Multimodal Vital Fluorochromes for Imaging

描述（由申请人提供）：为了确定移植器官的免疫介导的损伤、心脏或脑中缺血相关损伤的程度以及对癌症化疗的反应，已经采用了不同类型的探针来对细胞死亡进行成像。尽管细胞死亡在不同的病理学中起作用，但目前还没有成像剂满足对该过程进行成像的广泛需求。细胞死亡研究中的关键试剂--活性荧光染料（VF's）结合死细胞而非活细胞。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，我们合成了一种市售VF的修改版本，称为TO-PRO 1，并连接了顺磁性钆离子。由此产生的多模态活体荧光染料（MVF）能够通过MRI在体外和体内检测死细胞。MVF提供了一种广泛的方法来成像细胞死亡的基础上充分理解VF行为。此外，VF在死细胞中的选择性处置可以通过细胞生物学中的常用研究技术（FACS、显微镜）容易地验证。我们将合成具有不同物理和光学性质的MVF，并通过MRI和PET证明它们在人类疾病（缺血，癌症）的不同模型中的实用性。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的工具。 公共卫生相关性：尽管细胞死亡在多种病理中起着关键作用，但目前还没有成像剂满足对该过程进行成像的广泛需求。细胞死亡研究中的关键试剂--活性荧光染料（VF's）结合死细胞而非活细胞。然而，VF缺乏缀合放射性或磁性标记所需的反应基团，并且不能与临床成像方式一起使用。我们最近在荧光染料化学方面的进展允许将成像报告基团连接到VF，并通过不同的成像方式将其用于成像细胞死亡。将开发用于通过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18 F MVF，并且可以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.