Amide proton transfer (APT) imaging employs the chemical exchange saturation transfer (CEST) mechanism to detect mobile endogenous proteins and peptides. It can be used to detect pH reduction during acute ischemia and thus provide complementary information to perfusion-weighted (PWI) and diffusion-weighted (DWI) imaging. However, the APT contrast depends strongly on the choice of imaging parameters, especially the radiofrequency (RF) saturation time and strength, which need to be optimized. In this work it is shown that even though at least three proton pools are present, the description of the APT process during acute ischemia can be greatly simplified by means of a dual two-pool model analysis. With this approach, the experimentally measured RF irradiation power dependence of the effect in the rat brain was well predicted. The results showed an optimal RF strength of 0.75 μT for our particular coil setup, and a maximally obtainable APT ratio difference of 2.9% ± 0.3% between ischemic and normal brain regions. Magn Reson Med 57:405–410, 2007. © 2007 Wiley-Liss, Inc.