Noninvasive MR thermometry using paramagnetic lanthanide complexes of 1,4,7,10-tetraazacyclodoecane- α,α′,α′′,α′′′-tetramethyl-1,4,7,10-tetraacetic acid (DOTMA4-)

Noninvasive techniques to monitor temperature have numerous useful biomedical applications. However, MR thermometry techniques based on the chemical shift, relaxation rates, and molecular diffusion rate of the water H-1 signal suffer from poor thermal resolution. The feasibility of MR thermometry based on the strong temperature dependence of the hyperfine-shifted H-1 signal from the paramagnetic lanthanide complex thulium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (TmDOTA(-)) was recently demonstrated. The use of paramagnetic lanthanide complexes for MR thermometry can be further enhanced by improving the signal-to-noise ratio (SNR) of the observed signal. In this study, the use of lanthanide complexes of a methyl-substituted analog of DOTA(4-), 1,4,7,10-tetramethyl 1,4,7,10-tetra azacyclodoecane-1,4,7,10-tetraacetic acetate (DOTMA(4-)) was evaluated. DOTMA(4-) complexes have 12 magnetically equivalent methyl protons, which provide an intense and sharper resonance compared to the corresponding DOTA(-) complexes. Experiments with paramagnetic Pr3+, Yb3+, Tb3+, Dy3+, and Tm3+ complexes of DOTMA(4-) showed that the TM3+ complex is most favorable for MR thermometery because of the high temperature dependence of its chemical shift and its relatively narrow linewidth. The chemical shift of the methyl H-1 signal from TmDOTMA(-) was similar to60 times more sensitive to temperature than the water H-1 shift and was insensitive to changes in concentration, pH, [Ca2+], or the presence of other ions and macromolecules. The application of TmDOTMA- for measuring temperature in a subcutaneously implanted tumor model was demonstrated. Lastly, the feasibility of obtaining 3D images from the methyl H-1 resonance of TmDOTMA(-) was demonstrated in phantom and live animal experiments. Overall, TmDOTMA- appears to be a promising probe for MR thermometry in vivo. (C) 2005 Wiley-Liss, Inc.