Detection of atherosclerotic plaques in ApoE-deficient mice using 99mTc-duramycin

Abstract

Apoptosis of macrophages and smooth muscle cells is linked to atherosclerotic plaque destabilization. The apoptotic cascade leads to exposure of negatively charged phosphatidylethanolamine (PE) on the outer leaflet of the cell membrane, thereby making apoptosis detectable using probes targeting PE. The objective of this study was to exploit capabilities of a PE-specific imaging probe, 99mTc-duramycin, in localizing atherosclerotic plaque and assessing plaque evolution in apolipoprotein-E knockout (ApoE-/-) mice. Methods Atherosclerosis was induced in ApoE-/- mice by feeding an atherogenic diet. 99mTc-duramycin images were acquired using a small-animal SPECT imager. Six ApoE-/- mice at 20 weeks of age (Group I) were imaged and then sacrificed for ex vivo analyses. Six additional ApoE-/- mice (Group II) were imaged at 20 and 40 weeks of age before sacrifice. Six ApoE wild-type (ApoE+/+) mice (Group III) were imaged at 40 weeks as controls. Five additional ApoE-/- mice (40 weeks of age) (Group IV) were imaged with a 99mTc-labeled inactive peptide, 99mTc-LinDUR, to assess 99mTc-duramycin targeting specificity. Results Focal 99mTc-duramycin uptake in the ascending aorta and aortic arch was detected at 20 and 40 weeks in the ApoE-/- mice but not in ApoE+/+ mice. 99mTc-duramycin uptake in the aortic lesions increased 2.2-fold on quantitative imaging in the ApoE-/- mice between 20 and 40 weeks. Autoradiographic and histological data indicated significantly increased 99mTc-duramycin uptake in the ascending aorta and aortic arch associated with advanced plaques. Quantitative autoradiography showed that the ratio of activity in the aortic arch to descending thoracic aorta, which had no plaques and radioactive uptake, was 2.1 times higher at 40 weeks than at 20 weeks (6.62±0.89 vs. 3.18±0.29, P<0.01). There was barely detectable focal uptake of 99mTc-duramycin in the aortic arch of ApoE+/+ mice. No detectable 99mTc-LinDUR uptake was observed in the aortas of ApoE-/- mice. Conclusions PE-targeting properties of 99mTc-duramycin in the atherosclerotic mouse aortas were noninvasively characterized. 99mTc-duramycin is promising in localizing advanced atherosclerotic plaques.

99mTc-Duramycin SPECT Imaging of Early Tumor Response to Targeted Therapy: A Comparison with18F-FDG PET

“…Specificity of 99m Tc-duramycin for detecting phosphatidylethanolamine in apoptotic cells was demonstrated by using a 99m Tc-labeled linearized duramycin molecule ( 99m Tc-linear duramycin) that lacks affinity for phosphatidylethanolamine. This control peptide is an inactive form of duramycin that does not bind to phosphatidylethanolamine and has a minimally altered structure and the molecular weight of duramycin, as previously described by others (29,30). 99m Tc-linear duramycin exhibited a rapid blood clearance, and the biodistribution was prominent in the kidneys and liver similarly to 99m Tc-duramycin.…”

Optimization of an Adaptive SPECT System With the Scanning Linear Estimator

“…The exposure time for every imaging configuration in the optimization routine was set to one second. The activities are samples drawn from the measured bio-distribution data reported in [27] and are expressed in units of the percent injected dose per gram of the body weight of the mouse (% dose/g). The radius of the signal and its location are reported in units of millimeters.…”

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

“…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.…”