18F-FEAU作为单纯疱疹病毒胸苷激酶基因表达的放射性示踪剂：与其他正电子发射断层显像（PET）示踪剂的体外比较

18F-FEAU as a radiotracer for herpes simplex virus thymidine kinase gene expression: in-vitro comparison with other PET tracers.

作者信息

Buursma Anne Rixt, Rutgers Vera, Hospers Geke A P, Mulder Nanno H, Vaalburg Willem, de Vries Erik F J

机构信息

Department of Nuclear Medicine and Molecular Imaging, Medical Center Groningen, University of Groningen, The Netherlands.

出版信息

Nucl Med Commun. 2006 Jan;27(1):25-30. doi: 10.1097/01.mnm.0000186609.12895.20.

DOI:10.1097/01.mnm.0000186609.12895.20

PMID:16340720

Abstract

OBJECTIVE

The herpes simplex virus thymidine kinase (HSVtk) gene has frequently been applied as a reporter gene for monitoring transgene expression in animal models. In clinical gene therapy protocols, however, extremely low expression levels of the transferred gene are generally observed. Consequently, sensitive and selective radiotracers for imaging are required. This study describes the in-vitro evaluation of 2'-[18F]fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil (18F-FEAU) as a candidate tracer for HSVtk imaging with positron emission tomography (PET).

METHODS

In cellular accumulation experiments, the potential of 18F-FEAU as a PET tracer for HSVtk was compared to the known acyclic guanosine derivatives 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine (18F-FHPG) and 9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine (18F-FHBG), and the thymidine derivatives 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT), 2'-deoxy-2'-[18F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU) and 2'-deoxy-2'-[18F]fluoro-5-iodo-1-beta-D-arabinofuranosyluracil (18F-FIAU). For this purpose, C6 control cells and HSVtk-expressing C6tk cells were incubated with the different tracers for various periods of time and cellular uptake and initial uptake rates were analysed. The initial rate of tracer uptake was determined from the slope of the plot of tracer uptake versus incubation time.

RESULTS

After 2 h of tracer incubation, the C6tk/C6 accumulation ratio was 1.6 for 18F-FLT, 2.4 for F-FMAU, 5.5 for 18F-FHPG, 10.3 for 18F-FIAU, 40.8 for 18F-FHBG and 84.5 for 18F-FEAU. The initial tracer uptake rate in C6tk cells was in the order FLT>FMAU>FEAU>FIAU>FHBG>FHPG, whereas the initial tracer uptake rate in C6 control cells was FLT>FMAU>FIAU>FEAU approximately = FHBG approximately = FHPG. The highest HSVtk specific uptake was observed for FEAU.

CONCLUSION

This study indicates that the high uptake rate of FEAU together with its high selectivity make this tracer an excellent candidate as a PET tracer for HSVtk gene expression.

摘要

目的

单纯疱疹病毒胸苷激酶（HSVtk）基因常被用作报告基因，用于监测动物模型中的转基因表达。然而，在临床基因治疗方案中，通常观察到转移基因的表达水平极低。因此，需要用于成像的灵敏且选择性的放射性示踪剂。本研究描述了2'-[18F]氟-5-乙基-1-β-D-阿拉伯呋喃糖基尿嘧啶（18F-FEAU）作为正电子发射断层扫描（PET）用于HSVtk成像的候选示踪剂的体外评估。

方法

在细胞摄取实验中，将18F-FEAU作为HSVtk的PET示踪剂的潜力与已知的无环鸟苷衍生物9-[(3-[18F]氟-1-羟基-2-丙氧基)甲基]鸟嘌呤（18F-FHPG）和9-[4-[18F]氟-3-(羟甲基)丁基]鸟嘌呤（18F-FHBG），以及胸苷衍生物3'-脱氧-3'-[18F]氟胸苷（18F-FLT）、2'-脱氧-2'-[18F]氟-5-甲基-1-β-D-阿拉伯呋喃糖基尿嘧啶（18F-FMAU）和2'-脱氧-2'-[18F]氟-5-碘-1-β-D-阿拉伯呋喃糖基尿嘧啶（18F-FIAU）进行比较。为此，将C6对照细胞和表达HSVtk的C6tk细胞与不同示踪剂孵育不同时间，并分析细胞摄取和初始摄取率。示踪剂摄取的初始速率由示踪剂摄取与孵育时间的关系图的斜率确定。

结果

示踪剂孵育2小时后，18F-FLT的C6tk/C6积累比为1.6，F-FMAU为2.4，18F-FHPG为5.5，18F-FIAU为10.3，18F-FHBG为40.8，18F-FEAU为84.5。C6tk细胞中示踪剂的初始摄取速率顺序为FLT>FMAU>FEAU>FIAU>FHBG>FHPG，而C6对照细胞中示踪剂的初始摄取速率为FLT>FMAU>FIAU>FEAU≈FHBG≈FHPG。观察到FEAU的HSVtk特异性摄取最高。