title: The feasibility of imaging myocardial ischemic/reperfusion injury using (99m)Tc-labeled duramycin in a porcine model.
abstract: 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.
  
  
  CONCLUSIONS
  (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.
authors.affiliation: Department of Nuclear Medicine, Cardiovascular Institute & Fu Wai Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Nuclear Medicine, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Nuclear Medicine, Cardiovascular Institute & Fu Wai Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.affiliation: Department of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Johnson
authors.affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, WI, USA.
authors.forename: Said
authors.initials: S
authors.lastname: Audi
authors.affiliation: Nuclear Medicine Department, Northwestern Memorial Hospital, Chicago, IL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Zimmer
authors.affiliation: Department of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Holly
authors.affiliation: Department of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China. Electronic address: zhubao_999@126.com.
authors.forename: Bao
authors.initials: B
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: m-zhao@northwestern.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001430:Bacteriocins / Q000378:metabolism; D005240:Feasibility Studies; D005260:Female; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging* / Q000378:metabolism; D015609:Organotechnetium Compounds; D010455:Peptides / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D013552:Swine; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014057:Tomography, X-Ray Computed / Q000379:methods*
chemical_list: D001430:Bacteriocins; D015609:Organotechnetium Compounds; D010455:Peptides; D010714:Phosphatidylethanolamines; C040522:duramycin; C483858:phosphatidylethanolamine
keywords: Apoptosis; Duramycin; Ischemia–reperfusion injury; Phosphatidylethanolamine