Lei Wang1, Feng Wang2, Wei Fang1, Steven E Johnson3, Said Audi4, Michael Zimmer5, Thomas A Holly3, Daniel C Lee3, Bao Zhu6, Haibo Zhu7, Ming Zhao8. 1. Department of Nuclear Medicine, Cardiovascular Institute & Fu Wai Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, China. 2. Department of Nuclear Medicine, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China. 3. Department of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 4. Department of Biomedical Engineering, Marquette University, Milwaukee, WI, USA. 5. Nuclear Medicine Department, Northwestern Memorial Hospital, Chicago, IL, USA. 6. Department of Nuclear Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China. Electronic address: zhubao_999@126.com. 7. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China. Electronic address: zhuhaibo@imm.ac.cn. 8. Department of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: m-zhao@northwestern.edu.
Abstract
UNLABELLED: When pathologically externalized, phosphatidylethanolamine (PE) is a potential surrogate marker for detecting tissue injuries. (99m)Tc-labeled duramycin is a peptide-based imaging agent that binds PE with high affinity and specificity. The goal of the current study was to investigate the clearance kinetics of (99m)Tc-labeled duramycin in a large animal model (normal pigs) and to assess its uptake in the heart using a pig model of myocardial ischemia-reperfusion injury. METHODS: The clearance and distribution of intravenously injected (99m)Tc-duramycin were characterized in sham-operated animals (n=5). In a closed chest model of myocardial ischemia, coronary occlusion was induced by balloon angioplasty (n=9). (99m)Tc-duramycin (10-15mCi) was injected intravenously at 1hour after reperfusion. SPECT/CT was acquired at 1 and 3hours after injection. Cardiac tissues were analyzed for changes associated with acute cellular injuries. Autoradiography and gamma counting were used to determine radioactivity uptake. For the remaining animals, (99m)Tc-tetrafosamin scan was performed on the second day to identify the infarct site. RESULTS: Intravenously injected (99m)Tc-duramycin cleared from circulation predominantly via the renal/urinary tract with an α-phase half-life of 3.6±0.3minutes and β-phase half-life of 179.9±64.7minutes. In control animals, the ratios between normal heart and lung were 1.76±0.21, 1.66±0.22, 1.50±0.20 and 1.75±0.31 at 0.5, 1, 2 and 3hours post-injection, respectively. The ratios between normal heart and liver were 0.88±0.13, 0.80±0.13, 0.82±0.19 and 0.88±0.14. In vivo visualization of focal radioactivity uptake in the ischemic heart was attainable as early as 30min post-injection. The in vivo ischemic-to-normal uptake ratios were 3.57±0.74 and 3.69±0.91 at 1 and 3hours post-injection, respectively. Ischemic-to-lung ratios were 4.89±0.85 and 4.93±0.57; and ischemic-to-liver ratios were 2.05±0.30 to 3.23±0.78. The size of (99m)Tc-duramycin positive myocardium was qualitatively larger than the infarct size delineated by the perfusion defect in (99m)Tc-tetrafosmin uptake. This was consistent with findings from tissue analysis and autoradiography. CONCLUSION: (99m)Tc-duramycin was demonstrated, in a large animal model, to have suitable clearance and biodistribution profiles for imaging. The agent has an avid target uptake and a fast background clearance. It is appropriate for imaging myocardial injury induced by ischemia/reperfusion.
UNLABELLED: When pathologically externalized, phosphatidylethanolamine (PE) is a potential surrogate marker for detecting tissue injuries. (99m)Tc-labeled duramycin is a peptide-based imaging agent that binds PE with high affinity and specificity. The goal of the current study was to investigate the clearance kinetics of (99m)Tc-labeled duramycin in a large animal model (normal pigs) and to assess its uptake in the heart using a pig model of myocardial ischemia-reperfusion injury. METHODS: The clearance and distribution of intravenously injected (99m)Tc-duramycin were characterized in sham-operated animals (n=5). In a closed chest model of myocardial ischemia, coronary occlusion was induced by balloon angioplasty (n=9). (99m)Tc-duramycin (10-15mCi) was injected intravenously at 1hour after reperfusion. SPECT/CT was acquired at 1 and 3hours after injection. Cardiac tissues were analyzed for changes associated with acute cellular injuries. Autoradiography and gamma counting were used to determine radioactivity uptake. For the remaining animals, (99m)Tc-tetrafosamin scan was performed on the second day to identify the infarct site. RESULTS: Intravenously injected (99m)Tc-duramycin cleared from circulation predominantly via the renal/urinary tract with an α-phase half-life of 3.6±0.3minutes and β-phase half-life of 179.9±64.7minutes. In control animals, the ratios between normal heart and lung were 1.76±0.21, 1.66±0.22, 1.50±0.20 and 1.75±0.31 at 0.5, 1, 2 and 3hours post-injection, respectively. The ratios between normal heart and liver were 0.88±0.13, 0.80±0.13, 0.82±0.19 and 0.88±0.14. In vivo visualization of focal radioactivity uptake in the ischemic heart was attainable as early as 30min post-injection. The in vivo ischemic-to-normal uptake ratios were 3.57±0.74 and 3.69±0.91 at 1 and 3hours post-injection, respectively. Ischemic-to-lung ratios were 4.89±0.85 and 4.93±0.57; and ischemic-to-liver ratios were 2.05±0.30 to 3.23±0.78. The size of (99m)Tc-duramycin positive myocardium was qualitatively larger than the infarct size delineated by the perfusion defect in (99m)Tc-tetrafosmin uptake. This was consistent with findings from tissue analysis and autoradiography. CONCLUSION: (99m)Tc-duramycin was demonstrated, in a large animal model, to have suitable clearance and biodistribution profiles for imaging. The agent has an avid target uptake and a fast background clearance. It is appropriate for imaging myocardial injury induced by ischemia/reperfusion.
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