Our goal is to quantitatively measure extracellular pH (pHe) in the tumor microenvironment to assess tumor acidosis. These assessments can be used to improve evaluations of solid tumors, to aid in predicting the response to immunotherapy before the treatment is initiated, and to evaluate the early response of tumors to many types of drug treatment. These multiple applications can provide strong impact for studies of mouse tumor models, and eventually for patients who have solid tumors. To meet this goal, we propose to develop PET/MRI contrast agents that can quantitatively measure pHe, and apply these agents during simultaneous PET/MRI studies in mouse models of human cancers. Dynamic changes in the relaxation-based MR image contrast are sensitive to tumor pHe as well as the concentration of the agent in tumor tissue, while the PET image can be used to measure the concentration of the agent in the tumor. Therefore, the PET results can be used to account for the effect of concentration on MR image contrast, which can improve the quantitative measurement of tumor pHe. To overcome the difference in detection sensitivities of PET and MRI, we will co-inject 0.01% “hot” radiolabeled agent and 99.99% “cold” MRI contrast agent. Notably, this approach would fail to image cell receptors or intracellular biomarkers, but is ideally suited to interrogate the extracellular tumor microenvironment. In particular, these agents are designed to have the same pharmacokinetic delivery to the extracellular tumor microenvironment during the first 10 minutes after co- injection, so that the MBq radioactivity measurement with PET can be used to evaluate the M concentration of the MRI contrast agent. Therefore, our development of contrast agents for simultaneous PET/MRI has strong innovation for cancer imaging. Accurate and precise measurements of tumor pHe requires great attention to rigor, especially to address potential inaccuracies and imprecisions with both imaging modalities. Therefore, we have designed a strong research approach with careful attention to rigor. We have assembled a team of strong investigators who have extensive experience in developing “smart” MRI contrast agents and PET tracers, and performing molecular imaging studies with small animal tumor models especially for imaging tumor acidosis. We have recently obtained one of the few commercial PET/MRI systems for small animal imaging world-wide, and MD Anderson has an extensive infrastructure for radiochemistry and small animal imaging, which attests to our strong environment. Our deliverable is a fundamentally new class of contrast agents for molecular imaging with PET/MRI. As a longer term goal, our PET/MRI contrast agents have outstanding potential for clinical translation, which will provide a transformative “game changing technology” for clinical PET/MRI.