PET Imaging of Thrombus

描述（由申请人提供）：血栓正电子发射断层成像。本提案的目标是开发一种纤维蛋白特异性正电子发射断层扫描（PET）探针，用于血栓的直接成像。血栓与一系列病理有关，如缺血性中风、心肌梗死、肺栓塞和深静脉血栓形成。血栓的存在改变了治疗的决定，影像学被广泛应用于判断是否存在血栓。尽管有不同的成像方法可用，仍然有一个强烈的未满足的医疗需要直接识别血栓。例如，确定缺血性中风栓塞的来源对患者管理至关重要，但目前30- 40%的中风原因不明。这种提议的PET探针可以识别卒中来源，并确定哪些患者将受益于更积极的抗血栓治疗，以预防继发性卒中。在美国，中风是第三大死亡原因，也是发病率的主要原因。根据美国中风协会的数据，美国人今年将为中风相关的医疗费用和残疾支付近690亿美元。一种识别继发性卒中风险的成像工具可能会对卒中相关的发病率和死亡率产生积极影响。血栓探针基于一种肽，这种肽与循环纤维蛋白原或其他血浆蛋白结合并具有特异性。纤维蛋白高浓度存在于急性和亚慢性静脉和动脉血栓中，但纤维蛋白不存在于循环血液中。选择性纤维蛋白成像探针有望为血栓鉴定提供高灵敏度和特异性。虽然PET具有分子特异性，但它的空间分辨率低，缺乏解剖标志。混合PET -计算机断层扫描（CT）或PET -磁共振成像（MRI）设备现在可以使分子PET图像与CT或MRI获得的血管解剖图像共同注册。该建议建立在阳性的初步PET- mri血栓成像数据与原型PET探针。在Aim 1中，我们重点合成了一系列氟-18和铜-64标记肽，以优化血栓靶向PET探针的成像特性。在Aim 2中，我们将描述这些新探针对纤维蛋白靶点的亲和力，它们对纤维蛋白的特异性优于其他血浆蛋白，以及它们在血浆或肝脏匀浆存在下的代谢稳定性。在Aim 3中，我们利用PET-CT和PET-MRI探讨了这些探针在大鼠和家兔新鲜和老化血栓模型中的功效。将对优化的探针进行剂量估计，并对最有希望的探针进行急性毒性评估。这项研究的成果将是一种新的血栓成像探针，可能随后被开发用于人类。

DESCRIPTION (provided by applicant): Positron Emission Tomography Imaging of Thrombus. The goal of this proposal is to develop a fibrin-specific positron emission tomography (PET) probe for direct imaging of thrombus. Thrombus is implicated in a range of pathologies, e.g. ischemic stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis. The presence of thrombus changes treatment decisions and imaging is widely used rule in, or out, the presence of thrombus. Despite the different imaging methods available, there is still a strong unmet medical need for direct identification of thrombus. For instance, identification of the source of the embolus in ischemic stroke is critical to patient management, but currently 30- 40% of strokes are of unknown origin. This proposed PET probe may enable identification of stroke source and identify patients who would benefit from more aggressive antithrombotic therapy to prevent secondary stroke. Stroke is the third leading cause of death and the leading cause of morbidity in the US. According to the American Stroke Association, Americans will pay almost $69 billion dollars this year in stroke related medical costs and disability. An imaging tool to identify those at risk for secondary stroke may be expected to positively impact morbidity and mortality associated with stroke. The thrombus probe is based on a peptide that binds to and has specificity for fibrin over circulating fibrinogen or other plasma proteins. Fibrin is present in acute and sub-chronic venous and arterial thrombi in high concentrations, but fibrin is not present in circulating blood. A selective fibrin imaging probe is expected to provide high sensitivity and specificity for thrombus identification. While PET offers molecular specificity, it suffers from low spatial resolution and lacks anatomical landmarks. Hybrid PET - computed tomography (CT) or PET - magnetic resonance imaging (MRI) devices are now available that enable co-registration of the molecular PET image to the vascular anatomical images obtained by CT or MRI. This proposal builds on positive preliminary PET-MRI thrombus imaging data with a prototype PET probe. In Aim 1 we focus on synthesizing a series of fluorine-18 and copper-64 labeled peptides to optimize the imaging properties of thrombus-targeted PET probe. In Aim 2 we will characterize these new probes with respect to their affinity to the fibrin target, their specificity for fibrin over other plasma proteins, and their metabolic stability in the presence of plasma or liver homogenate. In Aim 3 we explore the efficacy of these probes in fresh and aged thrombus models in rats and rabbits using PET-CT and PET-MRI. Dosimetry estimates will be performed on optimized probes and the most promising will be evaluated for acute toxicity. The output of this research will be a novel thrombus imaging probe that may be subsequently developed for human use.