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

• 批准号: 10612920
• 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
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612920
• 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; Biological Availability; 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; 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; Transfection; Transgenic Mice; Vaccines; Viral Pneumonia; Visualization; Wild Type Mouse; 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

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 2019冠状病毒病（COVID-19）大流行是一种持续的全球大流行病，由严重急性 呼吸道综合征冠状病毒2型（SARS-CoV-2）。新增COVID-19病例和COVID-19相关死亡 继续迅速上升，目前没有有效的药物或疫苗。功能性进入受体 SARS-CoV-2利用的是血管紧张素转换酶2（ACE 2）。SARS-CoV-2与ACE 2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，患有呼吸道疾病等共病的患者， 心血管疾病、肾病、糖尿病和高血压的死亡率要高得多。Ace 抑制剂和血管紧张素受体阻断剂（ARB）经常用于治疗这些预先存在的病症， 问题仍然是这种治疗是否会影响COVID-19患者的结果， 对ACE 2表达的影响。许多专家担心，这些抑制剂用于治疗 这些潜在的疾病可能会加剧COVID-19的症状，并导致更高的死亡率。目前 ACE 2水平与感染严重程度之间的确切关系尚不清楚， 了解全身ACE 2表达水平和分布。在这里，我们建议设计和 合成了一系列新的氟-18标记的正电子发射断层扫描（PET）示踪剂，靶向ACE 2。的 将在体外评价放射性示踪剂的细胞结合亲和力、选择性和代谢稳定性。最 有前途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 成像，并与表达人ACE 2的小鼠中的生物分子分析相关。pet成像 该方法将为活体受试者ACE 2水平的无创和定量评估提供有力的工具。 此外，放射性示踪剂可能有助于揭示ACE 2水平与糖尿病严重程度之间的精确关系。 2019冠状病毒病。