Renal and Systemic pH Imaging by Contrast-Enhanced MRI

通过对比增强 MRI 进行肾脏和全身 pH 成像

• 批准号: 6561473
• 负责人: NATARAJAN RAGHUNAND
• 金额: $ 15.15万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561473
• 关键词: acidity /alkalinity; bioimaging /biomedical imaging; contrast media; gadolinium; image enhancement; imaging /visualization /scanning; kidney imaging /visualization; laboratory mouse; magnetic resonance imaging; pharmacokinetics; renal tubule acidosis; technology /technique development

DESCRIPTION (provided by applicant): This proposal seeks to develop a contrast-enhanced magnetic resonance imaging (MRI) method for imaging extracellular pH of tissues in vivo, with special emphasis on the kidneys. Perturbations of both renal and systemic pH may accompany diseases of the kidney such as renal tubular acidosis. The ability to image tissue pH, particularly renal pH, would be helpful to assess the extent and severity of such conditions, and also to non-invasively follow response to therapy in the affected tissue(s). GdDOTA-4AmP is a gadolinium-based MRI contrast agent with a pH-dependent longitudinal water-proton relaxivity. As with all other Gd-based contrast agents, the enhancement in water-proton relaxation rate produced by GdDOTA-4AmP is also dependent on its local concentration. In order to measure pH in vivo using GdDOTA-4AmP, one needs an independent measure of its pharmacokinetics in the animal being imaged. We propose a dual-contrast-agent strategy to image pH, in which GdDOTA-4AmP and a pH insensitive analogue, GdDOTP, are sequentially injected into the animal 1 h apart, with T1-weighted MRI images being dynamically collected following both injections. In preliminary experiments in mice we have made the assumption that the pharmacokinetics of GdDOTP and GdDOTA-4AmP are identical in a given animal, based on the similar size and charge of the two molecules. We have calculated preliminary pH images of the kidneys and surrounding tissues which distinctly show regions of acid pH corresponding to the collecting ducts, and pH 7.0-7.4 in other regions of the kidneys, in control mice. pH images of an acetazolamide-treated mouse showed an increase of 0.5-1.0 pH units in all renal pixels, with an apparent decrease of pH in extra-renal pixels, as compared to control mice. The goal of this proposal is to refine this dual-contrast-agent strategy for pH imaging using GdDOTA-4AmP and GdDOTP, and to characterize and minimize sources of error in the pH measurement. The specific aims of this proposal are three-fold: (i) To optimize the dual-contrast-agent technique for imaging renal pH; (ii) To optimize the dual-contrast-agent technique for imaging pH of non-renal tissues; (iii) To devise a compromise protocol for optimally imaging pH of renal and non-renal tissues in the same experiment, and apply it to measure dose vs. pH response in mice with acetazolamide-induced acidosis.

描述（由申请人提供）：本提案旨在开发一种对比度增强磁共振成像（MRI）方法，用于体内组织的细胞外pH成像，特别强调肾脏。肾脏和全身pH值的扰动可能伴随肾脏疾病，如肾小管酸中毒。对组织pH（特别是肾pH）成像的能力将有助于评估这种状况的程度和严重性，并且还有助于非侵入性地跟踪受影响组织中对治疗的响应。 GdDOTA-4AmP是一种钆基MRI造影剂，具有pH依赖性纵向水质子弛豫率。与所有其他Gd基造影剂一样，GdDOTA-4AmP产生的水-质子弛豫速率的增强也取决于其局部浓度。为了使用GdDOTA-4AmP测量体内pH，需要独立测量其在被成像动物中的药代动力学。我们提出了一种双造影剂的策略，图像pH值，其中GdDOTA-4AmP和pH不敏感的类似物，GdDOTP，依次注射到动物1小时间隔，与T1加权MRI图像被动态收集后两次注射。在小鼠的初步实验中，我们假设GdDOTP和GdDOTA-4AmP的药代动力学在给定动物中是相同的，这是基于两种分子的相似大小和电荷。我们已经计算了初步的pH值图像的肾脏和周围组织，清楚地显示区域的酸性pH值对应的集合管，和pH值7.0-7.4在其他地区的肾脏，在对照组小鼠。乙酰唑胺处理小鼠的pH图像显示，与对照小鼠相比，所有肾脏像素的pH值增加0.5-1.0个单位，肾外像素的pH值明显降低。 本提案的目标是使用GdDOTA-4AmP和GdDOTP完善pH成像的双造影剂策略，并表征pH测量中的误差来源并将其最小化。该提案的具体目标有三个方面：（i）优化双造影剂技术用于肾脏pH成像;（ii）优化双造影剂技术用于非肾脏组织pH成像;（iii）设计一种折衷方案，用于在同一实验中对肾脏和非肾脏组织的pH进行最佳成像，并将其应用于测量乙酰唑胺诱导的酸中毒小鼠的剂量与pH反应。