18F 标记的微型聚乙二醇间隔的 RGD 二聚体（18F-FPRGD2）：αvβ3 整合素表达的合成与微型正电子发射断层显像
18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of alphavbeta3 integrin expression.
作者信息
Wu Zhanhong, Li Zi-Bo, Cai Weibo, He Lina, Chin Frederick T, Li Fang, Chen Xiaoyuan
机构信息
The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd, P095, Stanford, CA 94305-5484, USA.
Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, People's Republic of China.
出版信息
Eur J Nucl Med Mol Imaging. 2007 Nov;34(11):1823-1831. doi: 10.1007/s00259-007-0427-0. Epub 2007 May 5.
PURPOSE
We have previously reported that (18)F-FB-Ec(RGDyK) ((18)F-FRGD2) allows quantitative PET imaging of integrin alpha(v)beta(3) expression. However, the potential clinical translation was hampered by the relatively low radiochemical yield. The goal of this study was to improve the radiolabeling yield, without compromising the tumor targeting efficiency and in vivo kinetics, by incorporating a hydrophilic bifunctional mini-PEG spacer.
METHODS
(18)F-FB-mini-PEG-Ec(RGDyK) ((18)F-FPRGD2) was synthesized by coupling N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) with NH(2)-mini-PEG-Ec(RGDyK) (denoted as PRGD2). In vitro receptor binding affinity, metabolic stability, and integrin alpha(v)beta(3) specificity of the new tracer (18)F-FPRGD2 were assessed. The diagnostic value of (18)F-FPRGD2 was evaluated in subcutaneous U87MG glioblastoma xenografted mice and in c-neu transgenic mice by quantitative microPET imaging studies.
RESULTS
The decay-corrected radiochemical yield based on (18)F-SFB was more than 60% with radiochemical purity of >99%. (18)F-FPRGD2 had high receptor binding affinity, metabolic stability, and integrin alpha(v)beta(3)-specific tumor uptake in the U87MG glioma xenograft model comparable to those of (18)F-FRGD2. The kidney uptake was appreciably lower for (18)F-FPRGD2 compared with (18)F-FRGD2 [2.0 +/- 0.2%ID/g for (18)F-FPRGD2 vs 3.0 +/- 0.2%ID/g for (18)F-FRGD2 at 1 h post injection (p.i.)]. The uptake in all the other organs except the urinary bladder was at background level. (18)F-FPRGD2 also exhibited excellent tumor uptake in c-neu oncomice (3.6 +/- 0.1%ID/g at 30 min p.i.).
CONCLUSION
Incorporation of a mini-PEG spacer significantly improved the overall radiolabeling yield of (18)F-FPRGD2. (18)F-FPRGD2 also had reduced renal uptake and similar tumor targeting efficacy as compared with (18)F-FRGD2. Further testing and clinical translation of (18)F-FPRGD2 are warranted.
目的
我们之前报道过，（18）F-FB-E[c（RGDyK）]（2）（（18）F-FRGD2）可实现整合素α（v）β（3）表达的定量PET成像。然而，相对较低的放射化学产率阻碍了其潜在的临床转化。本研究的目的是通过引入亲水性双功能微型聚乙二醇间隔臂，在不影响肿瘤靶向效率和体内动力学的前提下，提高放射性标记产率。
方法
通过将N-琥珀酰亚胺基-4-（18）F-氟苯甲酸酯（（18）F-SFB）与NH（2）-微型聚乙二醇-E[c（RGDyK）]（2）（记为PRGD2）偶联，合成了（18）F-FB-微型聚乙二醇-E[c（RGDyK）]（2）（（18）F-FPRGD2）。评估了新型示踪剂（18）F-FPRGD2的体外受体结合亲和力、代谢稳定性和整合素α（v）β（3）特异性。通过定量微型PET成像研究，在皮下接种U87MG胶质母细胞瘤的异种移植小鼠和c-neu转基因小鼠中评估了（18）F-FPRGD2的诊断价值。
结果
基于（18）F-SFB的衰变校正放射化学产率超过60%，放射化学纯度>99%。在U87MG胶质瘤异种移植模型中，（18）F-FPRGD2具有高受体结合亲和力、代谢稳定性和整合素α（v）β（3）特异性肿瘤摄取，与（18）F-FRGD2相当。与（18）F-FRGD2相比，（18）F-FPRGD2的肾脏摄取明显更低[注射后1小时（p.i.），（18）F-FPRGD2为2.0±0.2%ID/g，（18）F-FRGD2为3.0±0.2%ID/g（p<0.05）]。除膀胱外，所有其他器官的摄取均处于本底水平。（18）F-FPRGD2在c-neu肿瘤小鼠中也表现出优异的肿瘤摄取（注射后30分钟时为3.6±0.1%ID/g）。
结论
引入微型聚乙二醇间隔臂显著提高了（18）F-FPRGD2的整体放射性标记产率。与（18）F-FRGD2相比，（18）F-FPRGD2的肾脏摄取也有所降低，且肿瘤靶向疗效相似。（18）F-FPRGD2值得进一步测试和临床转化。
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