This proposal seeks to develop methods for the non-invasive measurement of extracellular pH in the brain with high spatial and temporal resolution. MRI can be used to obtain information about tissue function by acquiring data that are sensitive to endogenous tissue properties that modify the MRI signal. Such approaches include diffusion MRI or BOLD-weighted fMRI. In addition to intrinsic tissue MR properties, contrast agents can yield functional information about blood flow and tissue perfusion. Typical gadolinium (Gd)-based contrast agents modify the signal intensity primarily by increasing T1, T2 and T2* relaxation rates in a concentration-dependent manner. Recently, chemically modified Gd-chelating agents have been developed such that relaxivity is affected by the concentration of free ions such as H +. One such agent under development is Gd-DOTA-4AmP, which contains four protecting phosphonate moieties. This agent has a pH sensitive relaxivity that changes monotonically between pH 6 and 8.5. In preliminary work, this probe has been used to measure the extracellular/interstitial pH (pHo) of tumors and kidney. The current proposal seeks to use this agent to monitor the pHe in brain. If successful, such methods can be applied to basic studies of cerebral metabolism and physiology, as well as an important adjunct to functional magnetic resonance imaging (fMRI) investigations. Gadolinium chelates are not taken up in the extracellular space of normal brain from blood because of the blood brain barrier. However, it is possible to circumvent this limitation by direct infusion of contrast agent into the lateral ventricles. Preliminary studies using this route of injection have shown that Gd chelates can be non-toxic and that they can homogeneously distribute throughout the brain parenchyma. They are cleared from brain with time constants of several hours. Hence, contrast agents can be maintained at stable levels in brain for extended periods. The goal of the present study is to develop an MR method for mapping brain extracellular pH with high spatial and temporal resolution that takes advantage of the long life-time of the intraventricularly infused pH reporting compound, GdDOTA-4AmP. This work will be pursued in three specific aims: 1) to optimize agent delivery, 2) to estimate errors at different fields by propagation, and 3) to test the response of this agent to known perturbations of brain pHo.
