Selectin targeted ultrasound contrast agents for detection of acute coronary synd

描述（由申请人提供）：急性冠状动脉综合征（ACS）占医疗保健费用的增加水平，尽管患者发病率和死亡率仍然相对较高。目前用于评估急性环境中心脏缺血性损伤程度的方法提供了有限的灵敏度和特异性，这导致了缺血性心脏病的治疗不足和过度。 疑似ACS患者。在目前的项目中，我们建议开发一种新的分子显像剂，用于超声心动图显示近期心肌缺血。具体来说，我们的目标是开发一种针对最近缺血的分子标记的超声造影剂。在该项目的第一阶段，我们合成了一种带有选择素结合配体的造影剂，证实了其体外靶向结合活性，并证明了在细胞中的特异性摄取。 心肌缺血性损伤的小鼠模型。在第二阶段，我们建议开发的合成和分析方法，以允许临床规模的生产这种代理商，进行单剂量毒理学研究，在两个物种，表征我们的成像剂在小鼠模型的复杂冠状动脉疾病的行为，并验证成像效果使用临床规模的成像设备在闭胸犬模型。这些目标的成功完成将导致一种分子成像剂，可用于准确和快速地识别近期心肌缺血的患者。

DESCRIPTION (provided by applicant): Acute coronary syndrome (ACS) accounts for an increasing level of healthcare expense, although patient morbidity and mortality remain relatively high. Current methods for assessing the extent of cardiac ischemic injury in an acute setting offer limited sensitivity and specificity, which leads to both under- and over-treatment of patients with suspected ACS. In the current project, we propose to develop a novel molecular imaging agent for visualization of recent myocardial ischemia using echocardiography. Specifically, we aim to develop an ultrasound contrast agent targeted to a molecular marker of recent ischemia. In Phase I of this project, we synthesized a contrast agent bearing a selectin-binding ligand, confirmed its target-binding activity in vitro, and demonstrated specific uptake in a mouse model of myocardial ischemic injury. In Phase II, we propose to develop the synthetic and analytical methodology to allow for clinical-scale manufacture of this agent, perform single-dose toxicology studies in two species, characterize the behavior of our imaging agent in mouse models of complex coronary disease, and validate imaging efficacy using clinical-scale imaging equipment in a closed- chest canine model. Successful completion of these aims will result in a molecular imaging agent that may be used to accurately and rapidly identify patients with recent myocardial ischemia.