Measurement of Interstitial Brain pH by MRI

通过 MRI 测量脑间质 pH 值

• 批准号: 7117678
• 负责人: PAUL SCHORNACK
• 金额: $ 26.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117678
• 关键词: acidity /alkalinity; behavior test; bicarbonates; bioimaging /biomedical imaging; brain mapping; cerebral ventricles; cerebrovascular occlusions; contrast media; electrodes; extracellular; gadolinium; heterocyclic compounds; hypercapnia; injection /infusion; interstitial; laboratory rat; magnetic resonance imaging; method development; neurotoxicology; noninvasive diagnosis; organometallic compounds; psychomotor function

DESCRIPTION (provided by applicant): This proposal seeks to develop methods for the non-invasive measurement of extracellular pH in the brain with high spatial and temporal resolution. MRI can be used to obtain information about tissue function by acquiring data that are sensitive to endogenous tissue properties that modify the MRI signal. Such approaches include diffusion MRI or BOLD-weighted fMRI. In addition to intrinsic tissue MR properties, contrast agents can yield functional information about blood flow and tissue perfusion. Typical gadolinium (Gd)-based contrast agents modify the signal intensity primarily by increasing T1, T2 and T2* relaxation rates in a concentration-dependent manner. Recently, chemically modified Gd-chelating agents have been developed such that relaxivity is affected by the concentration of free ions such as H +. One such agent under development is Gd-DOTA-4AmP, which contains four protecting phosphonate moieties. This agent has a pH sensitive relaxivity that changes monotonically between pH 6 and 8.5. In preliminary work, this probe has been used to measure the extracellular/interstitial pH (pHo) of tumors and kidney. The current proposal seeks to use this agent to monitor the pHe in brain. If successful, such methods can be applied to basic studies of cerebral metabolism and physiology, as well as an important adjunct to functional magnetic resonance imaging (fMRI) investigations. Gadolinium chelates are not taken up in the extracellular space of normal brain from blood because of the blood brain barrier. However, it is possible to circumvent this limitation by direct infusion of contrast agent into the lateral ventricles. Preliminary studies using this route of injection have shown that Gd chelates can be non-toxic and that they can homogeneously distribute throughout the brain parenchyma. They are cleared from brain with time constants of several hours. Hence, contrast agents can be maintained at stable levels in brain for extended periods. The goal of the present study is to develop an MR method for mapping brain extracellular pH with high spatial and temporal resolution that takes advantage of the long life-time of the intraventricularly infused pH reporting compound, GdDOTA-4AmP. This work will be pursued in three specific aims: 1) to optimize agent delivery, 2) to estimate errors at different fields by propagation, and 3) to test the response of this agent to known perturbations of brain pHo.

描述（由申请人提供）： 该建议旨在开发用于以高空间和时间分辨率对大脑中细胞外pH的非侵入性测量方法的方法。 MRI可用于通过获取对修饰MRI信号的内源性组织特性敏感的数据来获取有关组织功能的信息。这种方法包括扩散MRI或大胆加权fMRI。除固有组织MR性质外，对比剂还可以产生有关血流和组织灌注的功能信息。典型的gadolinium（GD）基于造影剂的剂量主要通过以浓度依赖性方式增加T1，T2和T2*弛豫速率来改变信号强度。最近，已经开发出化学修饰的GD螯合剂，以使宽松受到自由离子（例如H +）的浓度的影响。正在开发中的一种这样的药物是GD-DOTA-4AMP，其中包含四个保护膦酸酯部分。该药物具有pH敏感性的敏感性，在pH 6和8.5之间单调地变化。在初步工作中，该探针已用于测量肿瘤和肾脏的细胞外/间质pH（PHO）。当前的提案试图使用该试剂来监测大脑中的PHE。如果成功，则可以将这种方法应用于脑代谢和生理学的基础研究，以及功能磁共振成像（fMRI）研究的重要辅助。由于血脑屏障，在正常脑的细胞外空间中不接受螯合物。但是，可以通过直接输注造影剂到外侧心室来规避这一限制。使用这种注射途径的初步研究表明，GD螯合物可能无毒，并且它们可以均匀地分布在整个脑实质中。它们的时间常数为几个小时，将它们从大脑中清除。因此，造影剂可以长时间保持大脑的稳定水平。本研究的目的是开发一种MR方法，用于用高空间和时间分辨率映射脑外pH值，以利用脑室内注入的pH报告化合物GDDOTA-4AMP的长寿命。这项工作将在三个特定的目的中进行：1）优化代理输送，2）通过传播估算不同领域的错误，3）测试该药物对已知的脑pho扰动的响应。