The development of hyperpolarized magnetic resonance imaging (MRI) agents, i.e., MRI-visible compounds whose magnetization is much higher than that normally achieved at in vivo temperatures, presents both unprecedented opportunities as well as new technical challenges. In particular, with signal-to-noise ratio (SNR) enhancements on the order of the 10,000-fold, dynamic nuclear polarization (DNP) of metabolically active substrates theoretically permits high-resolution in vivo chemical shift imaging (CSI) of both the injected agent and downstream metabolic products, providing a unique method to assess dynamic metabolic processes. Recent studies have demonstrated that both anaerobic and aerobic metabolism can be studied in vivo following the bolus injection of hyperpolarized 13C1-pyruvate, and applications include tumor diagnosis and monitoring, the study of cardiovascular pathologies, and the evaluation of metabolic disorders. Although, reliable, well-validated methods are critical for the successful application of hyperpolarized CSI to the study of in vivo metabolism, optimized data acquisition and analysis tools have yet to be developed. This 4- year technical development project proposes to significantly enhance this new technology through the implementation of high-speed volumetric CSI techniques (Aim 1) in conjunction with robust kinetic modeling algorithms (Aim 2) for the quantitative evaluation of in vivo data. The resulting tools will be optimized for imaging hyperpolarized substrates in animal models with the final acquisition methods and data analysis algorithms evaluated in simulations, phantoms, and in vivo rodent models (Aim 3). Although this proposal is focused on imaging hyperpolarized 13C-pyruvate and its downstream metabolic products, much of the work will be equally applicable to other agents as they are developed. The successful completion of these goals will provide the quantitative tools necessary to allow the direct imaging of metabolism in normal and pathologic conditions, the longitudinal monitoring of disease processes, and the early evaluation of therapeutic interventions. Given the noninvasive nature of the technology, translation of this new metabolic imaging capability from the laboratory to the clinic is anticipated occur within the next 3-5 years, with the first human trial using hyperpolarized pyruvate for the evaluation of prostate cancer scheduled for 2009.
Hyperpolarized magnetic resonance imaging with Dynamic Nuclear Polarization, that enhances signal-to-noise ratio on the order of the 10,000-fold, of injectable metabolically active substrates provides a unique method to assess metabolic processes and presents unprecedented opportunities for in vivo interrogation of normal and disease altered metabolism. It also poses new technical challenges as optimized data acquisition and analysis tools have yet to be developed. The goal of this technical development project is to implement and evaluate a robust set of sensitive techniques for the in vivo imaging of hyperpolarized substrates and their metabolic products.
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