Cerenkov Specific Contrast Agents

描述（由申请人提供）：本申请的目的是开发针对切伦科夫成像功能的新型造影剂。切伦科夫光发射发生时，β粒子在放射性衰变过程中发射超过光速的介电介质。切伦科夫发射是多光谱的，在可见波长上是连续的。释放的光子中有很大一部分波长大于600纳米，因此可以使用通常用于小动物的光学成像技术检测切伦科夫辐射。这可以用来增加正电子发射断层扫描（PET）成像的功能，但也可以作为一个独立的成像方式。我们在这里提出了基于选择性带宽猝灭功能的切伦科夫特异性造影剂。功能发色团对选定波段的光子的吸收，在确定的波长范围内衰减发射，并允许使用放射性标记探针测量特定活动。为了证明这一点，我们基于标准pH指标合成了18f标记的pH响应切伦科夫探针原型。从酸性到碱性的转变导致颜色变化，选择性地吸收光子带，减少探测到的切伦科夫辐射。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，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，因为它们是肿瘤生物学中的重要措施，因为有已知的染料和可用的研究来验证我们的方法。在Aim 1中，我们将综合优化pH敏感染料的pKa， max和亲脂性，用于肿瘤pH的体内检测，并在乳酸脱氢酶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，我们将通过优化比例成像的采集参数来提高特异性，并通过设计dota螯合90Y探针将检测到的信号增加20-30倍来提高灵敏度。在Aim 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。利用选择性带宽猝灭调制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。有许多染料在化学或生理刺激下改变其吸收功能，其中许多染料吸收波长适合切伦科夫成像。该平台的成功开发将允许创建广泛的双切伦科夫- pet成像造影剂，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.