新型^(18)F-RGD二聚体的正常生物分布及U87MG荷瘤裸鼠小动物PET/CT显像研究

Biodistribution in healthy KM mice and micro PET/CT imaging in U87MG tumor-bearing nude mice of a new ^(18)F-labeled cyclic RGD dimer

背景与目的:整合素αvβ3受体在促进、维持以及调节血管生成的过程中有着至关重要的作用,高表达于多种肿瘤细胞及新生血管内皮细胞。RGD多肽序列可与整合素αvβ3受体特异性结合,有助于评价肿瘤的生长状况和侵袭性。本实验主要研究18F标记的RGD二聚体18F-E[c(RGDfK)2]在正常昆明小鼠体内的生物分布和荷人神经胶质瘤裸鼠模型的小动物PET/CT显像情况。方法:以硝基RGD二聚体4-NO2-3-TFMBz-E[c(RGDfK)2]为前体,使用改进的自动化合成模块Explora GN,一步法直接标记合成18F-E[c(RGDfK)2]。用昆明小鼠分析18F-E[c(RGDfK)2]0.5、1、2、4 h的生物分布,计算每克组织放射性占注入量的百分比(%ID/g)。观察荷人神经胶质瘤裸鼠模型1、2、4 h的小动物PET/CT显像情况。结果:18F-E[c(RGDfK)2]的标记率约为10%,放化纯度>98%,稳定性可达10 h。18F-E[c(RGDfK)2]主要经肾排泄,血液清除迅速,注射后1 h,肾、肝、小肠、肌肉和血的放射性摄取值分别为(1.02±0.16)%ID/g、(0.24±0.06)%ID/g、(0.35±0.03)%ID/g、(0.13±0.03)%ID/g和(0.11±0.03)%ID/g。注射后1 h,肿瘤对18F-E[c(RGDfK)2]的摄取达到高峰(5.2±0.56)%ID/g,T/M为5.36。阻断显像中,可见肿瘤组织放射性摄取明显减低,T/M平均值为1.57。结论:18F-E[c(RGDfK)2]与整合素受体特异性结合,肿瘤摄取较高、显像清晰,可用于整合素表达阳性肿瘤的预后判断、血管靶向治疗适应证的选择及疗效判断。

Background and purpose： Integrinαvβ3 receptor plays an important role in promoting, sustaining and regulating the angiogenesis. It is overexpressed on neovascular endothelial cells and tumor cells. RGD peptide specifically binds to integrin αvβ3, which could evaluate growth status and invasiveness of tumor. This study aimed to investigate the biodistribution in healthy KM mice and micro PET/CT imaging in U87MG tumor-bearing mice of ^18F-E[c（RGDfK）2]. Methods： ^18F-E[c（RGDfK）2] was produced using an automated synthesis module via a simple one-step ^18F-labeling strategy of the precursor 4-NO2-3-TFMBz-E[c（RGDfK）2]. The percentage activity of injection dose per gram of tissue （%ID/g） was calculated at 0.5, 1, 2, 4 h post injection of the probe. Micro PET/CT images of U87MG tumor-bearing nude mice with or without ^18F-E[c（RGDfK）2] blocking were acquired at each time point. Results： The labeling efficiency and radiochemical purity of ^18F-E[c（RGDfK）2] were 10% and 98%, respectively. ^18F-E[c（RGDfK）2] was excreted via renal route, with a high blood clearance. The other organs had background- level activity accumulation. At 1 h, the %ID/g of kidney, liver, intestine, muscle and blood was （1.02±0.16）%ID/g,（0.24±0.06）%ID/g, （0.35±0.03）%ID/g, （0.13±0.03）%ID/g and （0.11±0.03）%ID/g ^18F-E[c（RGDfK）2] had initial high tunor uptake [（5.2±0.56）%ID/g] and good tumor-to-background contrast （5.36） at 1 h post injection. Tumor uptake for blocking group was lower than those without blocking, and T/M reduced to 1.57. Conclusion： ^18F-E[c（RGDfK）2] appears a promising PET molecular imaging probe targeting integrin αvβ3, with high tumor uptake. It could be suitable for prognosis evaluation of integrin-positive tumor, selection of vascular targeting therapy and therapy effect monitoring.