Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Eur J Nucl Med Mol Imaging. 2012 Apr;39(4):683-92. doi: 10.1007/s00259-011-2052-1. Epub 2012 Jan 25.
The α(v)β(3) 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(v)β(3)-targeting positron emission tomography (PET) probe, (18)F-AlF-NOTA-PRGD2, for angiogenesis imaging in a myocardial infarction/reperfusion (MI/R) animal model.
Male Sprague-Dawley rats underwent 45-min transient left coronary artery occlusion followed by reperfusion. The myocardial infarction was confirmed by ECG, (18)F-fluorodeoxyglucose (FDG) imaging, and cardiac ultrasound. In vivo PET imaging was used to determine myocardial uptake of (18)F-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.
Myocardial origin of the (18)F-AlF-NOTA-PRGD2 accumulation was confirmed by (18)F-FDG and autoradiography. PET imaging demonstrated increased focal accumulation of (18)F-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 (18)F-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 β(3) expression as measured by CD31 and CD61 immunostaining analysis.
PET imaging using one-step labeled (18)F-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.
α(v)β(3)整联蛋白是血管生成非侵入性成像的潜在靶点。本研究旨在评估一种新型一步标记整合素α(v)β(3)靶向正电子发射断层扫描(PET)探针(18)F-AlF-NOTA-PRGD2，用于心肌梗死/再灌注(MI/R)动物模型中的血管生成成像。
雄性 Sprague-Dawley 大鼠进行 45 分钟短暂性左冠状动脉闭塞，随后再灌注。通过心电图、(18)F-氟脱氧葡萄糖(FDG)成像和心脏超声确认心肌梗死。再灌注后不同时间点进行活体 PET 成像，以确定(18)F-AlF-NOTA-PRGD2 在心肌中的摄取。用类似的程序标记对照肽 RAD，以确认特异性。进行离体放射性自显影分析和 CD31/CD61 双重免疫荧光染色以验证 PET 结果。
(18)F-FDG 和放射性自显影证实了(18)F-AlF-NOTA-PRGD2 聚集的心肌来源。PET 成像显示，在梗死区开始于第 3 天(0.28±0.03%ID/g，p<0.05)，并在 1 至 3 周之间达到峰值(0.59±0.16 和 0.55±0.13%ID/g，分别)，并在再灌注 4 个月后仍保持较高水平(0.31±0.01%ID/g，p<0.05)。用未标记的精氨酸-甘氨酸-天冬氨酸(RGD)肽预处理可显著降低示踪剂摄取，表明该示踪剂具有整合素特异性。在 MI/R 后 1 周，在梗死区，对照示踪剂(不与整合素结合的 18)F-AlF-NOTA-RAD 的摄取仅为 0.21±0.01%ID/g。放射性自显影显示心肌梗死区摄取呈相同趋势。焦点示踪剂摄取的时间过程与通过 CD31 和 CD61 免疫染色分析测量的血管密度和整合素β(3)表达模式一致。
使用一步标记的(18)F-AlF-NOTA-PRGD2 进行 PET 成像可实现缺血/再灌注诱导的心肌血管生成的非侵入性纵向可视化。这种整合素靶向 PET 示踪剂具有良好的体内动力学和易于生产的方法，有利于其未来在闭塞性心血管疾病患者中的临床转化，用于病变评估和治疗反应监测。
