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

¹ Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Division of Nuclear Medicine, Stanford University, Stanford, California; ² Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota; ³ Department of Bioengineering, Stanford University, Stanford, California; ⁴ Department of Cardiology, Stanford University, Stanford, California; and ⁵ Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Texas

Correspondence: For correspondence or reprints contact: Sanjiv Sam Gambhir, MD, PhD, Stanford University School of Medicine, Bio-X Program, Departments of Radiology and Bioengineering, The James H. Clark Center, 318 Campus Dr., Clark E150, Stanford, CA 94305-5427. E-mail: sgambhir{at}stanford.edu

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.

Key Words: myocardial infarction • angiogenesis • vascular endothelial growth factor (VEGF) • VEGF receptor (VEGFR) • PET • ⁶⁴Cu

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JNM 2008 49: 11A-12A. [Full Text]