利用（111）铟-二乙三胺五乙酸-羧基化去唾液酸糖蛋白（In-DTPA-cNGR）和（99m）锝-甲氧基异丁基异腈（Tc-sestamibi）双同位素心肌单光子发射计算机断层扫描（SPECT）对心肌梗死后血管生成进行分子成像
Molecular imaging of angiogenesis after myocardial infarction by (111)In-DTPA-cNGR and (99m)Tc-sestamibi dual-isotope myocardial SPECT.
作者信息
Hendrikx Geert, De Saint-Hubert Marijke, Dijkgraaf Ingrid, Bauwens Matthias, Douma Kim, Wierts Roel, Pooters Ivo, Van den Akker Nynke Ms, Hackeng Tilman M, Post Mark J, Mottaghy Felix M
机构信息
Department of Nuclear Medicine, Maastricht University Medical Centre (MUMC+), Postbox 5800, 6202 AZ Maastricht, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
Department of Biochemistry, Maastricht University, Maastricht, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
出版信息
EJNMMI Res. 2015 Jan 28;5:2. doi: 10.1186/s13550-015-0081-7. eCollection 2015.
BACKGROUND
CD13 is selectively upregulated in angiogenic active endothelium and can serve as a target for molecular imaging tracers to non-invasively visualise angiogenesis in vivo. Non-invasive determination of CD13 expression can potentially be used to monitor treatment response to pro-angiogenic drugs in ischemic heart disease. CD13 binds peptides and proteins through binding to tripeptide asparagine-glycine-arginine (NGR) amino acid residues. Previous studies using in vivo fluorescence microscopy and magnetic resonance imaging indicated that cNGR tripeptide-based tracers specifically bind to CD13 in angiogenic vasculature at the border zone of the infarcted myocardium. In this study, the CD13-binding characteristics of an (111)In-labelled cyclic NGR peptide (cNGR) were determined. To increase sensitivity, we visualised (111)In-DTPA-cNGR in combination with (99m)Tc-sestamibi using dual-isotope SPECT to localise CD13 expression in perfusion-deficient regions.
METHODS
Myocardial infarction (MI) was induced in Swiss mice by ligation of the left anterior descending coronary artery (LAD). (111)In-DTPA-cNGR and (99m)Tc-sestamibi dual-isotope SPECT imaging was performed 7 days post-ligation in MI mice and in control mice. In addition, ex vivo SPECT imaging on excised hearts was performed, and biodistribution of (111)In-DTPA-cNGR was determined using gamma counting. Binding specificity of (111)In-DTPA-cNGR to angiogenic active endothelium was determined using the Matrigel model.
RESULTS
Labelling yield of (111)In-DTPA-cNGR was 95% to 98% and did not require further purification. In vivo, (111)In-DTPA-cNGR imaging showed a rapid clearance from non-infarcted tissue and a urinary excretion of 82% of the injected dose (I.D.) 2 h after intravenous injection in the MI mice. Specific binding of (111)In-DTPA-cNGR was confirmed in the Matrigel model and, moreover, binding was demonstrated in the infarcted myocardium and infarct border zone.
CONCLUSIONS
Our newly designed and developed angiogenesis imaging probe (111)In-DTPA-cNGR allows simultaneous imaging of CD13 expression and perfusion in the infarcted myocardium and the infarct border zone by dual-isotope micro-SPECT imaging.
背景
CD13在血管生成活跃的内皮细胞中选择性上调，可作为分子成像示踪剂的靶点，用于在体内非侵入性地可视化血管生成。非侵入性测定CD13表达可能用于监测缺血性心脏病中促血管生成药物的治疗反应。CD13通过与三肽天冬酰胺-甘氨酸-精氨酸（NGR）氨基酸残基结合来结合肽和蛋白质。先前使用体内荧光显微镜和磁共振成像的研究表明，基于cNGR三肽的示踪剂在梗死心肌边缘区的血管生成脉管系统中特异性结合CD13。在本研究中，测定了一种（111）In标记的环状NGR肽（cNGR）的CD13结合特性。为了提高灵敏度，我们使用双同位素SPECT将（111）In-DTPA-cNGR与（99m）Tc- sestamibi联合成像，以在灌注缺陷区域定位CD13表达。
方法
通过结扎左冠状动脉前降支（LAD）在瑞士小鼠中诱导心肌梗死（MI）。在结扎后7天对MI小鼠和对照小鼠进行（111）In-DTPA-cNGR和（99m）Tc- sestamibi双同位素SPECT成像。此外，对切除的心脏进行离体SPECT成像，并使用γ计数法测定（111）In-DTPA-cNGR的生物分布。使用基质胶模型确定（111）In-DTPA-cNGR对血管生成活跃内皮细胞的结合特异性。
结果
（111）In-DTPA-cNGR的标记率为95%至98%，无需进一步纯化。在体内，（111）In-DTPA-cNGR成像显示在非梗死组织中快速清除，在MI小鼠静脉注射后2小时，尿液排泄量为注射剂量（I.D.）的82%。在基质胶模型中证实了（111）In-DTPA-cNGR的特异性结合，此外，在梗死心肌和梗死边缘区也证实了结合。
结论
我们新设计和开发的血管生成成像探针（111）In-DTPA-cNGR通过双同位素微SPECT成像能够同时对梗死心肌和梗死边缘区的CD13表达和灌注进行成像。
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