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: 6751949
• 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 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751949
• 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(申请人提供)：这项提案寻求开发一种对比度增强磁共振成像(MRI)方法，用于成像体内组织的细胞外pH，特别强调肾脏。肾脏和全身pH值的紊乱可能伴随着肾脏疾病，如肾小管性酸中毒。成像组织pH值的能力，特别是肾脏的pH值，将有助于评估这种情况的程度和严重性，也有助于对受影响组织的治疗进行非侵入性跟踪(S)。GdDOTA-4AmP是一种基于GdDOTA-4AmP的磁共振造影剂，具有依赖于pH的纵向水质子弛豫特性。与所有其他基于Gd的造影剂一样，GdDOTA-4AmP对水质子弛豫速率的增强也依赖于其局部浓度。为了使用GdDOTA-4AmP测量体内的pH，需要对其在被成像动物体内的药代动力学进行独立的测量。我们提出了一种双对比剂成像策略，将GdDOTA-4AmP和pH不敏感的类似物GdDOTP顺序注射到动物体内，间隔1h，并在两次注射后动态采集T1加权MRI图像。在小鼠的初步实验中，我们假设GdDOTP和GdDOTA-4AmP在给定的动物体内的药代动力学是相同的，这是基于这两个分子的相似的大小和电荷。我们已经计算了对照组小鼠肾脏和周围组织的初步pH图像，这些图像清楚地显示了与收集管相对应的酸性pH区域，以及肾脏其他区域的pH 7.0-7.4。用乙酰唑胺处理的小鼠的pH图像显示，与对照组相比，所有肾脏像素的pH单位增加了0.5-1.0个单位，而肾外像素的pH明显降低。这项建议的目标是完善使用GdDOTA-4AmP和GdDOTP进行pH成像的双造影剂策略，并表征和减少pH测量中的误差来源。这项建议的具体目标有三个：(I)优化肾脏pH成像的双造影剂技术；(Ii)优化非肾组织pH成像的双造影剂技术；(Iii)设计一种折衷方案，以在同一实验中最佳地成像肾和非肾组织的pH，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。