pH-dependent modulation of relaxivity and luminescence in macrocyclic gadolinium and europium complexes based on reversible intramolecular sulfonamide ligation

A series of macrocyclic Eu, Gd, and Tb complexes has been prepared in which the intramolecular ligation of a beta-arylsulfonamide nitrogen is rendered pH-dependent, giving rise to changes in the hydration state, q, at the lanthanide center. In complexes based on DO3A, variation of the p-substituent in the arylsulfonamide moiety determines the apparent protonation constant log K(MLH) with values of 5.7, 6.4, and 6.7 for the -CF(3), -Me, and -OMe substituents, respectively. Introduction of three beta-carboxyalkyl substituents, alpha to three ring nitrogens, inhibits displacement of the bound water by added protein and also suppresses intermolecular binding by endogenous anions (lactate, HCO(3)(-)). Measurements of the pH dependence of the form and intensity of the Eu complexes revealed that intramolecular carboxylate coordination occurred competitively. This was reduced either by enhancing the electron density at the sulfonamide nitrogen or by enlarging the chelate ring from 7--8. Amplification of the relaxivity changes in the pH range 8--5 occurred on protein binding, and over the pH range 7.4--6.8 a 48% change in relaxivity was defined for Gd.3a] (298 K, 65.6 MHz) in 50% human serum solution.