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

用于定量、无创高分辨率 pH Mappig 的双 PET-MR 探针

• 批准号: 7886843
• 负责人: Peter D Caravan
• 金额: $ 24.31万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886843
• 关键词: Acidosis; Biodistribution; Biological Markers; Contrast Media; Data; Dependence; Devices; Diagnosis; Disease; Drug Kinetics; Electrodes; Environmental Risk Factor; Fluorine; Gadolinium; Hand; Heart Diseases; Image; Ions; Ischemia; Isotopes; Kidney Diseases; Label; Limb structure; Link; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Maps; Measurement; Measures; Metabolism; Methods; Modeling; Molecular; Monitor; Muscle; Myocardial Ischemia; Oryctolagus cuniculus; Patient Monitoring; Patients; Physiologic pulse; Positron; Positron-Emission Tomography; Problem Solving; Property; Protons; Radiolabeled; Rattus; Reperfusion Therapy; Reporting; Resolution; Signal Transduction; Stroke; Temperature; Testing; Time; Tissues; Water; disease diagnosis; enzyme activity; extracellular; imaging probe; in vivo; new technology; public health relevance; radiochemical; radiotracer; response; sensor; tool

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.

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 值可能是识别疾病和监测治疗反应的非常有用的生物标志物，但常规评估体内 pH 值仍然是一个挑战。测量 pH 值的方法要么是侵入性的，要么灵敏度低，例如磁共振（MR）波谱。 MR 成像探针通过与水分子的相互作用来间接检测，并且 MR 信号取决于探针的浓度和探针的分子特性（称为弛豫率）。对于某些 MR 探头，如果 pH 值发生变化，弛豫度也会发生变化。原则上，这种响应式探针可以充当非侵入式 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）可以定量估计探针浓度。我们假设将 PET 同位素纳入响应 MR 探针并使用同步 PET-MR 成像将能够确定探针浓度和弛豫率，从而提供 pH 的定量图。我们将把发射正电子的氟 18 标记结合到已建立的 pH 响应 MR 探针 GdDOTA-4AMP 中。使用新型 PET-MRI 组合设备，我们将同时测量导致 pH 值下降的肌肉缺血模型中的 MR 和 PET 信号。 PET 数据将被建模以确定探针的组织​​浓度作为时间的函数。该浓度数据将用于从 MR 信号中提取时间和空间相关的弛豫数据，并使我们能够生成定量 pH 值图。使用 PET-MR 识别低 pH 值的组织可能会影响患者的诊断，并提供一种工具来监测患者对治疗的反应。除了 pH 值之外，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。迄今为止，这些响应性 MR 探针由于无法将 MR 信号分解为弛豫度和体内钆浓度而受到限制。双 PET-MR 探头可以解决这个问题。这里描述的体内概念验证研究可以为酶活性、离子通量和代谢物浓度的无创定量成像开辟多种可能性。公共健康相关性：低 pH 值（酸中毒）与癌症、中风和心脏病等多种疾病有关，但很难对患者进行无创测量。我们正在开发一种新的成像测试，可以测量 pH 值，并且可能有助于诊断疾病或监测患者对治疗的反应。