Imaging of VEGF Receptor in a Rat Myocardial Infarction Model Using PET

Abstract

Myocardial infarction (MI) leads to left ventricular (LV) remodeling, which leads to the activation of growth factors such as vascular endothelial growth factor (VEGF). However, the kinetics of a growth factor's receptor expression, such as VEGF, in the living subject has not yet been described. We have developed a PET tracer (⁶⁴Cu-DOTA-VEGF₁₂₁ [DOTA is 1,4,7,10-tetraazadodecane-N,N′,N″,N‴-tetraacetic acid]) to image VEGF receptor (VEGFR) expression after MI in the living subject. Methods: In Sprague–Dawley rats, MI was induced by ligation of the left coronary artery and confirmed by ultrasound (n = 8). To image and study the kinetics of VEGFRs, ⁶⁴Cu-DOTA-VEGF₁₂₁ PET scans were performed before MI induction (baseline) and on days 3, 10, 17, and 24 after MI. Sham-operated animals served as controls (n = 3). Results: Myocardial origin of the ⁶⁴Cu-DOTA-VEGF₁₂₁ signal was confirmed by CT coregistration and autoradiography. VEGFR specificity of the ⁶⁴Cu-DOTA-VEGF₁₂₁ probe was confirmed by in vivo use of a ⁶⁴Cu-DOTA-VEGF_mutant. Baseline myocardial uptake of ⁶⁴Cu-DOTA-VEGF₁₂₁ was minimal (0.30 ± 0.07 %ID/g [percentage injected dose per gram of tissue]); it increased significantly after MI (day 3, 0.97 ± 0.05 %ID/g; P < 0.05 vs. baseline) and remained elevated for 2 wk (up to day 17 after MI), after which time it returned to baseline levels. Conclusion: We demonstrate the feasibility of imaging VEGFRs in the myocardium. In summary, we imaged and described the kinetics of ⁶⁴Cu-DOTA-VEGF₁₂₁ uptake in a rat model of MI. Studies such as the one presented here will likely play a major role when studying pathophysiology and assessing therapies in different animal models of disease and, potentially, in patients.