68Ga-labeled cyclic RGD dimers with Gly3 and PEG4 linkers: promising agents for tumor integrin αvβ3 PET imaging
68Ga-labeled cyclic RGD dimers with Gly3 and PEG4 linkers: promising agents for tumor integrin αvβ3 PET imaging
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DOI：
10.1007/s00259-008-1045-1
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发表时间：
2009-06-01
影响因子：
9.1
通讯作者：
Chen, Xiaoyuan
中科院分区：
文献类型：
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作者：
Liu, Zhaofei;Niu, Gang;Chen, Xiaoyuan
放射性标记的环RGD（Arg-Gly-Asp）肽在肿瘤的早期检测、无创性监测肿瘤转移和治疗反应方面具有巨大的潜力。F-18标记的RGD类似物（[F-18]-AH 111585和[F-18]半乳糖-RGD）已在癌症患者中整联蛋白表达的正电子发射断层扫描（PET）成像的临床试验中进行了研究。为了开发具有更高的肿瘤积累、改善的体内动力学、容易获得和低成本的新的RGD放射性示踪剂，我们开发了两种新的RGD肽，并用发生器洗脱的Ga-68（t（1/2）= 68 min）标记它们，用于肿瘤异种移植模型中整联蛋白α（v）β（3）表达的PET成像。设计、合成了（P-4-RGD 2，PEG（4）= 15-氨基-4，7，10，13-四氧杂十五烷酸）和E[Gly（3）-c（RGDfK）]（2）（G（3）-RGD 2，G（3）= Gly-Gly-Gly），并与1，4，7-三氮杂环壬烷三乙酸（NOTA）偶联用于Ga-68标记。在整合素α（v）β（3）阳性的异种移植瘤中研究了Ga-68标记的RGD示踪剂的microPET成像和生物分布。具有Gly（3）和PEG（4）接头的新的RGD二聚体显示出比无接头的RGD二聚体（RGD 2）更高的整合素α（v）β（3）结合亲和力。NOTA-G（3）-RGD 2和NOTA-P-4-RGD 2可以在30 min内用Ga-68标记，具有较高的纯度（> 98%）和比活性（8.88-11.84 MBq/nmol）。Ga-68-NOTA-P-4-RGD 2和Ga-68-NOTA-G（3）-RGD 2的肿瘤摄取和肿瘤/正常组织比均显著高于Ga-68-NOTA-RGD 2。由于它们的高亲和力、高特异性和优良的药代动力学特性，有必要进一步研究这两种新型RGD二聚体用于癌症患者中整合素α（v）β（3）表达的临床PET成像。
Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides have great potential for the early tumor detection and noninvasive monitoring of tumor metastasis and therapeutic response. F-18-labeled RGD analogs ([F-18]-AH111585 and [F-18]Galacto-RGD) have been investigated in clinical trials for positron emission tomography (PET) imaging of integrin expression in cancer patients. To develop new RGD radiotracers with higher tumor accumulation, improved in vivo kinetics, easy availability and low cost, we developed two new RGD peptides and labeled them with generator-eluted Ga-68 (t(1/2) = 68 min) for PET imaging of integrin alpha(v)beta(3) expression in tumor xenograft models.The two new cyclic RGD dimers, E[PEG(4)-c(RGDfK)](2) (P-4-RGD2, PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and E[Gly(3)-c(RGDfK)](2) (G(3)-RGD2, G(3) = Gly-Gly-Gly) were designed, synthesized and conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) for Ga-68 labeling. The microPET imaging and biodistribution of the Ga-68 labeled RGD tracers were investigated in integrin alpha(v)beta(3)-positive tumor xenografts.The new RGD dimers with the Gly(3) and PEG(4) linkers showed higher integrin alpha(v)beta(3) binding affinity than no-linker RGD dimer (RGD2). NOTA-G(3)-RGD2 and NOTA-P-4-RGD2 could be labeled with Ga-68 within 30 min with higher purity (> 98%) and specific activity (8.88-11.84 MBq/nmol). Both Ga-68-NOTA-P-4-RGD2 and Ga-68-NOTA-G(3)-RGD2 exhibited significantly higher tumor uptake and tumor-to-normal tissue ratios than Ga-68-NOTA-RGD2.Because of their high affinity, high specificity and excellent pharmacokinetic properties, further investigation of the two novel RGD dimers for clinical PET imaging of integrin alpha(v)beta(3) expression in cancer patients is warranted.