The pH sensitivity of -NH exchange in LnDOTA-tetraamide complexes varies with amide substituent

The amide proton exchange rates in various lanthanide(III) DOTAtetraamide complexes were investigated by CEST as a function of variable chemical structures and charges on the amide substituents. Comparisons were made between YbDOTA(gly)4- (Yb-1), YbDOTA(NHCH2PO3)45- (Yb-2) and YbDOTA(NHCH2PO3Et2)43+ (Yb-3). The general shapes of the CEST vs pH profiles were similar for the three complexes but they showed maximum CEST intensities at different pH values, pH 8.3, 8.8 and 6.9 for Yb-1, Yb-2 and Yb-3, respectively. This indicates that a more negatively charged substituent on the amide helps stabilize the partial positive charge on the amide nitrogen and consequently more base is required to catalyze proton exchange. The chemical shifts of the NH protons in Yb-1 and Yb-2 were similar (-17?ppm) while the NH proton in Yb-3 was at -13?ppm. This shows that the crystal field produced by the amide oxygen donor atoms in Yb-3 is substantially weaker than that in the other two complexes. In an effort to expand the useful range of pH values that might be measured using these complexes as CEST agents, the shapes of the CEST vs pH curves were also determined for two thulium(III) complexes with much larger hyperfine shifted NH proton resonances. The ratio of CEST from NH exchange in Tm-1 compared with CEST from NH exchange in Tm-3 was found to be linear over an extended pH range, from 6.3 to 7.4. This demonstrates a potential advantage of using mixtures of lanthanide(III) DOTAtetraamides for mapping tissue pH by use of ratiometric CEST imaging. Copyright (C) 2011 John Wiley & Sons, Ltd.