The feasibility of imaging myocardial ischemic/reperfusion injury using 99mTc-labeled duramycin in a porcine model

Abstract

When pathologically externalized, phosphatidylethanolamine (PE) is a potential surrogate marker for detecting tissue injuries. 99mTc-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 99mTc-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 99mTc-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). 99mTc-duramycin (10-15 mCi) was injected intravenously at 1 hour after reperfusion. SPECT/CT was acquired at 1 and 3 hours after injection. Cardiac tissues were analyzed for changes associated with acute cellular injuries. Autoradiography and gamma counting was used to determine radioactivity uptake. For the remaining animals, 99mTc-tetrafosamin scan was performed on the second day to identify the infarct site. Results Intravenously injected 99mTc-duramycin cleared from circulation predominantly via the renal/urinary tract with an α-phase half-life of 3.6 ± 0.3 minutes and β-phase half-life of 179.9 ± 64.7 minutes. 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 3 hours 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 30 min post injection. The in vivo ischemic-to-normal uptake ratios were 3.57 ± 0.74 and 3.69 ± 0.91 at 1 and 3 hours 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 99mTc-duramycin positive myocardium was qualitatively larger than the infarct size delineated by the perfusion defect in 99mTc-tetrafosmin uptake. This was consistent with findings from tissue analysis and autoradiography. Conclusion 99mTc-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.

99m Tc-labeled Duramycin for detecting and monitoring cardiomyocyte death and assessing cardioprotection of atorvastatin in acute myocardial infarction

“…In addition, 99m Tc-linear-duramycin imaging showed no radioactive uptake in the area of infarction region, confirming 99m Tc-duramycin specific uptake. Although the result of this study was similar to other findings, where the 99m Tc-duramycin is predominantly excreted through the urinary system with relatively low systemic and hepatic background in its mouse model [13,26] . Hence, this study indicated that 99m Tc-duramycin enabled the detection of myocardial cell death effectively.…”

“…It is an ideal target for detecting death including apoptosis and necrosis, which can specifically bind to PE with high affinity and low background [11] . Some studies had shown extensively application of 18 F or 99m Tc labelled duramycin for detecting apoptosis in ischemia reperfusion injury, atherosclerosis, and tumors [12][13][14][15][16] . In this study, we evaluated the feasibility that the 99m Tc-labeled duramycin used to monitor myocardial cell death in a mouse model of acute myocardial infarction.…”

Early Prediction of Tumor Response to Treatment: Preclinical Validation of 99mTc-Duramycin

“…The in vivo avidity of 99m Tc-duramycin for cell death has previously been demonstrated in animal models of whole-body irradiation and cerebral and myocardial ischemia and reperfusion (8,10,12). We recently demonstrated the usefulness of 99m Tc-duramycin in an oncology setting showing ability to detect irinotecan-induced tumor apoptosis early (11).…”

Characterization of [99mTc]Duramycin as a SPECT Imaging Agent for Early Assessment of Tumor Apoptosis

“…The low molecular weight (MW) of duramycin (∼2 kDa) confers this tracer with favorable pharmacokinetics and biodistribution properties for in vivo imaging of apoptosis [ 16 ]. [ 99m Tc]Duramycin has been successfully used as a probe for the imaging of cell death in animal models of cerebral [ 17 ] and myocardial [ 18 , 19 ] ischemia–reperfusion, accumulating in tissue sites of injury where there is high apoptotic activity. Additionally, this probe was also effectively used to assess tissue damage after whole-body irradiation [ 20 ].…”