PET Imaging of Thrombus

项目摘要 中风是全球第二大致死原因，而缺血性中风占全世界中风的85%。 美国。卒中治疗的一个关键步骤是对其病因的识别，这具有深远的意义 治疗和预后方面的影响。对于缺血性(栓塞性)中风，确定栓子的来源 允许做出知情的治疗决定，以防止中风复发。尽管识别出 关于中风的病因，大约30%-40%的缺血性中风是“隐源性的”，而中风的来源 血栓栓塞症从未被发现。隐源性卒中的潜在来源包括未检测到的心房 纤颤/心内血栓，主动脉弓的动脉粥样硬化，颈动脉或椎动脉的动脉硬化， 以及跨卵圆孔未闭的深静脉血栓的矛盾栓塞症。当前正在识别 中风的来源涉及多项成像研究，包括经食道超声心动图(TEE)、磁学检查 磁共振成像、计算机断层扫描和双功超声，通常是阴性的。此外，这些 技术依赖于回声物质或充盈缺陷的存在来检测血栓，这不提供 关于血栓的任何生物信息。为了解决这些限制，我们开发了纤维蛋白结合 PET探头64Cu-FBP8。在该奖项的前几个周期中，我们发明了这种探头，并在临床前进行了验证 在动脉、静脉和栓塞性血栓形成的啮齿动物模型中。接下来，我们进行了IND以实现临床前安全性 和制造研究，并从FDA获得IND将64Cu-FBP8转化为临床研究。成象 在健康志愿者中建立了良好的剂量学，快速的肾脏清除，以及低背景信号 头部、颈部、胸部和深静脉。在24例心房颤动患者中，64Cu-FBP8正电子发射计算机体层摄影术100%敏感。 以TEE为金标准，诊断左心耳血栓的特异度为84%。拥有 验证了64Cu-FBP8在稳定的门诊患者中检测LAA血栓的准确性，我们现在寻求 扩大该探头的使用范围，以检测急性住院患者的血栓，特别是 急性中风。本次更新的目的是使用64Cu-FBP8的PET-CT来检测脑缺血的栓子来源。 中风，特别是隐源性中风。64Cu-FBP8的多站PET成像将提供全身 血栓负荷的读数，将使中风发病机制中的重要问题得到解决。在……里面 此外，64CuFBP8的签名将提供血栓年龄的指数，允许这一影响 栓塞症待定。在提案的目标1中，我们将验证64Cu-FBP8的PET-CT检测能力 住院患者的血栓形成。在目标2中，我们将在病因已知的急性中风患者中使用该试剂， 在目标3中，我们将研究患有隐源性中风的对象。这项研究的实施将提供重要的见解 为64Cu-FBP8在卒中防治中的应用奠定了基础。

Project Summary Stroke is the second leading cause of mortality worldwide, and ischemic stroke represents 85% of strokes in the United States. A key step in the management of stroke is the identification of its cause, which has profound therapeutic and prognostic implications. For ischemic (embolic) stroke, identifying the source of the embolus allows informed treatment decisions to be made to prevent recurrent stroke. Despite the importance of identifying the etiology of stroke, some 30-40% of ischemic strokes are “cryptogenic,” where the source of the thromboembolism is never identified. Underlying sources of cryptogenic stroke include undetected atrial fibrillation/intracardiac thrombi, atheroma of the aortic arch, atherosclerosis of the carotid or vertebral arteries, and paradoxical embolism of deep venous thrombosis across a patent foramen ovale. Currently identifying the source of stroke involves multiple imaging studies including transesophageal echocardiography (TEE), magnetic resonance imaging, computed tomography and duplex ultrasound, and is frequently negative. In addition, these techniques rely of the presence of echogenic material or filling defects to detect thrombus, which provides no biological information at all on the thrombus. To address these limitations we have developed the fibrin-binding PET probe 64Cu-FBP8. In the previous cycles of this award, we invented this probe and validated it preclinically in rodent models of arterial, venous, and embolic thrombosis. We next performed IND enabling preclinical safety and manufacturing studies, and obtained an IND from FDA to translate 64Cu-FBP8 to clinical research. Imaging in healthy volunteers established favorable dosimetry, rapid renal clearance, and low background signal in the head, neck, thorax, and deep veins. In 24 patients with atrial fibrillation, 64Cu-FBP8 PET was 100% sensitive and 84% specific for the detection of left atrial appendage (LAA) thrombus, using TEE as the gold standard. Having validated the accuracy of 64Cu-FBP8 for the detection of LAA thrombus in stable outpatients, we now seek to expand the use of the probe to detect thrombus in acutely ill hospitalized patients and, specifically, patients with acute stroke. The aim of this renewal is to use PET-CT of 64Cu-FBP8 to detect the source of embolus in ischemic stroke and in particular cryptogenic stroke. Multi-station PET imaging of 64Cu-FBP8 will provide a whole-body readout of thrombus burden and will allow important questions in stroke pathogenesis to be addressed. In addition, the signature from 64Cu-FBP8 will provide an index of thrombus age, allowing the impact of this on embolism to be determined. In aim 1 of the proposal we will validate the ability of PET-CT of 64Cu-FBP8 to detect thrombus in hospitalized patients. In aim 2 we will use the agent in subjects with acute stroke of known origin, and in aim 3 we will study subjects with cryptogenic stroke. Execution of the study will provide important insights and lay the foundation for the use of 64Cu-FBP8 in the prevention and management of stroke.