Noninvasive MR thermometry using paramagnetic lanthanide complexes of 1,4,7,10-tetraazacyclodoecane-a,a',a",a"'- tetramethyl-1,4 acid (DOTMA super(4-))

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 super(1)H signal suffer from poor thermal resolution. The feasibility of MR thermometry based on the strong temperature dependence of the hyperfine-shifted super(1)H signal from the paramagnetic lanthanide complex thulium-1,4,7,10-tetraazacyclododecane -1,4,7,10-tetraacetate (TmDOTA super(-)) 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 super(4-), 1,4,7,10-tetramethyl 1,4,7,10-tetra azacyclodoecane-1,4,7,10-tetraacetic acetate (DOTMA super(4-)) was evaluated. DOTMA super(4-) complexes have 12 magnetically equivalent methyl protons, which provide an intense and sharper resonance compared to the corresponding DOTA super(-) complexes. Experiments with paramagnetic Pr super(3+), Yb super(3+), Tb super(3+), Dy super(3+), and Tm super(3+) complexes of DOTMA super(4-) showed that the Tm super(3+) 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 super(1)H signal from TmDOTMA super(-) was similar to 60 times more sensitive to temperature than the water super(1)H shift and was insensitive to changes in concentration, pH, [Ca super(2+)], or the presence of other ions and macromolecules. The application of TmDOTMA super(-) for measuring temperature in a subcutaneously implanted tumor model was demonstrated. Lastly, the feasibility of obtaining 3D images from the methyl super(1)H resonance of TmDOTMA super(-) was demonstrated in phantom and live animal experiments. Overall, TmDOTMA super(-) appears to be a promising probe for MR thermometry in vivo.