Magnetic Resonance Chemical Exchange Saturation Transfer Imaging of Intracellular pH

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The overall goal of this research program is to develop novel magnetic resonance imaging (MRI) methods to map tissue pH in living organisms. Tissue pH regulates many cellular processes and is tightly controlled under normal conditions. Therefore, pH is a sensitive indicator of cellular dysfunction and distress, particularly when there is insufficient oxygen for normal function. Several methods have been developed recently to map pH in living organisms with high resolution and sensitivity. For example, my laboratory has previously developed a specific type of MRI contrast agent that can be used to generate image contrast that is dependent on tissue pH. We have found that these agents perform pH measurement well in solutions, but do not work as effectively in living organisms because detection sensitivity is reduced. Given this limitation, we have more recently developed a different method to measure tissue pH that uses the same type of MRI contrast but originates from signals found naturally in tissue. This method is effective at measuring pH in-vivo, however there remain a number of challenges to overcome to improve the quality of the measurements to realize the full potential of this technology. We will focus our efforts in three areas designed to improve image quality. First, we will make improvements to the MRI acquisition sequence used to acquire the data, and to the fitting methods used to model and analyze the data. Specifically, the duration of the MRI acquisition used to generate pH contrast is long making the images very sensitive to motion and magnetic field fluctuations during the acquisition.  We will develop a novel approach for the tracking and correction of motion and magnetic field fluctuations during the acquisition. Then we will incorporate our mathematical models of the MRI signal response into the analysis of the data to improve the precision of pH measurements. Second, we will examine a new set of small molecules to determine if they can be detected in the brain using the same contrast mechanism that we use to obtain pH maps. Using existing small molecules that cross easily into the brain could allow us to increase our sensitivity to pH dependent processes. Finally, we will study the dependence of the pH measurement on magnetic field strength and on tissue type. Specifically, we will examine how well our methods work at different magnetic field strengths (9.4 Tesla, 7 Tesla, and 3 Tesla) using MRI scanners that are available at Western. In-vivo high-resolution tissue pH mapping will provide new information about evolving biological processes in living organisms, paving the way for broad applications in medicine and the pharmaceutical industry.