A Novel Method for Glutamate Imaging

描述（由申请人提供）：谷氨酸既是重要的代谢中间体，也是大脑中的主要兴奋性神经递质，其变化被认为在许多中枢神经系统（CNS）疾病中起关键作用。谷氨酸的神经传递已成为治疗几种神经精神疾病的药物开发的目标，这突出了开发新的非侵入性工具来研究整个人脑中谷氨酸浓度的基线和动态波动的重要性。目前用于研究这种代谢物的主要非侵入性方法是正电子发射断层扫描（PET）和质子磁共振波谱（1H MRS）。PET的主要局限性是辐射暴露、放射性配体的半衰期短以及它们对动态研究的有限适用性。虽然1H MRS目前是 作为测量人皮层谷氨酸浓度的金标准，其主要局限性是低空间分辨率和长采集时间，这妨碍了病理条件下脑谷氨酸空间变化的高分辨率成像。该提案的主要目的是进一步优化最近开发的谷氨酸成像方法（GluCEST）在疾病条件下绘制谷氨酸变化的空间变化。具体来说，我们将开发和优化的GluCEST技术通过实验已知的phantomy和评估的浓度和pH值的依赖性GluCEST在生理条件下。该方法将被优化用于体内测量，并用于研究在与该代谢物畸变相关的疾病中检测脑谷氨酸调节的潜力。这将通过研究帕金森病（PD）和I型谷氨酸血症（GA-I）的动物模型来实现，这些模型涉及以空间依赖性方式快速和广泛的脑谷氨酸变化。最后，该方法将被优化用于测量健康人体研究中谷氨酸的区域变化。正如有希望的初步数据所证明的那样，所提出的方法提供了一种非常新颖的，非侵入性的，非放射性的方法来测量谷氨酸在整个大脑中的体内分布。该方法具有内在的能力，优于1H MRS的至少两个数量级的灵敏度。此外，GluCEST有可能提供以下信息： 与病理状况相关的pH值变化。一旦在具有疾病介导的快速谷氨酸变化的动物模型和健康人类上进行优化和验证，这些实验就可以很容易地转化为临床环境，为处理一系列神经精神疾病的人类研究铺平道路。

DESCRIPTION (provided by applicant): Glutamate is both a significant metabolic intermediate as well as the major excitatory neurotransmitter in the brain and its changes are thought to play a crucial role in many central nervous system (CNS) disorders. Neurotransmission of glutamate has become an increasing target of drug development for the treatment of several neuropsychiatric disorders, which highlights the significance of developing novel noninvasive tools to investigate baseline and dynamic fluctuations in glutamate concentrations throughout the human brain. The major noninvasive approaches that are currently used to study this metabolite are positron emission tomography (PET) and proton Magnetic Resonance Spectroscopy (1H MRS). The primary limitations of PET are radiation exposure, short half-lives of radio ligands, and their limited applicability to dynamic studies. While 1H MRS is presently the gold standard for measuring human cortical glutamate concentration, its main limitations are low spatial resolution and long acquisition times, which preclude high resolution imaging of the spatial variation of brain glutamate under pathological conditions. The major objective of this proposal is to further optimize the recently developed glutamate imaging method (GluCEST) in mapping spatial variation of glutamate changes under disease conditions. Specifically, we will develop and optimize the GluCEST technique via experiments on known phantoms and evaluate the concentration and pH dependence of GluCEST under physiological conditions. This method will be optimized for in vivo measurements and exploited to investigate the potential of detecting brain glutamate modulation in diseases associated with aberrations of this metabolite. This will be accomplished by studying animal models of Parkinson's disease (PD) and glutaric acidemia type I (GA-I), which involve rapid and wide range of brain glutamate changes in a spatially dependent manner. Finally, the methodology will be optimized for measuring regional variation of glutamate in healthy human studies. As demonstrated by the promising preliminary data, the proposed method offers a highly novel, non-invasive, and nonradioactive method of measuring glutamate distribution in vivo throughout the brain. The method has the inherent capacity to outperform 1H MRS by at least two orders of magnitude with respect to sensitivity. In addition, GluCEST has the potential for providing information about pH changes associated with pathological conditions. Once optimized and validated on animal models with disease mediated rapid glutamate changes, and healthy humans, these experiments can be readily translated to the clinical setting paving the way for human studies dealing with an array of neuropsychiatric disorders.