Comparison of radiolabeled nucleoside probes (FIAU, FHBG, and FHPG) for PET imaging of HSV1-tk gene expression.
Comparison of radiolabeled nucleoside probes (FIAU, FHBG, and FHPG) for PET imaging of HSV1-tk gene expression.
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发表时间：
2002-08
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通讯作者：
J. Tjuvajev;M. Doubrovin;T. Akhurst;S. Cai;J. Balatoni;M. Alauddin;R. Finn;W. Bornmann;H. Thaler;P. Conti;R. Blasberg
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作者：
J. Tjuvajev;M. Doubrovin;T. Akhurst;S. Cai;J. Balatoni;M. Alauddin;R. Finn;W. Bornmann;H. Thaler;P. Conti;R. Blasberg
未标记的目前感兴趣的3种放射性标记的探针用于PET体内成像单纯疱疹病毒1型胸苷激酶（HSV 1-tk）表达的功效，包括（124）I-或（131）I-标记的2 ′-氟-2 ′-脱氧-1-β-D-阿拉伯呋喃糖基-5-碘尿嘧啶（FIAU），（18）F-标记的9-[4-氟-3-（4-氟-3-甲基嘧啶-1-基）-5-碘尿嘧啶（FIAU），（羟甲基）丁基]鸟嘌呤（FHBG）和（18）F标记的9-[3-氟-1-羟基-2-丙氧基甲基]鸟嘌呤（FHPG）。方法建立两种大鼠胶质瘤细胞系，稳定转导的RG 2 TK+和野生型RG 2，用于体外探针积累的配对比较和无胸腺rnu/rnu大鼠皮下异种移植物的配对比较。结果在RG 2 TK+细胞中，FIAU的体外配对探针摄取量（0-3 h）比FHBG高15倍，比FHPG高41倍。对于FIAU、FHBG和FHPG，计算的RG 2 TK+细胞的净蓄积速率值（+/-SD）分别为0.317 +/- 0.066、0.022 +/- 0.001和0.0077 +/- 0.0003 mL/min/g细胞。这些结果和在RG 2野生型细胞中的类似摄取研究表明FHBG和FHPG可能存在细胞膜转运限制。配对的2小时体内摄取研究在FIAU和FHBG（1.22 +/- 0.21 vs. 0.074 +/-0.49%剂量/g）以及FIAU和FHPG（1.27 +/- 0.14 vs. 0.023 +/-0.008%剂量/g）的RG 2 TK+异种移植物中产生了相似的差异。这些差异在图像上清晰可见。24 h时FIAU蓄积为1.53 +/-0.40%剂量/g。血浆清除率FHBG > FHPG >> FIAU。FIAU图像显示显著的胃和一些肠背景放射性，而对于鸟苷类似物，肝胆和肠背景放射性非常高（FHBG > FHPG）。动态成像显示FIAU在RG 2 TK+异种移植物中的早期（约10分钟）选择性定位，而FHBG和FHPG在最初的2小时成像期间从HSV 1-tk转导和野生型异种移植物中清除。结论FIAU是一种比FHBG或FHPG更有效的HSV 1-tk表达显像探针，具有更高的灵敏度和对比度，且在2和24 h的腹部背景放射性水平更低。
UNLABELLED The efficacy of 3 radiolabeled probes of current interest for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) expression in vivo with PET, including (124)I- or (131)I-labeled 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodouracil (FIAU), (18)F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (FHBG), and (18)F-labeled 9-[3-fluoro-1-hydroxy-2-propoxymethyl]guanine (FHPG), was compared. METHODS Two established rat glioma cell lines, stably transduced RG2TK+ and wild-type RG2, were used for paired comparisons of probe accumulation in vitro and for paired comparisons of subcutaneous xenografts produced from these cell lines in athymic rnu/rnu rats. RESULTS The in vitro paired probe uptake (0-3 h) comparisons in RG2TK+ cells showed that FIAU accumulation was 15-fold greater than that of FHBG and 41-fold greater than that of FHPG. The net accumulation rate values (+/-SD) calculated for RG2TK+ cells were 0.317 +/- 0.066, 0.022 +/- 0.001, and 0.0077 +/- 0.0003 mL/min/g cells for FIAU, FHBG, and FHPG, respectively. These results and similar uptake studies in RG2 wild-type cells suggest a possible cell membrane transport limitation for FHBG and FHPG. The paired 2-h in vivo uptake studies produced similar differences in RG2TK+ xenografts for FIAU and FHBG (1.22 +/- 0.21 vs. 0.074 +/- 0.49 %dose/g) and for FIAU and FHPG (1.27 +/- 0.14 vs. 0.023 +/- 0.008 %dose/g). These differences were clearly visible on the images. FIAU accumulation at 24 h was 1.53 +/- 0.40 %dose/g. Plasma clearance was FHBG > FHPG >> FIAU. The FIAU images showed significant stomach and some intestinal background radioactivities, whereas hepatobiliary and intestinal background activities were very high for the guanosine analogs (FHBG > FHPG). Dynamic imaging showed early ( approximately 10 min) selective localization of FIAU in RG2TK+ xenografts, whereas FHBG and FHPG are being cleared from the HSV1-tk transduced and wild-type xenografts over the initial 2-h imaging period. CONCLUSION The in vitro and in vivo results (including the PET images) show that FIAU is a substantially more efficient probe than FHBG or FHPG for imaging HSV1-tk expression, with greater sensitivity and contrast as well as lower levels of abdominal background radioactivity at 2 and 24 h.