Development and Evaluation of Radiotracers for PET Imaging Angiotensin-Converting Enzyme 2 (ACE2)

PET 成像血管紧张素转换酶 2 (ACE2) 放射性示踪剂的开发和评估

基本信息

批准号：
10286888
负责人：
Xuyi Yue
金额：
$ 21.3万
依托单位：
ALFRED I. DU PONT HOSP FOR CHILDREN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286888
关键词：
2019-nCoV ACE2 Adult Affect Affinity Angiotensin I Angiotensin II Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Animal Model Binding Bioavailable Biodistribution Biological Assay COVID-19 COVID-19 detection COVID-19 mortality COVID-19 pandemic COVID-19 patient COVID-19 severity COVID-19 therapeutics COVID-19 treatment Cardiovascular Diseases Cells Child Cleaved cell Coronavirus Development Diabetes Mellitus Disease Disputes Equilibrium Evaluation Experimental Models Fluorine Goals Heart Heart failure Histologic Hormonal Human Hypertension Image Imaging Techniques Immune response In Vitro Infection Inflammatory Kidney Kidney Diseases Knockout Mice Label Lead Lesion Lower respiratory tract structure Lung Lung diseases MLN4760 Metabolic Metalloproteases Molecular Analysis Mus Organ Outcome Patients Permeability Pharmaceutical Preparations Phase Physiology Plasma Play Positron-Emission Tomography Property Quantitative Evaluations Renin-Angiotensin System Reporting Research Respiratory Failure Role SARS-CoV-2 infection Scanning Scientist Series Severe Acute Respiratory Syndrome Severities Symptoms Testing Time Tracer Transgenic Mice Vaccines Viral Pneumonia Wild Type Mouse base blood pressure regulation comorbidity design fluorodeoxyglucose positron emission tomography human subject hypertension treatment imaging modality imaging probe immune activation in vivo in vivo evaluation inhibitor/antagonist membrane activity metabolic rate molecular marker mortality mouse model novel pandemic disease pediatric patients pneumocyte protective effect radiotracer receptor receptor expression severe COVID-19 tool treatment response uptake

项目摘要

PROJECT SUMMARY The coronavirus disease2019 (COVID-19) pandemic is an ongoing global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). New COVID-19 cases and COVID-19 related deaths continue to rise rapidly and no effective drugs or vaccines are currently available. The functional entry receptor utilized by SARS-CoV-2 is Angiotensin-Converting Enzyme 2 (ACE2). SARS-CoV-2 binds to ACE2 in the lower respiratory tracts of infected patients to gain entry into lung cells, leading to viral pneumonia and potentially fatal respiratory failure. Many studies have shown that patients with comorbid conditions including respiratory disease, cardiovascular disease, kidney disease, diabetes, and hypertension have much higher mortality rates. ACE inhibitors and angiotensin receptor blockers (ARB) are frequently used to treat these pre-existing conditions and the question remains whether such treatment may affect the outcome in COVID-19 patients due to the inhibitors' effects on ACE2 expression. Many experts are concerned that those inhibitors for the treatment of patients with such underlying conditions may exacerbate COVID-19 symptoms and lead to higher mortality rates. Currently the precise relationship between ACE2 levels and severity of the infection is not well understood, due to a lack of understanding of whole-body ACE2 expression levels and distribution. Here we propose to design and synthesize a series of new fluorine-18 labeled positron emission tomography (PET) tracers targeting ACE2. The radiotracers will be evaluated in vitro for cellular binding affinity, selectivity, and metabolic stability. The most promising radiotracer will be moved to in vivo studies including whole body biodistribution with dynamic PET imaging, and correlation with biomolecular analysis in mice that express human ACE2. The PET imaging modality will provide a powerful tool for noninvasive and quantitative evaluation of ACE2 levels in living subjects. Furthermore, the radiotracer may help to unveil the precise relationship between ACE2 levels and severity of COVID-19.

项目概要 2019 年冠状病毒病（COVID-19）大流行是一场持续的全球大流行，由严重急性传染病引起呼吸综合征冠状病毒 2 (SARS-CoV-2)。新的 COVID-19 病例和与 COVID-19 相关的死亡持续快速上升，目前尚无有效药物或疫苗。功能性进入受体 SARS-CoV-2 使用的是血管紧张素转换酶 2 (ACE2)。 SARS-CoV-2 在下层细胞中与 ACE2 结合感染患者的呼吸道进入肺细胞，导致病毒性肺炎并可能致命呼吸衰竭。许多研究表明，患有呼吸道疾病等合并症的患者，心血管疾病、肾脏疾病、糖尿病和高血压的死亡率要高得多。高手抑制剂和血管紧张素受体阻滞剂 (ARB) 经常用于治疗这些已有病症问题仍然是，由于抑制剂的作用，这种治疗是否会影响 COVID-19 患者的结果对 ACE2 表达的影响。许多专家担心这些抑制剂用于治疗患有糖尿病的患者这些潜在疾病可能会加剧 COVID-19 症状并导致更高的死亡率。现在由于缺乏 ACE2 水平与感染严重程度之间的确切关系，目前尚不清楚了解全身 ACE2 表达水平和分布。在这里我们建议设计和合成了一系列针对 ACE2 的新型氟 18 标记正电子发射断层扫描 (PET) 示踪剂。这将在体外评估放射性示踪剂的细胞结合亲和力、选择性和代谢稳定性。最有前景的放射性示踪剂将转移到体内研究，包括动态 PET 的全身生物分布表达人类 ACE2 的小鼠的成像以及与生物分子分析的相关性。 PET 成像该模式将为活体受试者中 ACE2 水平的无创和定量评估提供强大的工具。此外，放射性示踪剂可能有助于揭示 ACE2 水平与严重程度之间的精确关系。新冠肺炎。