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Journal of Nuclear Medicine Vol. 43 No. 8 1072-1083
© 2002 by Society of Nuclear Medicine

Basic Science Investigations

Comparison of Radiolabeled Nucleoside Probes (FIAU, FHBG, and FHPG) for PET Imaging of HSV1-tk Gene Expression

Juri Gelovani Tjuvajev, MD, PhD1,2, Mikhail Doubrovin, MD, PhD1, Timothy Akhurst, MD2,3, Shangde Cai, PhD4, Julius Balatoni, PhD1, Mian M. Alauddin, PhD5, Ronald Finn, PhD2,4, William Bornmann, PhD6, Howard Thaler, PhD7, Peter S. Conti, MD5 and Ronald G. Blasberg, MD1,2

1 Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York
2 Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York
3 Nuclear Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, New York
4 Radiochemistry/Cyclotron Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York
5 Department of Radiology, PET Imaging Science Center, University of Southern California, Los Angeles, California
6 Preparative Core Resource Facility, Memorial Sloan-Kettering Cancer Center, New York, New York
7 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York

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 124I- or 131I-labeled 2'-fluoro-2'-deoxy-1-ß-D-arabinofuranosyl-5-iodouracil (FIAU), 18F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (FHBG), and 18F-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 (~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.

Key Words: HSV1-tk • PET • 2'-fluoro-2'-deoxy-1-ß-D-arabinofuranosyl-5-iodouracil • 9-[3-fluoro-1-hydroxy-2-propoxymethyl] • guanine • 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine • 124I • 18F • reporter gene




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