Cerenkov Specific Contrast Agents

描述(由申请人提供)：本申请的目的是开发切伦科夫成像专用的新型造影剂。当放射性衰变过程中发射的贝塔粒子超过介质介质中的光速时，切伦科夫光发射就会发生。切伦科夫辐射是多光谱的，在可见光波长上是连续的。释放出的大部分光子的波长大于600纳米，因此，可以使用小动物常规使用的光学成像技术来检测切伦科夫辐射。这可以用来增加正电子发射断层扫描(PET)成像的功能，但也可以作为一种独立的成像方式。我们在这里提出了切伦科夫特定的造影剂，这种造影剂基于选择性带宽猝灭来报告功能。功能性发色团对选定波段的光子的吸收在规定的波长范围内衰减发射，并允许使用放射性标记的探测器测量特定的活度。为了证明这一点，我们合成了基于标准pH指示剂的18F标记的pH响应型切伦科夫探针的原型。从酸性到碱性的转变会导致颜色变化，选择性地吸收一条光子带，从而减少检测到的切伦科夫发射。这种选择性的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，不同波长的比率成像不仅可以报告染料赋予的功能，还可以估计包括探头深度在内的其他参数。在这项应用中，我们将合成并测试切伦科夫特定的造影剂，用于检测肿瘤的pH值和氧化还原状态。虽然选择性带宽猝灭的概念是普遍适用的，但我们之所以选择这些方法，是因为它们是肿瘤生物学中的重要测量方法，而且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体内检测肿瘤pH的pH敏感染料的pKa、�max和亲脂性，并在乳酸脱氢酶已被沉默的复杂的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的采集参数来提高特异性，并通过设计DOTA螯合的90Y探针来提高灵敏度，使检测信号增加20-30倍。在目标3中，我们将通过设计切伦科夫特定的对比剂来扩展整体概念，用于在体外和体内检测氧化还原状态。利用选择性带宽猝灭对切伦科夫发射的调制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。有许多染料会因化学或生理刺激而在功能上改变其吸收，其中许多染料的吸收波长适合切伦科夫成像。这一平台的成功开发将为双切伦科夫-PET成像创造更广泛的造影剂，以全面描述肿瘤环境、代谢和治疗。

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.