Cerenkov Specific Contrast Agents

切伦科夫专用造影剂

• 批准号: 8826118
• 负责人: EDWARD J DELIKATNY
• 金额: $ 34.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826118
• 关键词: 90Y; Address; Alkalinization; Animals; Attenuated; Beta Particle; Biodistribution; Biological; Bioluminescence; Breast Cancer Model; Charge; Chemicals; Color; Contrast Media; Detection; Development; Dyes; Electrons; Environment; Glutathione; Goals; Health; Image; Imaging Techniques; Imidazole; In Situ; In Vitro; Label; Lactate Dehydrogenase; Link; Magnetic Resonance Spectroscopy; Measurement; Measures; Metabolism; Methods; Mus; Nature; Oxidation-Reduction; Photons; Physiological; Positioning Attribute; Positron; Positron-Emission Tomography; Property; Radiation; Radioactive; Radiolabeled; Relative (related person); Reporter; Reporting; Sensitivity and Specificity; Series; Signal Transduction; Solubility; Specificity; Stimulus; Structure; Testing; Time; Tissues; Tumor Biology; Vacuum; Water; absorption; base; chelation; chromophore; design; extracellular; imaging modality; imaging platform; improved; in vitro testing; in vivo; light emission; lightspeed; lipophilicity; methyl group; molecular imaging; mouse model; neoplastic cell; novel; optical imaging; particle; prototype; radiotracer; ratiometric; response; sensor; tissue phantom; tool; tumor; urinary

DESCRIPTION (provided by applicant): The aim of this application is to develop novel contrast agents functionally specific to Cerenkov imaging. Cerenkov light emission occurs when beta particles emitted during radioactive decay exceed the speed of light in a dielectric medium. Cerenkov emission is multispectral and continuous across the visible wavelengths. A substantial fraction of the photons released are at wavelengths greater than 600 nm and as a result Cerenkov radiation can be detected using optical imaging techniques routinely used in small animals. This could be used to add functional capabilities to positron emission tomography (PET) imaging but can also act as a stand-alone imaging modality. We propose here Cerenkov specific contrast agents that report on function based on selective bandwidth quenching. The absorption of a selected band of photons by a functional chromophore attenuates the emission within a defined wavelength range and allows the measurement of a specific activity using a radiolabeled probe. To demonstrate this we synthesized prototype 18F-labeled pH-responsive Cerenkov probes based on standard pH indicators. A transition from acidic to basic causes a color change that selectively absorbs a band of photons, reducing detected Cerenkov emission. This selective bandwidth quenching can be achieved intermolecularly or intramolecularly and can be measured in vitro and in vivo. Moreover, ratiometric imaging at different wavelengths can report not only on the function imparted by the dye but also estimate other parameters including the depth of the probe. In this application we will synthesize and test Cerenkov specific contrast agents for detection of pH and redox status in tumors. Although the concept of selective bandwidth quenching is generally applicable, we chose these because they are important measures in tumor biology and because there are known dyes and studies available to validate our methods. In Aim 1 we will synthetically optimize the pKa, ¿max and lipophilicity of the pH sensitive dyes for in vivo detection of tumor pH and test these compounds in a sophisticated murine breast cancer model where lactate dehydrogenase has been silenced. In Aim 2, we will increase specificity by optimizing acquisition parameters for ratiometric imaging and sensitivity by designing DOTA-chelated 90Y probes to increase detected signal by 20-30 fold. In Aim 3, we will extend the overall concept by designing Cerenkov specific contrast agents for the detection of redox status in vitro and in vivo. The modulation of Cerenkov emission using selective bandwidth quenching defines a new imaging platform that can be used for the direct imaging of non-fluorescent chromophores in vivo. There are numerous dyes that functionally alter their absorption in response to chemical or physiological stimuli and many of these absorb at wavelengths appropriate for Cerenkov imaging. The successful development of this platform will allow the creation a wide range for contrast agents for dual Cerenkov-PET imaging to comprehensively describe tumor environment, metabolism and treatment.

描述（由申请人提供）：本申请的目的是开发在放射性衰变过程中发射的β粒子超过介电介质中的光速时发生切伦科夫成像的新型造影剂，并且切伦科夫发射是多光谱的。所释放的光子的大部分波长大于 600 nm，因此可以使用通常用于小动物的光学成像技术来检测切伦科夫辐射。用于为正电子发射断层扫描 (PET) 成像添加功能，但也可以作为独立的成像模式，我们在此提出基于选择性带宽淬灭的功能报告。通过功能性发色团减弱特定波长范围内的发射，并允许使用放射性标记探针测量特定活性。为了证明这一点，我们合成了 18F 标记的 pH 响应原型。基于标准 pH 指示剂的切伦科夫探针。从酸性到碱性的转变会导致颜色变化，从而选择性地吸收光子带，从而减少检测到的切伦科夫发射。这种选择性带宽猝灭可以在分子间或分子内实现，并且可以在体外和体内进行测量。此外，不同波长的比率成像不仅可以报告染料赋予的功能，还可以估计其他参数，包括探针的深度。在本应用中，我们将合成和测试切伦科夫特定造影剂。尽管选择性带宽猝灭的概念普遍适用，但我们选择这些是因为它们是肿瘤生物学中的重要措施，并且因为有已知的染料和研究可用于验证我们的方法。将综合优化 pKa, ¿用于体内检测肿瘤 pH 值的 pH 敏感染料的最大值和亲脂性，并在乳酸脱氢酶已被沉默的复杂小鼠乳腺癌模型中测试这些化合物。在目标 2 中，我们将通过优化比率成像和灵敏度的采集参数来提高特异性。通过设计 DOTA 螯合 90Y 探针将检测到的信号增加 20-30 倍 在目标 3 中，我们将通过设计用于检测的 Cerenkov 特异性造影剂来扩展总体概念。使用选择性带宽猝灭调节切伦科夫发射定义了一种新的成像平台，可用于体内非荧光发色团的直接成像有许多染料可以在功能上改变其响应吸收。该平台的成功开发将允许创建多种用于双切伦科夫-PET 成像的造影剂，以全面描述肿瘤环境、代谢和功能。治疗。