Magnetic Resonance Imaging of Paramagnetic Chemical Exchange Saturation Transfer Contrast Agents in Biological Systems

Recently, a novel contrast strategy called paramagnetic chemical exchange saturation transfer (PARACEST) for magnetic resonance imaging has been discovered and applied to the measurement of physiological parameters such as temperature and pH that can provide insight into pathological processes. These agents can also be designed to be sensitive to metabolites and proteins. Until recently, the development of PARACEST agents was limited to in vitro studies. However, in vivo, PARACEST agent detection is complicated by the simultaneous excitation of tissue macromolecules that can significantly reduce PARACEST contrast.;A novel PARACEST agent (Eu3+-DOTAM-Gly-Phe) was shown to have a large CEST effect at physiological temperature and pH at 9.4 Tesla. The strong linear dependence of the chemical shift of the bound water pool on temperature (0.3 ppm/°C) allowed the formation of temperature maps with standard deviations <1°C in aqueous solution and mouse brain tissue.;To investigate how the intrinsic magnetization transfer (MT) effect of macromolecules associated with tissue affects the CEST sensitivity of PARACEST agents, a four-pool model was developed by incorporating the exchange terms into the Bloch equations. It was found that the MT effect no longer diminishes the CEST sensitivity when the chemical shift of the bound protons is beyond the MT range (> 150 ppm). Experimental validation of the model was performed at 9.4 Tesla using Eu3+-DOTAM-Gly-Phe in both aqueous solution and samples containing 10% bovine serum albumin (BSA). The model was then used to measure the agent bound water chemical shift of a sample of cells labeled with Eu3+-DOTAM-Gly-Phe and a phantom containing mouse brain tissue with Eu3+-DOTAM-Gly-Phe. A chemical shift map with standard deviation < 0.7 ppm was obtained in the brain tissue phantom.;Finally, the model was applied to the optimization of acquisition parameters for the on-resonance paramagnetic chemical exchange effects (OPARACHEE), again, in the presence of the macromolecule MT effect. It was found that there is an optimal preparation pulse duration that maximizes the OPARACHEE contrast. This predication was verified by experimental spectroscopic and imaging results from a BSA phantom and a tissue phantom containing Tm3+-DOTAM- Gly-Lys.;The overall goal of this work is to develop PARACEST agents suitable for in vivo temperature mapping, and to model the PARACEST effect incorporating the contribution of endogenous tissue macromolecules. The model was used to determine the optimal acquisition parameters and guide to the development of more effective PARACEST agents.;Overall, the results from this thesis demonstrated that in vivo detection of the PARACEST effect is possible for the current generation of PARACEST agents despite the reduced sensitivity in vivo due to the endogenous macromolecule MT effect. However, in vivo detection requires millimolar concentrations. Future work should focus on the development of PARACEST agents with high sensitivity and large chemical shift (> 150 ppm) to avoid macromolecule MT induced sensitivity loss.;Keywords: Magnetic resonance imaging, CEST, PARACEST, OPARACHEE.