124I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection

Abstract

Purpose Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by lung injury that we sought to model. Activated macrophages/phagocytes have an important role in lung injury, which is responsible for subsequent respiratory failure and death. We performed pulmonary PET/CT with 124 I-iodo-DPA-713, a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by activated macrophages cells, to evaluate the local immune response in a hamster model of SARS-CoV-2 infection. Procedures Pulmonary 124 I-iodo-DPA-713 PET/CT was performed in SARS-CoV-2-infected golden Syrian hamsters. CT images were quantified using a custom-built lung segmentation tool. Studies with DPA-713-IRDye680LT and a fluorescent analog of DPA-713 as well as histopathology and flow cytometry were performed on post-mortem tissues. Results Infected hamsters were imaged at the peak of inflammatory lung disease (7 days post-infection). Quantitative CT analysis was successful for all scans and demonstrated worse pulmonary disease in male versus female animals ( P < 0.01). Increased 124 I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary 124 I-iodo-DPA-713 PET activity was noted in male versus female hamsters ( P = 0.02). DPA-713-IRDye680LT also localized to the pneumonic lesions. Flow cytometry demonstrated a higher percentage of myeloid and CD11b + cells (macrophages, phagocytes) in male versus female lung tissues ( P = 0.02). Conclusion 124 I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, 124 I-Iodo-DPA-713 PET could serve as a noninvasive, clinically translatable approach to monitor SARS-CoV-2-associated pulmonary inflammation and expedite the development of novel therapeutics for COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s11307-021-01638-5.

Medical imaging of pulmonary disease in SARS-CoV-2-exposed non-human primates

“…Some of these PET radiotracers have already been examined in small animal models of COVID-19, and studies in NHPs are ongoing. For example, 124 I-iodo-N,N-diethyl-2-5,7-dimethylpyrazolo [1,5-a]pyrimidine-3-acetamide (DPA-713), a radiotracer with translocator protein (TSPO) as a target selectively trapped by activated macrophages, was found to accumulate in pneumonic lesions in SARS-CoV-2-exposed golden hamsters [93]. The inflammation-specific peptide DOTATATE [paired with gallium-68 ( 68 Ga) or copper-64 ( 64 Cu)], a radiotracer with specificity for somatostatin receptor 2 (SSTR2), was developed to improve the diagnosis of neuroendocrine tumors [94].…”

Dynamic single-cell RNA sequencing reveals BCG vaccination curtails SARS-CoV-2 induced disease severity and lung inflammation

“…Prior to PET imaging, hamsters were administered ∼10.22 MBq of 18 F-FDG (SOFIE, Sterling VA, USA) via the surgically implanted center venous catheter. Given that SCV2 is designated as a BSL-3 pathogen, live SCV2-infected animals were imaged inside transparent and sealed biocontainment cells developed in-house, compliant with BSL-3 containment and capable of delivering air-anesthetic mixture to sustain live animals during imaging (68, 69). A 15-min PET acquisition and subsequent CT were performed using the nanoScan PET/CT (Mediso Alrington, VA).…”

“…A 15-min PET acquisition and subsequent CT were performed using the nanoScan PET/CT (Mediso Alrington, VA). CT images were visualized and analyzed using the VivoQuant 2020 lung segmentation tool (Invicro, MA, USA)(69). Briefly, an entire lung volume (LV) was created, and volumes of interests (VOIs) were shaped around the pulmonary lesions using global thresholding for Hounsfield Units (HU) ≥ 0, and disease severity (CT score) was quantified as the percentage of diseased lung in each animal.The investigators were blinded to the group assignments.…”

Novel application of [18F]DPA714 for visualizing the pulmonary inflammation process of SARS-CoV-2-infection in rhesus monkeys (Macaca mulatta)

“…However, as TSPO is distributed over the entire body, the radiotracer may visualize inflammatory processes in other organs than the brain as well. This makes TSPO a valuable tool to visualize the progress in infectious diseases, and in this regard focused on, respiratory infections [7] , [8] , [9] , [10] .…”

“…One endemic disease for which it is of utmost importance to gain more insights in the disease progress, is coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Syrian hamsters ( Mesocricetus auratus ) and nonhuman primates (NHPs) are used as models for SARS-CoV-2 infection and visualization of the respiratory tract infection [10] , [11] , [12] . Both species are established animal models to study COVID-19 as the distribution of angiotensin converting enzyme 2 (ACE2), the cellular receptor of SARS-CoV-2, in these species is comparable to humans.…”