Methods for Human Brain Metabolic Imaging using Hyperpolarized [2-13C]Pyruvate

Hyperpolarized (HP) 13C magnetic resonance imaging (MRI) has demonstrated the powerful potential for investigating and assessing tissue metabolism and microenvironmental alterations in diseases. Monitoring the distribution and biochemical conversion of injected HP 13C probes has recently enabled first-in-man clinical trials using novel quantitative imaging markers and shown an ability for noninvasive diagnosis and evaluation of many unmet clinical needs including cancer aggressiveness, response to therapy, and also for cardiac, kidney and liver disease. The modality has shown safety and feasibility for in vivo quantitative detection of metabolites in organs including the liver, brain, kidney, prostate and heart. This dissertation focuses on the development and application of the novel HP 13C molecular probe [2-13C]pyruvate, to measure its metabolism for the first time in the brain of healthy human volunteers. MR spectroscopic data acquired from the first HP [2-13C]pyruvate studies of human brain metabolism are presented with kinetic models estimating rates showing similar but not identical inter-subject values, culminating in the first MRI experiments using HP [2-13C]pyruvate with a spectral spatial excitation pulse spotlighting spatial localization of its conversion to [5-13C]glutamate and [2-13C]lactate. Methods for introducing new parameters to improve quantification of HP [2-13C]pyruvate to [5-13C]glutamate using a two-site exchange model, and experimental designs to investigate the effects of unhealthy sleep for early detection of neurodisorders are also presented. The success of these first HP [2-13C]pyruvate studies of human brain metabolism enables the design of further investigations and clinical trials to quantify human disease and disorders in new ways