Cerenkov Specific Contrast Agents

切伦科夫专用造影剂

基本信息

批准号：
9272896
负责人：
EDWARD J DELIKATNY
金额：
$ 35.3万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272896
关键词：
90Y Address Alkalinization Animals Attenuated Beta Particle Biodistribution Biological Bioluminescence Breast Cancer Model Cells Charge Chelating Agents Chemicals Cherenkov Radiation Color Contrast Media Detection Development Dyes Electrons Environment Glutathione Goals 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 Radioactive Radiolabeled Reporter Reporting Sensitivity and Specificity Series Signal Transduction Solubility Specificity Stimulus Structure Testing Time Tissues Tumor Biology Vacuum Water absorption base chelation cherenkov imaging chromophore design direct application extracellular imaging modality imaging platform improved in vitro testing in vivo in vivo imaging system light emission lightspeed lipophilicity methyl group molecular imaging mouse model multimodality novel optical imaging particle prototype public health relevance ratiometric response sensor tissue phantom tool tumor urinary

项目摘要

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（由应用程序提供）：本应用的目的是开发新颖的对比剂在功能上特定于Cerenkov Imaging。当放射性衰减期间发出的β颗粒超过介电介质中的光速时，就会发生Cerenkov的光发射。 Cerenkov的发射是多光谱的，并且在可见的波长之间是连续的。释放的照片中有很大一部分是在大于600 nm的波长下，因此可以使用通常在小动物中使用的光学成像技术检测Cerenkov辐射。这可以用来为极性发射断层扫描（PET）成像添加功能功能，但也可以充当独立的成像方式。我们在这里提出了Cerenkov特定的对比剂，该对比剂基于选择性带宽淬火报告功能。通过功能性发色团吸收所选照片的吸收会减弱定义的波长范围内的发射，并允许使用放射性标记的探针测量特定活性。为了证明这一点，我们根据标准的pH指标合成了18F标记的pH响应性Cerenkov探针。从酸性到碱性的过渡会导致颜色变化，从而选择性地吸收了一张照片带，从而减少了Cerenkov发射。可以在分子间或分子内进行选择性带宽淬火，并且可以在体外和体内进行测量。此外，在不同波长处的比例计量成像不仅可以报告染料赋予的函数，还可以估算包括探针深度在内的其他参数。在此应用中，我们将合成并测试Cerenkov特异性对比剂，以检测肿瘤中的pH和氧化还原状态。尽管通常适用选择性带宽淬火的概念，但我们之所以选择它们是因为它们是肿瘤生物学的重要措施，并且因为有已知的染料和研究可用于验证我们的方法。在AIM 1中，我们将合成优化pH敏感染料的PKA，最大和亲脂性，以在体内检测肿瘤pH值，并在复杂的鼠类乳腺癌模型中测试这些化合物，在这些模型中，乳酸脱氢酶已被沉默。在AIM 2中，我们将通过设计DOTA固定的90Y问题以将检测到的信号提高20-30倍来优化比率成像和灵敏度的采集参数来提高特异性。在AIM 3中，我们将通过设计Cerenkov特定的对比剂来扩展整体概念，以检测体外和体内氧化还原状态。使用选择性带宽淬火对Cerenkov发射的调制定义了一个新的成像平台，可用于直接对体内非荧光发色团进行直接成像。有许多染料在功能上改变了对化学或物理刺激的响应的吸收，其中许多染料以适合Cerenkov成像的波长吸收。该平台的成功开发将使对比剂的对比代理的范围很广，以全面描述肿瘤环境，代谢和治疗。