Molecular Imaging of Ischemic Memory with Ultrasound - Transition to Humans

描述(由申请人提供)：具有靶向成像探针的分子成像技术是在考虑到特定的临床目标的情况下开发的。在心血管疾病方面，通过及早发现疾病或提高对危及生命的疾病的诊断准确性，分子成像有望对患者的管理产生积极影响。在出现急性或近期胸痛但有非诊断性心电图的患者中，通过对心肌缺血引起的分子变化进行成像(“缺血记忆”成像)，有可能改善和加快急性冠脉综合征的诊断。这一策略已经在新陈代谢靶向放射性核素剂的临床试验中进行了测试。对于评估这些患者来说，一种更快速、更便携的方法将具有实际优势，因为他们中的大多数都在急诊科。我们已经开发了超声分子成像探针，通过靶向P-选择素的微泡造影剂来检测缺血(伴或不伴梗死)。P-选择素在小鼠短暂缺血模型中表达的超声分子成像检测近期心肌缺血的存在和程度。我们最近开发了一种适合人类使用的试剂，它是通过将重组二聚体PSGL-1类似物与微泡结合而产生的。这种类似物本身是安全的，目前正在进行改善器官移植损伤的第二阶段研究。这项挑战拨款的目的是将检测最近缺血的分子成像技术转化为临床试验。为了准备这份报告，我们的研究小组与一家主要的造影剂制造商(BrTobo Imagine)已作出安排，在GMP设施中生产该试剂。对于这项挑战拨款提案，我们有四个主要里程碑：(1)在非人类灵长类动物短暂心肌缺血的闭合胸腔模型中测试P-选择素靶向成像的有效性和安全性；(2)完成IND探索性应用所需的药理学/毒理学研究；(3)在正常志愿者中描述IND批准的药物的安全性；(4)研究在急性冠脉综合征首次经皮介入治疗后立即对稳定的患者进行近期心肌缺血成像的可行性。这些研究将为开发一种有前景的诊断方法来快速诊断不稳定心绞痛和心肌梗死患者，或为通过负荷或多巴酚丁胺超声心动图对冠状动脉疾病进行非侵入性评估的患者检测应激诱导的缺血提供必要的数据。 公共卫生相关性：目前诊断急性冠脉综合征(不稳定型心绞痛和心肌梗死)的算法存在重大局限性，导致延迟或漏诊。在这项提案中，我们将测试一种新的超声靶向成像技术的有效性和安全性，该技术能够检测心脏小血管在缺血期间或之后发生的分子变化(低血流到心脏)。我们的目标的成功完成将导致开发一种新的战略，可以用于更准确地诊断威胁生命的冠状动脉疾病。

DESCRIPTION (provided by applicant): Molecular imaging techniques with targeted imaging probes have been developed with specific clinical goals in mind. In cardiovascular disease, there is hope that molecular imaging will have a positive impact on patient management by early detection of disease or by increasing diagnostic accuracy for life-threatening illnesses. In patients who present with acute or recent chest pain but who have a non-diagnostic ECG, it may be possible to improve and expedite the diagnosis of acute coronary syndromes by imaging molecular alterations that occur with myocardial ischemia ("ischemic memory" imaging). This strategy is already being tested in clinical trials with metabolism-targeted radionuclide agents. A more rapid and portable approach would have practical advantages for evaluating these patients, most of whom are seen in the emergency department. We have developed ultrasound molecular imaging probes for detection of ischemia (with or without infarction) by targeting microbubble contrast agents to P-selectin. Ultrasound molecular imaging of P-selectin expression in murine models of brief ischemia detects the presence and extent of recent myocardial ischemia. We have recently developed an agent that is suitable for human use that is produced by conjugating a recombinant dimeric PSGL-1 analogue to microbubbles. The analogue alone is safe and is being tested in Phase-2 studies for amelioration of organ transplant injury. The purpose of this challenge grant is to transition molecular imaging technology for detection of recent ischemia into clinical trials. In preparation for this submission, arrangements have been made between our research group and a major contrast manufacturer (Bracco Imaging) for production of the agent in a GMP facility. We have four major milestones for this challenge grant proposal: (1) to test efficacy and safety of P-selectin targeted imaging in a non-human primate closed-chest model of brief myocardial ischemia; (2) to complete pharmacology/toxicology studies needed for Exploratory IND application; (3) to profile safety of the IND-approved agent in normal volunteers; and (4) to examine feasibility of imaging recent myocardial ischemia in stable patients immediately after primary percutanous intervention for acute coronary syndrome. These studies will provide necessary data for the development of a promising diagnostic approach to rapid diagnosis of patients with unstable angina and myocardial infarction, or for the detection of stress-induced ischemia in patients referred for non-invasive evaluation for coronary artery disease with stress or dobutamine echocardiography. PUBLIC HEALTH RELEVANCE: Current algorithms for the diagnosis of acute coronary syndromes (unstable angina and myocardial infarction) have major limitations leading to delayed or missed diagnosis. In this proposal, we will test the efficacy and safety of a new ultrasound targeted imaging technique that is able to detect molecular alterations in the small vessels of heart that occur during or after ischemia (low blood flow to the heart). The successful completion of our aims will lead to the development of a new strategy that can be used to more accurately diagnosis life-threatening coronary artery disease.