Comparison of radiolabeled nucleoside probes (FIAU, FHBG, and FHPG) for PET imaging of HSV1-tk gene expression.
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.


CONCLUSIONS
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.
Tjuvajev
Juri Gelovani
JG
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Doubrovin
Mikhail
M
Akhurst
Timothy
T
Cai
Shangde
S
Balatoni
Julius
J
Alauddin
Mian M
MM
Finn
Ronald
R
Bornmann
William
W
Thaler
Howard
H
Conti
Peter S
PS
Blasberg
Ronald G
RG
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives*; D002250:Carbon Radioisotopes; D019788:Fluorodeoxyglucose F18; D015870:Gene Expression; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D007457:Iodine Radioisotopes; D009705:Nucleosides; D019275:Radiopharmaceuticals; D051381:Rats; D011923:Rats, Nude; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics*; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D007457:Iodine Radioisotopes; D009705:Nucleosides; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D001086:Arabinofuranosyluracil; C043457:fialuridine; D013937:Thymidine Kinase