Noninvasive thermometry is pivotal to the future advances of regional hyperthermia as a treatment modality. Current magnetic resonance (MR) thermometry methods suffer from poor resolution due to relatively weak dependence of chemical shift of the 1H water signal on temperature. The main objective of this research is to develop noninvasive MR thermometry methods for reliable and accurate monitoring and imaging of temperature in tumors using a paramagnetic lanthanide complex. Our preliminary data show that 1H chemical shifts of a prototype lanthanide complex, thulium- 1,4,7,10-tetraazacyclododecane-1 ,4,7,10- tetraacetate (TmDOTA), are about two orders of magnitudes more sensitive to temperature than the water and thus, provide excellent accuracy and resolution. In addition, TmDOTA proton shifts are insensitive to the paramagnetic complex concentration, ph, [Ca2+] or presence of plasma macromolecules and ions. This will greatly simplify the procedures for using the lanthanide complex for MR thermometry because hyperthermia is known to produce changes in tissue pH and other parameters. The main goals of this project are: 1) to investigate the use of methyl substituted analogs of TmDOTK, thulium 1,4,7,1 0-Tetraazacyclodoecane-a,a ,a,""""""""a""""""""-tetramethyl-1 ,4,7, 1 0-tetraacetate (TmDOTMA) for MR thermometry, 2) to develop MR thermometry techniques for reliable, accurate and rapid imaging of temperature using a TmDOTMk complex, 3) to demonstrate feasibility of in vivo monitoring and imaging of temperature during hyperthermia in a mouse tumor model, and 4) to perform a preliminary study on acute effects of hyperthermia on tumor lactate and perfusion. The major advantage of the TmDOTMA is that the proton signals from methyl groups are more intense and sharper compared to the proton signals from TmDOTA. This will greatly help in improving the spatial, temporal and thermal resolution in temperature imaging. TmDOTk and TmDOTMK are expected to be non-toxic because similar complexes of gadolinium are clinically used as MR contrast agents.
