The capability to determine in vivo pH in a non-invasive manner would represent a major advance in oncology. MRI contrast media are now widely used but the agents currently in clinical use are insensitive to biological information such as changes in ion concentrations, enzyme activity or the presence of specific binding sites. Despite the fact that agents capable of reporting pH have been known for a number of years, none have gone beyond a few small animal imaging studies. The most significant problem faced when designing a system to measure pH in vivo by MRI is that the concentration of the contrast agent must be known in order to generate a pH map. We propose a simple, convenient solution to this problem in this project. All contrast media that have been developed to report changes in pH exhibit a similar pH profile. The relaxivity, or efficacy of the agent, typically begins low and increases with changes in solution pH. This means that both the """"""""on"""""""" state and the """"""""off"""""""" state will be detected by MRI and, since distribution of the agent in tissue may not be uniform, some tissue regions that contain a higher concentration of agent in its """"""""off"""""""" state may be indistinguishable from other tissue regions that contain a lower concentration of agent in its """"""""on"""""""" state. This means that a """"""""concentration marker"""""""" is required to get absolute pH values;this would be an agent that would allow the concentration of the pH responsive agent to be mapped without affecting its ability to report variations in pH. This project aims to take advantage of the ideal pH reporting characteristics of GdNP- DO3A and GdDOTA-4AmP5-, simple low molecular weight pH sensitive agents, recently reported by our group. The goal of the present research is to add a concentration marker component to this system to provide a single injectable agent that will yield an image map of extra-cellular pH of tissue in a single imaging study. We propose to link the two complexes to a dysprosium complex that will increase the magnetic susceptibility of the system, shortening T2* of the sample equally at all pH values. We plan to use this susceptibility effect of dysprosium to generate a T2* map of tissue which may be used to calculate concentration maps of the tissue. This will ultimately provide a method by which tissue pH can be determined in a single imaging study.
