Renal and Systemic pH Imaging by Contrast-Enhanced MRI

描述（由申请人提供）：本提案旨在开发一种对比增强磁共振成像（MRI）方法来成像体内组织的细胞外pH值，特别强调肾脏。肾脏和全身pH值的紊乱可能伴随肾脏疾病，如肾小管酸中毒。组织pH值成像的能力，特别是肾脏pH值，将有助于评估这种疾病的程度和严重程度，也有助于无创地跟踪受影响组织的治疗反应。GdDOTA-4AmP是一种基于钆的MRI造影剂，具有ph依赖的纵向水质子弛豫度。与所有其他基于gd的造影剂一样，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值，需要对其在被成像动物体内的药代动力学进行独立测量。我们提出了一种双重造影剂的pH成像策略，其中GdDOTA-4AmP和pH不敏感的类似物GdDOTP依次间隔1小时注射到动物体内，并在两次注射后动态收集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，基于这两种分子的大小和电荷相似。我们计算了对照小鼠肾脏和周围组织的初步pH值图像，该图像清楚地显示了与收集管对应的酸性pH值区域，而肾脏其他区域的pH值为7.0-7.4。与对照小鼠相比，乙酰唑胺处理小鼠的pH值图像显示，所有肾像元的pH值增加了0.5-1.0个单位，肾外像元的pH值明显降低。本提案的目标是完善使用GdDOTA-4AmP和GdDOTP进行pH成像的双造影剂策略，并表征和最小化pH测量中的误差来源。本建议的具体目的有三个：(i)优化双造影剂技术成像肾脏pH值；（ii）优化双造影剂技术对非肾组织pH值的成像；（iii）设计一种折衷方案，在同一实验中对肾脏和非肾脏组织的pH值进行最佳成像，并将其应用于乙酰唑胺引起的酸中毒小鼠的剂量与pH反应的测量。

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.