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 CaII (log K CaL = 8.4) were determined by pH potentiometry. The stability of the LaIII 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 d,obs of only 1.0 × 10-7 s-1. A series of Ln(F-DOTPME)- complexes (LnIII = 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-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 19F 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 19F 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. 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.