Comparison of Three Dimeric 18F-AlF-NOTA-RGD Tracers
Comparison of Three Dimeric 18F-AlF-NOTA-RGD Tracers
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三种二聚体 18F-AlF-NOTA-RGD 示踪剂的比较
DOI：
10.1007/s11307-013-0668-1
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发表时间：
2014-04-01
影响因子：
3.1
通讯作者：
Chen, Xiaoyuan
中科院分区：
文献类型：
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作者：
Guo, Jinxia;Lang, Lixin;Chen, Xiaoyuan
基于RGD肽的放射性示踪剂被公认为整合素α（v）β（3）成像探针，以评估肿瘤血管生成或缺血或梗死后的组织重塑。为了优化成像探针的标记工艺和药代动力学，我们合成了三种聚乙二醇修饰和未修饰的RGD二聚肽，并进行了体内筛选，通过F-18铝氟化物配合物与环状螯合剂1，4，7-三氮杂环壬烷-1，4，7-三乙酸（NOTA）反应实现了放射性标记。合成了三种成像探针F-18-AlF-NOTA-E[c（RGDfK）]（2）、F-18-AlF-NOTA-PEG（4）-E[c（RGDfK）]（2）和F-18-AlF-NOTA-E[PEG（4）-c（RGDfk）]（2）。通过竞争性细胞结合试验测定受体结合亲和力，并通过小鼠血清孵育评价稳定性。通过直接组织取样和荷瘤小鼠的PET定量来比较三种示踪剂的肿瘤摄取和全身分布。所有三种化合物与小鼠血清孵育120 min后保持完整。它们在U87 MG肿瘤中均具有快速且相对较高的示踪剂摄取，具有良好的靶向背景比。与其他两种示踪剂相比，F-18-AlF-NOTA-E[PEG（4）-c（RGDfk）]（2）在肝脏中具有最高的肿瘤摄取和最低的蓄积。通过共注射未标记的二聚体RGD肽证实了整合素受体的特异性，并成功应用F-18-氟化铝与NOTA-肽缀合物复合的快速一步放射性标记策略合成了三种二聚体RGD肽。在开发的三种探针中，具有相对低的肝脏摄取和高肿瘤蓄积的F-18-AlF-NOTA-E[PEG（4）-c（RGDfk）]（2）似乎是进一步转化研究的有希望的候选物。
RGD peptide-based radiotracers are well established as integrin alpha(v)beta(3) imaging probes to evaluate tumor angiogenesis or tissue remodeling after ischemia or infarction. In order to optimize the labeling process and pharmacokinetics of the imaging probes, we synthesized three dimeric RGD peptides with or without PEGylation and performed in vivo screening.Radiolabeling was achieved through the reaction of F-18 aluminum-fluoride complex with the cyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Three imaging probes were synthesized as F-18-AlF-NOTA-E[c(RGDfK)](2), F-18-AlF-NOTA-PEG(4)-E[c(RGDfK)](2), and F-18-AlF-NOTA-E[PEG(4)-c(RGDfk)](2). The receptor binding affinity was determined by competitive cell binding assay, and the stability was evaluated by mouse serum incubation. Tumor uptake and whole body distribution of the three tracers were compared through direct tissue sampling and PET quantification of U87MG tumor-bearing mice.All three compounds remained intact after 120 min incubation with mouse serum. They all had a rapid and relatively high tracer uptake in U87MG tumors with good target-to-background ratios. Compared with the other two tracers, F-18-AlF-NOTA-E[PEG(4)-c(RGDfk)](2) had the highest tumor uptake and the lowest accumulation in the liver. The integrin receptor specificity was confirmed by co-injection of unlabeled dimeric RGD peptide.The rapid one-step radiolabeling strategy by the complexation of F-18-aluminum fluoride with NOTA-peptide conjugates was successfully applied to synthesize three dimeric RGD peptides. Among the three probes developed, F-18-AlF-NOTA-E[PEG(4)-c(RGDfk)](2) with relatively low liver uptake and high tumor accumulation appears to be a promising candidate for further translational research.