Multimodal Vital Fluorochromes for Imaging

描述（由申请人提供）：已采用多种类型的探针对细胞死亡进行成像，以确定移植器官的免疫介导的损伤、心脏或大脑中缺血相关损伤的程度以及对癌症化疗的反应。尽管细胞死亡在多种病理学中发挥着重要作用，但目前还没有成像剂能够满足对该过程成像的广泛需求。重要荧光染料 (VF) 是细胞死亡研究中的关键试剂，可结合死亡细胞，但不结合活细胞。然而，光衰减阻碍了 VF 作为荧光探针的临床应用，并且它们缺乏缀合放射性或磁性标记所需的反应基团。最近，我们合成了市售 VF 的改进版本，称为 TO-PRO 1，并附加了顺磁性钆离子。由此产生的多模式活体荧光染料 (MVF) 能够通过 MRI 在体外和体内检测死细胞。 MVF 提供了一种基于充分理解的 VF 行为来成像细胞死亡的广泛方法。此外，VF 在死细胞中的选择性配置可以通过细胞生物学中的常见研究技术（FACS、显微镜）轻松验证。我们将合成具有不同物理和光学特性的 MVF，并通过 MRI 和 PET 展示其在多种人类疾病（缺血、癌症）模型中的效用。设计用于通过 MRI 对细胞死亡进行成像的钆 MVF 和用于通过 PET 对细胞死亡进行成像的 18F MVF 可以成为诊断成像中广泛使用的高度通用工具。 公共健康相关性：尽管细胞死亡在多种病理学中发挥着关键作用，但目前还没有成像剂能够满足对该过程成像的广泛需求。重要荧光染料 (VF) 是细胞死亡研究中的关键试剂，可结合死亡细胞，但不结合活细胞。然而，VF 缺乏结合放射性或磁性标记所需的反应基团，因此不能用于临床成像模式。我们在荧光染料化学方面的最新进展允许将成像报告基团附着到 VF 上，并使用它们通过不同的成像方式对细胞死亡进行成像。将开发设计用于通过 MRI 对细胞死亡进行成像的钆 MVF 和用于通过 PET 对细胞死亡进行成像的 18F MVF，并将成为诊断成像中广泛使用的高度通用工具。

DESCRIPTION (provided by applicant): Diverse types of probes have been employed to image cell death, in order to determine the immune mediated damage of transplanted organs, the extent of ischemia related damage in the heart or brain, and the response to cancer chemotherapy. Despite the role cell death plays in diverse pathologies, there currently is no imaging agent that meets the widespread need to image this process. Vital fluorochromes (VF's), key reagents in cell death research, bind dead but not live cells. However, light attenuation blocks the clinical use of VF's as fluorescent probes, and they lack the reactive groups needed for the conjugation of radioactive or magnetic labels. Recently, we synthesized a modified version of a commercially available VF known as TO-PRO 1 and attached a paramagnetic gadolinium ion. The resulting multimodal vital fluorochrome (MVF) was able to detect dead cells in vitro and in vivo by MRI. MVF's provide a broad approach to imaging cell death based on well-understood VF behavior. In addition the selective disposition of VF's in dead cells can be easily verified by common research techniques in cell biology (FACS, microscopy). We shall synthesize MVF's with different physical and optical properties, and demonstrate their utility in diverse models of human diseases (ischemia, cancer) by MRI and PET. A gadolinium MVF designed for imaging cell death by MRI and an 18F MVF for imaging cell death by PET can become widely used, highly general tools in diagnostic imaging. PUBLIC HEALTH RELEVANCE: Despite the key role cell death plays in diverse pathologies, there currently is no imaging agent that meets the widespread need to image this process. Vital fluorochromes (VF's), key reagents in cell death research, bind dead but not live cells. However, VF's lack the reactive groups needed for the conjugation of radioactive or magnetic labels and cannot be used with clinical imaging modalities. Our recent advances in fluorochrome chemistry permit the attachment of imaging reporter groups to VF's, and their use for imaging cell death by different imaging modalities. A gadolinium MVF designed for imaging cell death by MRI and an 18F MVF for imaging cell death by PET will be developed and can become widely used, highly general tools in diagnostic imaging.