PET Imaging of Thrombus

描述(申请人提供)：血栓的正电子发射断层成像。这项提议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，用于直接对血栓进行成像。血栓与多种病理因素有关，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决定，而成像被广泛用于排除或排除血栓的存在。尽管有不同的成像方法可用，但直接识别血栓的医学需求仍然强烈，尚未得到满足。例如，确定缺血性卒中栓子的来源对患者管理至关重要，但目前30-40%的卒中起源不明。这一建议的PET探头可以识别卒中的来源，并识别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，中风是第三大致死原因，也是致病的首要原因。根据美国中风协会的数据，美国人今年将在与中风相关的医疗费用和残疾方面支付近690亿美元。一种用于识别继发性中风高危人群的成像工具有望对与中风相关的发病率和死亡率产生积极影响。血栓探头基于一种与循环纤维蛋白原或其他血浆蛋白上的纤维蛋白结合并具有特异性的多肽。纤维蛋白在急性和亚慢性静脉和动脉血栓中以高浓度存在，但在循环血液中不存在。一种选择性纤维蛋白成像探针有望为血栓识别提供高灵敏度和特异性。虽然PET提供了分子特异性，但它存在空间分辨率低和缺乏解剖标志的问题。现在有了混合的PET-计算机断层扫描(CT)或PET-磁共振成像(MRI)设备，可以将分子PET图像与通过CT或MRI获得的血管解剖图像共同配准。这项建议建立在阳性的初步PET-MRI血栓成像数据和原型PET探头的基础上。在目标1中，我们致力于合成一系列氟-18和铜-标记的多肽，以优化血栓靶向PET探针的成像性能。在目标2中，我们将从它们与纤维蛋白靶标的亲和力、它们对纤维蛋白的特异性超过其他血浆蛋白以及它们在血浆或肝匀浆存在下的代谢稳定性来表征这些新的探针。在目的3中，我们利用PET-CT和PET-MRI研究了这些探针在大鼠和兔新鲜血栓模型和老年血栓模型中的作用。剂量学评估将在优化的探测器上进行，最有希望的探测器将进行急性毒性评估。这项研究的成果将是一种新的血栓成像探头，随后可能会开发出供人类使用的探头。

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.