TR&D3: Novel Imaging Agents & Physiological Modeling for Quantitative PET/MR

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ABSTRACT PET and MRI offer complementary views of physiology. The ability to measure data from both modalities concurrently has many advantages; in addition to perfect registration, it offers the possibility of studying biological mechanisms in ways that were heretofore impossible to realize in intact animals, including human subjects. PET and MRI are based upon different physical principles and generally reflect different in vivo phenomena, so the availability of multimodal hardware and data acquisition raises new opportunities and challenges for probe development, image analysis and interpretation. Our approach to PET/MR is therefore to develop methods that exploit the complementary information from PET and MRI, including the creation of new radiotracers, acquisition protocols, and analysis techniques where appropriate. In the previous funding cycle, our pharmacokinetic modeling and radiochemistry efforts resulted in the development of imaging methods and radiotracers for PET/MR enabling non-invasive measurement of neuroreceptor signaling with PET/fMRI, mitochondrial membrane potential in cardiac studies with a voltage-sensitive tracer and extracellular volume by T1 mapping, radiolabeled nitroxide radicals for imaging oxidative stress, and development of radiolabeled nanoparticles. Our recent findings and collaborations motivated methods for improved quantification of tau burden as well as mapping cellular membrane potential and demyelination as new directions. In the renewal application, we will build on progress made during the first funding cycle and advance our technologies to their next stages of development. Specifically, we propose to develop PET/MR imaging methods and radiotracers for measuring cellular membrane potential in the myocardium and mitochondrial membrane potential outside the heart, demyelination in the brain, and immune function throughout the body. Together these novel imaging technologies span diverse organ systems, physiological processes, and potential disease applications that will be pursued in detail through interactions with numerous Collaborative and Service Projects.