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

A new macrocyclic ligand 1,4,7,10,-tetraazacyclododecane-1,4,7,10-tetrakis(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 K 1 = 10.5, log K 2 = 6.7) and its stability constant with Ca II (log K CaL = 8.4) were determined by pH potentiometry. The stability of the La III complex could not be determined by potentiometry so it was evaluated in an EDTA competition experiment using 31 P NMR to monitor the reaction. The dissociation kinetics of La(F-DOTPME) - was slow, with a k d,obs 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 19 F resonances in the NMR spectra of the Dy(F-DOTPME) -, Tm(F-DOTPME) -, 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 hyperfine 19 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 Δ- SSSS isomer, while neutral polyethylene glycol affected the 19 F chemical shifts of some isomers without altering their populations. Gd(F-DOTPME) - displayed a water proton relaxivity ( R 1 ) of 2.5 mM - 1 s - 1 at 25 °C and 40 MHz, typical of complexes lacking an inner-sphere-coordinated water molecule. 17 O 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.