solutions of Gd(F-DOTPME)^- produced a 4-fold increase in water relaxivity, and an analysis of binding curves indicated the fluorinated complex binds to HSA with a binding constant of about 0.17 mM.