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.