Dual PET-MR Probes for Quantitative, Noninvasive High Resolution pH Mappig

描述（由申请人提供）：细胞外pH值降低与癌症和缺血性疾病（如中风、缺血性心脏病和肾病）相关。pH值可能是一种非常有用的生物标志物，用于识别疾病和监测对治疗的反应，但常规评估体内pH值仍然是一个挑战。用于测量pH的方法是侵入性的或具有低灵敏度，例如磁共振（MR）光谱法。MR成像探针通过其与水分子的相互作用间接检测，并且MR信号取决于探针的浓度和称为弛豫率的探针的分子性质。对于某些MR探针，如果pH改变，弛豫率可以改变。原则上，这种响应探针可以充当非侵入性pH传感器。然而，由于组织中的MR信号变化取决于弛豫率和探针浓度（两个未知数），这严重限制了这种响应探针的实用性。另一方面，正电子发射断层扫描（PET）可以定量地估计探针浓度。我们假设，将PET同位素纳入到一个响应的MR探头，并同时使用PET-MR成像将使探针浓度和弛豫率的测定，从而提供了一个定量的pH值的地图。我们将纳入一个正电子发射氟-18标签到建立的pH响应MR探头GdDOTA-4AMP。使用一种新的组合PET-MRI设备，我们将同时测量MR和PET信号在肌肉缺血模型，导致pH值降低。PET数据将被建模，以确定组织浓度的探头作为时间的函数。该浓度数据将用于从MR信号中提取时间和空间依赖性弛豫率数据，并使我们能够生成定量pH图。使用PET-MR识别低pH组织可能会影响患者诊断，并提供一种监测患者对治疗反应的工具。除了pH值，MR探针还可以响应其他环境因素，如温度、酶活性、离子通量或代谢物浓度。到目前为止，这些响应MR探针已经受到限制，无法因素MR信号到弛豫率和钆浓度在体内。双PET-MR探头可以解决这个问题。本文所述的概念研究的体内验证可以为酶活性、离子通量和代谢物浓度的非侵入性定量成像开辟许多可能性。公共卫生相关性：低pH值（酸中毒）与许多疾病有关，如癌症，中风和心脏病，但很难在患者中进行无创测量。我们正在开发一种新的成像测试，可以测量pH值，这可能有助于疾病诊断或监测患者对治疗的反应。

DESCRIPTION (provided by applicant): Decreased extracellular pH is associated with cancer and ischemic diseases such as stroke, ischemic heart disease, and kidney disease. pH could be a very useful biomarker to identify disease and monitor response to therapy, but it remains a challenge to routinely assess pH in vivo. Methods for measuring pH are either invasive or suffer from low sensitivity, e.g. magnetic resonance (MR) spectroscopy. MR imaging probes are detected indirectly via their interaction with water molecules and the MR signal depends on both the concentration of probe and a molecular property of the probe termed relaxivity. For certain MR probes, relaxivity can change if pH changes. In principle, such responsive probes could act as non-invasive pH sensors. However since the MR signal change in tissue depends on both relaxivity and probe concentration (two unknowns), this severely limits the utility of such a responsive probe. On the other hand, positron emission tomography (PET) can quantitatively estimate probe concentration. We hypothesize that incorporation of a PET isotope into a responsive MR probe and using simultaneous PET-MR imaging will enable determination of both probe concentration and relaxivity and thereby provide a quantitative map of pH. We will incorporate a positron emitting fluorine-18 label into the established pH-responsive MR probe GdDOTA-4AMP. Using a new combined PET-MRI device, we will simultaneously measure the MR and PET signals in a model of muscle ischemia that results in decreased pH. The PET data will be modeled to determine tissue concentration of the probe as function of time. This concentration data will be used to extract the time- and spatially dependent relaxivity data from the MR signal and enable us to generate quantitative pH maps. Using PET-MR to identify tissue with low pH may impact patient diagnosis and provide a tool to monitor how the patient responds to treatment. Besides pH, MR probes can be made to be responsive to other environmental factors like temperature, enzymatic activity, ion flux, or metabolite concentrations. To date, these responsive MR probes have been limited by the inability to factor MR signal into relaxivity and gadolinium concentration in vivo. A dual PET-MR probe may solve this problem. The in vivo proof of concept studies described here could open up scores of possibilities for noninvasive quantitative imaging of enzyme activity, ion flux, and metabolite concentrations. PUBLIC HEALTH RELEVANCE: Low pH (acidosis) is linked to a number of diseases such as cancer, stroke, and heart disease, but it is very difficult to noninvasively measure in patients. We are developing a new imaging test that will enable the measurement of pH and which may prove useful in diagnosis of disease or for monitoring how patients are responding to therapy.