Atherosclerotic plaque uptake of a novel integrin tracer ¹8F-Flotegatide in a mouse model of atherosclerosis.

INTRODUCTION: Rupture of unstable atherosclerotic plaque that leads to stroke and myocardial infarction may be induced by macrophage infiltration and neovessel formation. A tracer that selectively binds to integrin αvß3 a protein expressed by macrophages and neovascular endothelium may identify rupture prone plaque. METHODS: (18)F-labeled "R-G-D" containing tripeptide (Flotegatide), a click chemistry derived radiotracer that binds to integrin αvß3 was injected in ApoE knockout mice fed a high fat diet. Uptake of Flotegatide by atherosclerotic plaque was visualized by micro-PET, autoradiography, and correlated to histologic markers of inflammation and angiogenesis. RESULTS: We found that Flotegatide preferentially binds to aortic plaque in an ApoE knockout mouse model of atherosclerosis. The tracer's uptake is strongly associated with presence of histologic markers for macrophage infiltration and integrin expression. There is a weaker but detectable association between Flotegatide uptake and presence of an immunohistochemical marker for neovascularization. DISCUSSION: We hypothesize that Flotegatide may be a useful tracer for visualization of inflamed plaque in clinical subjects with atherosclerosis and may have potential for detecting vulnerable plaque.

Noninvasive molecular imaging of apoptosis in a mouse model of anthracycline-induced cardiotoxicity.

BACKGROUND: Anthracycline-induced cardiotoxicity and myocardial dysfunction may be associated with apoptosis. Caspase 3 catalyzes a terminal step in apoptosis, and its expression may serve as a marker of cardiomyocyte apoptosis. We synthesized 18F-CP18, a caspase-3 substrate and evaluated cardiac 18F-CP18 uptake in a mouse model of anthracycline cardiotoxicity. METHODS AND RESULTS: For 12 weeks, mice were injected with doxorubicin, 3 mg/kg/week, or vehicle (control). Left ventricular fractional shortening was quantified by echocardiography. CP18 uptake after intravenous injection of 250 µCi of 18F-CP18, 24 hours post-doxorubicin treatment was quantified by microPET, autoradiography, and gamma counting. Apoptosis was assessed by enzymatic assay of myocardial caspase 3 and TUNEL staining of tissue sections. Compared with controls, at 6 and 12 weeks of doxorubicin treatment, fractional shortening was reduced (20.7%±2.5% versus 31%±3.5%, P=0.010; and 20.3%±3.1% versus 32.4%±2.1%, P=0.011). Doxorubicin treatment was associated with increased 18F-CP18 uptake in %ID/g by gamma counting from 0.36±0.01 (week 1) to 0.78±0.01 (week 12), P=0.003. A similar increase in 18F-CP18 uptake was observed by microPET (0.41±0.04 versus 0.73±0.1, P=0.014) and autoradiography (1.1±0.3 versus 2.8±0.2 P=0.001). Caspase 3 enzymatic activity and apoptosis by TUNEL staining were also increased after 12 weeks of doxorubicin compared with weeks 1 and 3. CP18 uptake in controls was relatively unchanged at weeks 1, 3, and 12. CONCLUSIONS: In a mouse model of cardiotoxicity, doxorubicin treatment is associated with increased myocardial caspase 3 expression and an increase in CP18 uptake. 18F-CP18 may be useful for detection of anthracycline-induced myocardial apoptosis.