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功能上特异于切伦科夫成像的新型造影剂。切伦科夫光发射发生在放射性衰变过程中发射的β粒子超过电介质中的光速时。切伦科夫发射是多光谱的，并且在可见光波长范围内是连续的。释放的光子的相当大一部分是在大于600 nm的波长，因此切伦科夫辐射可以使用常规用于小动物的光学成像技术检测。这可用于为正电子发射断层扫描（PET）成像增加功能，但也可用作独立的成像模式。我们在这里提出切伦科夫特定的造影剂，报告功能的基础上选择性带宽淬灭。通过功能性发色团吸收选定的光子带，衰减了限定波长范围内的发射，并允许使用放射性标记的探针测量比活度。为了证明这一点，我们基于标准pH指示剂合成了原型18F标记的pH响应性切伦科夫探针。从酸性到碱性的转变导致颜色变化，选择性地吸收光子带，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测量。此外，在不同波长下的比率成像不仅可以报告染料赋予的功能，而且还可以估计包括探针深度在内的其他参数。在本申请中，我们将合成和测试切伦科夫特异性造影剂，用于检测肿瘤中的pH和氧化还原状态。虽然选择性带宽猝灭的概念是普遍适用的，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。在目标1中，我们将综合优化用于肿瘤pH的体内检测的pH敏感染料的pKa、最大值和亲脂性，并在乳酸脱氢酶已被沉默的复杂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的采集参数来提高特异性，并通过设计DOTA螯合的90 Y探针来提高灵敏度，以将检测信号提高20-30倍。在目标3中，我们将通过设计用于体外和体内氧化还原状态检测的切伦科夫特异性造影剂来扩展整体概念。使用选择性带宽猝灭的切伦科夫发射的调制定义了一种新的成像平台，其可用于体内非荧光发色团的直接成像。有许多染料响应于化学或生理刺激而在功能上改变其吸收，并且这些染料中的许多在适合于切伦科夫成像的波长处吸收。该平台的成功开发将允许创建用于双Cerenkov-PET成像的广泛造影剂，以全面描述肿瘤环境，代谢和治疗。