PET imaging of angiogenesis after myocardial infarction/reperfusion using a one-step labeled integrin-targeted tracer 18F-AlF-NOTA-PRGD2

Abstract

Purpose The α_vβ₃ integrin represents a potential target for noninvasive imaging of angiogenesis. The purpose of this study was to evaluate a novel one-step labeled integrin α_vβ₃-targeting positron emission tomography (PET) probe, ¹⁸F-AlF-NOTA-PRGD2, for angiogenesis imaging in a myocardial infarction/reperfusion (MI/R) animal model. Methods Male Sprague-Dawley rats underwent 45-min transient left coronary artery occlusion followed by reperfusion. The myocardial infarction was confirmed by ECG, ¹⁸F-fluorodeoxyglucose (FDG) imaging, and cardiac ultrasound. In vivo PET imaging was used to determine myocardial uptake of ¹⁸F-AlF-NOTA-PRGD2 at different time points following reperfusion. The control peptide RAD was labeled with a similar procedure and used to confirm the specificity. Ex vivo autoradiographic analysis and CD31/CD61 double immunofluorescence staining were performed to validate the PET results. Results Myocardial origin of the ¹⁸F-AlF-NOTA-PRGD2 accumulation was confirmed by ¹⁸F-FDG and autoradiography. PET imaging demonstrated increased focal accumulation of ¹⁸F-AlF-NOTA-PRGD2 in the infarcted area which started at day 3 (0.28 ± 0.03%ID/g, p < 0.05) and peaked between 1 and 3 weeks (0.59 ± 0.16 and 0.55 ± 0.13%ID/g, respectively). The focal accumulation decreased but still kept at a higher level than the sham group after 4 months of reperfusion (0.31 ± 0.01%ID/g, p < 0.05). Pretreatment with unlabeled arginine-glycine-aspartic acid (RGD) peptide significantly decreased tracer uptake, indicating integrin specificity of this tracer. At 1 week after MI/R, uptake of the control tracer ¹⁸F-AlF-NOTA-RAD that does not bind to integrin, in the infarcted area, was only 0.21 ± 0.01%ID/g. Autoradiographic imaging showed the same trend of uptake in the myocardial infarction area. The time course of focal tracer uptake was consistent with the pattern of vascular density and integrin β₃ expression as measured by CD31 and CD61 immunostaining analysis. Conclusion PET imaging using one-step labeled ¹⁸F-AlF-NOTA-PRGD2 allows noninvasive visualization of ischemia/reperfusion-induced myocardial angiogenesis longitudinally. The favorable in vivo kinetics and easy production method of this integrin-targeted PET tracer facilitates its future clinical translation for lesion evaluation and therapy response monitoring in patients with occlusive cardiovascular diseases.