Department of Nuclear Medicine, Seoul National University, Seoul, Korea,
Angiogenesis. 2013 Oct;16(4):837-46. doi: 10.1007/s10456-013-9359-4. Epub 2013 Jul 16.
Gallium-68-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-cyclic Arg-Gly-Asp-D-Tyr-Lys (c(RGDyK)) was developed for αvβ3 targeting, and is a promising agent for imaging of cancer and disorders related to angiogenesis. In this study, we performed kinetic analysis of (68)Ga-NOTA-c(RGDyK) in rats with surgically induced forelimb ischemia, and immunohistochemical analysis was also performed to assess αvβ3 immuno-staining level. Animal models were created by excision of the left brachial vessels, and a sham operation was performed on the right brachial region under 2 % isoflurane anesthesia. Using an animal positron emission tomography/computed tomography (PET/CT) scanner, a list mode PET scan (120 min) was started with the injection of (68)Ga-NOTA-c(RGDyK) via the tail vein at 3, 5 and 7 days after ischemic surgery. Volumes of interest were drawn on the left ventricle, sham operation, control, and ischemic regions. Compartmental and two graphical analyses (Logan and RE plots) were performed for kinetic parameter estimation. The immunohistochemical analysis was also performed after the last PET scan, and cell components were scored on a six point scale for quantification of immuno-staining level (0-negative to 5-very high). A 3-compartment model with reversible binding best described the tissue time-activity curves. The distribution volume of the ischemic region was significantly higher than that of the sham operation (P < 10(-6)) and control region (P < 10(-9)). Both the Logan and RE plots showed high correlation with compartmental analysis (R(2) = 0.96 and 0.95 for Logan and RE, respectively). The temporal changes in distribution volume and binding potential were not significant. The immuno-staining level of the ischemic region was significantly higher than that of sham operation (P < 10(-4)) and control region (P < 10(-8)). Kinetic modeling studies with dynamic (68)Ga-NOTA-c(RGDyK) PET scan are feasible based on an image-derived input function in a rat ischemia model. The kinetic modeling analysis performed in this study will be useful for the quantitative evaluation of (68)Ga-NOTA-c(RGDyK) binding to αvβ3 in angiogenic tissues.
镓-68 标记的 1,4,7-三氮杂环壬烷-1,4,7-三乙酸（NOTA）-环精氨酸-甘氨酸-天冬氨酸-D-酪氨酸-赖氨酸（c（RGDyK））被开发用于靶向αvβ3，是一种用于成像癌症和与血管生成相关疾病的有前途的试剂。在这项研究中，我们对手术诱导的前肢缺血大鼠中的（68）Ga-NOTA-c（RGDyK）进行了动力学分析，并进行了免疫组织化学分析以评估αvβ3免疫染色水平。动物模型通过切除左肱血管创建，并且在 2%异氟烷麻醉下对右肱区域进行假手术。使用动物正电子发射断层扫描/计算机断层扫描（PET/CT）扫描仪，通过尾静脉注射（68）Ga-NOTA-c（RGDyK）后，在缺血手术后 3、5 和 7 天开始进行列表模式 PET 扫描（120 分钟）。在左心室、假手术、对照和缺血区域上绘制了感兴趣的体积。进行了房室和两个图形分析（Logan 和 RE 图）以进行动力学参数估计。在最后一次 PET 扫描后还进行了免疫组织化学分析，并对细胞成分进行了六点评分以量化免疫染色水平（0-阴性至 5-非常高）。具有可逆结合的 3 房室模型最佳描述了组织时间-活性曲线。缺血区域的分布体积明显高于假手术（P < 10（-6））和对照区域（P < 10（-9））。Logan 和 RE 图均与房室分析高度相关（Logan 和 RE 的 R（2）分别为 0.96 和 0.95）。分布体积和结合势的时间变化没有意义。缺血区域的免疫染色水平明显高于假手术（P < 10（-4））和对照区域（P < 10（-8））。基于大鼠缺血模型中的图像衍生输入函数，动态（68）Ga-NOTA-c（RGDyK）PET 扫描的动力学建模研究是可行的。本研究中的动力学建模分析将有助于定量评估血管生成组织中（68）Ga-NOTA-c（RGDyK）与αvβ3 的结合。
