A Novel Method for Glutamate Imaging

描述(申请人提供)：谷氨酸既是一种重要的代谢中间产物，也是大脑中主要的兴奋性神经递质，它的变化被认为在许多中枢神经系统(CNS)疾病中起着关键作用。谷氨酸的神经传递已经成为治疗几种神经精神疾病的药物开发的越来越多的靶点，这突显了开发新的非侵入性工具来研究整个人类大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(1HMRS)。正电子发射计算机断层扫描的主要局限性是辐射暴露，放射性配体的半衰期短，以及它们在动态研究中的应用有限。而1H MRS目前是 测量人体皮质谷氨酸浓度的金标准，其主要局限性是空间分辨率低，采集时间长，无法对病理条件下大脑谷氨酸的空间变化进行高分辨率成像。这项建议的主要目的是进一步优化最近发展的谷氨酸成像方法(GluCEST)，以绘制疾病条件下谷氨酸变化的空间变异。具体地说，我们将通过对已知模体的实验来开发和优化GluCEST技术，并评估GluCEST在生理条件下的浓度和pH依赖性。这种方法将被优化用于活体测量，并被用于研究与这种代谢物的异常相关的疾病中检测大脑谷氨酸调制的潜力。这将通过研究帕金森氏病(PD)和戊二酸I型(GA-I)的动物模型来实现，该模型涉及以空间依赖的方式快速和广泛的大脑谷氨酸变化。最后，在健康人体研究中测量谷氨酸的区域差异的方法将得到优化。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、非侵入性和非放射性的方法来测量体内谷氨酸在整个大脑中的分布。该方法具有在灵敏度方面比1H MRS高至少两个数量级的固有能力。此外，GluCEST还有可能提供以下信息 PH值的变化与病理条件有关。一旦在疾病介导的谷氨酸快速变化的动物模型和健康的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，为人类研究一系列神经精神疾病铺平道路。

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.