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损伤、心脏或大脑缺血相关损伤的程度以及对癌症化疗的反应，已使用各种类型的探针对细胞死亡进行成像。尽管细胞死亡在不同的病理过程中发挥了作用，但目前还没有一种显像剂能满足对这一过程进行成像的广泛需求。重要的荧光染料(VF‘s)是细胞死亡研究中的关键试剂，它能结合死亡细胞，但不能结合活细胞。然而，光衰减阻碍了VF作为荧光探针的临床应用，而且它们缺乏连接放射性或磁性标记所需的反应基团。最近，我们合成了一种商业上可用的VF的改良版，称为TO-PRO 1，并连接了一个顺磁性Gd离子。由此产生的多峰生命荧光色素(MVF)能够通过MRI在体外和体内检测死亡细胞。MVF提供了一种基于众所周知的VF行为来成像细胞死亡的广泛方法。此外，VF在死亡细胞中的选择性处置可以很容易地通过细胞生物学的常见研究技术(FACS、显微镜)来验证。我们将合成具有不同物理和光学性质的MVF，并通过磁共振成像和正电子发射计算机断层扫描(PET)展示它们在各种人类疾病(缺血、癌症)模型中的应用。用于MRI细胞死亡成像的Gd MVF和用于PET细胞死亡成像的18F MVF可以成为诊断成像中广泛使用的、高度通用的工具。 与公共健康相关：尽管细胞死亡在不同的病理过程中扮演着关键角色，但目前还没有一种显像剂能够满足对这一过程进行成像的广泛需求。重要的荧光染料(VF‘s)是细胞死亡研究中的关键试剂，它能结合死亡细胞，但不能结合活细胞。然而，VF缺乏结合放射性或磁性标记所需的反应基团，不能用于临床成像。我们在荧光化学方面的最新进展允许将成像报告基团附着到VF上，并通过不同的成像方式将其用于成像细胞死亡。用于MRI细胞死亡成像的Gd MVF和用于PET细胞死亡成像的18F MVF将被开发出来，并将成为广泛使用的、高度通用的诊断成像工具。

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.