Dynamic Metabolic Imaging of Hyperpolarized Substrates

描述（由申请人提供）：超极化磁共振成像（MRI）试剂的开发，即MRI可见化合物，其磁化强度远高于体内温度下的正常磁化强度，既带来了前所未有的机遇，也带来了新的技术挑战。特别是，由于代谢活性底物的信噪比（SNR）提高了10,000倍，理论上，动态核极化（DNP）允许注射剂和下游代谢产物的高分辨率体内化学位移成像（CSI），为评估动态代谢过程提供了一种独特的方法。最近的研究表明，在体内注射超极化13c1 -丙酮酸后，可以研究无氧和有氧代谢，其应用包括肿瘤诊断和监测、心血管病理研究和代谢紊乱的评估。虽然可靠且经过验证的方法对于成功地将超极化CSI应用于体内代谢研究至关重要，但优化的数据采集和分析工具尚未开发出来。这项为期4年的技术开发项目建议通过实施高速体积CSI技术（Aim 1）以及用于体内数据定量评估的稳健动力学建模算法（Aim 2）来显著增强这项新技术。所得到的工具将被优化，用于在动物模型中成像超偏振底物，并在模拟、幻影和活体啮齿动物模型中评估最终的采集方法和数据分析算法（目标3）。虽然本研究的重点是超极化13c -丙酮酸及其下游代谢产物的成像，但大部分工作同样适用于其他药物的开发。这些目标的成功完成将提供必要的定量工具，以便在正常和病理条件下直接成像代谢，对疾病过程进行纵向监测，并对治疗干预进行早期评估。鉴于该技术的非侵入性，这种新的代谢成像能力有望在未来3-5年内从实验室转化为临床，第一次使用超极化丙酮酸评估前列腺癌的人体试验计划于2009年进行。

DESCRIPTION (provided by applicant): 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.