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：
10451820
负责人：
Xuyi Yue
金额：
$ 17.75万
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/10451820
关键词：
2019-nCoV ACE2 Adult Affect Affinity Angiotensin I Angiotensin II Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Animal Model Binding 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 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 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 Disease 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 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.

项目摘要冠状病毒疾病2019（Covid-19）大流行是由严重急性引起的持续全球大流行呼吸综合征冠状病毒2（SARS-COV-2）。新的Covid-19案件和Covid-19相关死亡继续迅速上升，目前没有有效的药物或疫苗。功能输入受体由SARS-COV-2使用的是血管紧张素转换酶2（ACE2）。 SARS-COV-2与较低的ACE2结合受感染患者的呼吸道进入肺部细胞，导致病毒性肺炎和潜在致命呼吸衰竭。许多研究表明，患有合并症的患者，包括呼吸道疾病，心血管疾病，肾脏疾病，糖尿病和高血压的死亡率更高。高手抑制剂和血管紧张素受体阻滞剂（ARB）经常用于治疗这些先前存在的疾病和问题仍然是，由于抑制剂的抑制剂，这种治疗是否可能影响199名患者的结果对ACE2表达的影响。许多专家担心那些用于治疗患者的抑制剂这种潜在条件可能会加剧199症状，并导致更高的死亡率。现在由于缺乏了解全身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Fluorine-18标记为正电子发射断层扫描（PET）示踪剂。这放射性示例将在体外评估细胞结合亲和力，选择性和代谢稳定性。最多有希望的放射性示踪剂将移至体内研究，包括全身生物分布和动态PET 成像，与表达人ACE2的小鼠中的生物分子分析相关。宠物成像模式将为生命受试者中ACE2水平的非侵入性和定量评估提供强大的工具。此外，radiotracer可能有助于揭示ACE2水平与严重程度之间的确切关系新冠肺炎。