The ability to measure proton exchange rates in tissue using MRI would be very useful for quantitative assessment of magnetization transfer properties, both in conventional MT imaging and in the more recent chemical exchange saturation transfer (CEST) approach. CEST is a new MR contrast mechanism that depends on several factors, including the exchange rate of labile protons in the agent in a pH-dependent manner. Two new methods to monitor local exchange rate based on CEST are introduced. The two MRI-compatible approaches to measure exchange are quantifying exchange using saturation time (QUEST) dependence and quantifying exchange using saturation power (QUESP) dependence. These techniques were applied to poly-L-lysine (PLL) and a generation-5 polyamidoamine dendrimer (SPD-5) to measure the pH dependence of amide proton exchange rates in the physiologic range. Data were fit both to an analytical expression and to numerical solutions to the Bloch equations. Results were validated by comparison with exchange rates determined by two established spectroscopic methods. The exchange rates determined using the four methods were pooled for the pH-calibration curve of the agents consisting of contributions from spontaneous (k 0 ) acid catalyzed (k a ), and base catalyzed (k b ) exchange rate constants. These constants were k 0 ‫؍‬ 68.9 Hz, k a ‫؍‬ 1 Chemical exchange saturation transfer (CEST) has recently been proposed as a new imaging contrast mechanism (1) in which the radiofrequency-induced saturation of labile protons in the agent is transferred to water protons. The resulting MRI signal intensity depends on a multitude of parameters, including agent concentration, number of exchangeable protons, proton exchange rate, T 1 , T 2 , saturation time, and saturation efficiency (1-8). Of these, the chemical exchange rate is often the parameter of interest that reflects tissue pH and the molecular environment, such as salt or metal content. During saturation, labile protons of the lowconcentration solute are saturated and exchange multiple times with unsaturated protons of the large water pool, resulting in a fractional reduction of the water line. If this exchange rate and the T 1 of water are sufficiently large, there is an amplification of the MR sensitivity with respect to the agent concentration (1). Recently, we showed that macromolecules with multiple amide groups (2) or imino groups (5) can give a CEST effect within the micromolar range. The exchange rates of these proton types have a strong pH dependence in the physiologic range (9,10) and may be useful as pH reporters. Measurement of these rates would be a powerful means for pH calibration (3,4,11-15), but existing technologies for this, such as the water exchange (WEX) sequence (16) and measurement of linewidths, are spectroscopy (MRS) based. As a consequence, they are time consuming for the lower rates because of the low contrast agent concentration and not suitable for measuring the faster rates at high pH because of signal loss due to line broadening. If such ...

The classic definition of the ischemic penumbra is a hypoperfused region in which metabolism is impaired, but still sufficient to maintain cellular polarization. Perfusion-and diffusion-weighted MRI (PWI, DWI) can identify regions of reduced perfusion and cellular depolarization, respectively, but it often remains unclear whether a PWI-DWI mismatch corresponds to benign oligemia or a true penumbra. We hypothesized that pH-weighted MRI (pHWI) can subdivide the PWI-DWI mismatch into these regions. Twenty-one rats underwent permanent middle cerebral artery occlusion and ischemic evolution over the first 3.5 h post-occlusion was studied using multiparametric MRI. End point was the stroke area defined by T 2 -hyperintensity at 24 h. In the acute phase, areas of reduced pH were always larger than or equal to DWI deficits and smaller than or equal to PWI deficits. Group analysis showed that pHWI deficits during this phase coincided with the resulting infarct area at endpoint. Final infarcts were smaller than PWI deficits (range 65% to 90%, depending on the severity of the occlusion) and much larger than acute DWI deficits. These data suggest that the outer boundary of the hypoperfused area showing a decrease in pH without DWI abnormality may correspond to the outer boundary of the ischemic penumbra, while the hypoperfused region at normal pH may correspond to benign oligemia. These first results show that pHWI can provide information complementary to PWI and DWI in the delineation of ischemic tissue.