SPECT imaging of herpes simplex virus type1 thymidine kinase gene expression by [(123)I]FIAU(1).
OBJECTIVE
Introduction of suicide genes, such as herpes simplex virus type1 thymidine kinase (HSV1-tk), in tumor cells has provided a useful method for tumor gene therapy. Several L-nucleosides, such as Lamivudine (3TC) and Clevudine (L-FMAU), have been successfully tested as high-potency antiviral agents. To investigate the potential differences between D- and L-isomers of nucleosides, [(125/123)I]-2'-fluoro-2'-deoxy-1beta-D/L-arabino-furanosy-5-iodo-uracil (D/L-FIAU) have been synthesized and evaluated as potential SPECT agents for imaging HSV1-tk gene expression.


METHODS
[(125/123)I]D- and L-FIAU were prepared by iododestannylation of the respective tin precursors with (125/123)I-sodium iodide. In vitro cell uptake studies were performed by incubation of [(125)I]D- and L-FIAU in RG2 cells expressing HSV1-tk (RG2TK+). In vivo studies including biodistribution and SPECT were performed in RG2TK+ and RG2TK- tumor-bearing nude mice using [(123)I]D- and L-FIAU.


RESULTS
Cell uptake and biodistribution studies indicated that [(125/123)I]L-FIAU did not show any high accumulation (sensitivity) or uptake ratios (selectivity) in HSV1-TK-positive (RG2TK+) tumors as compared to control tumors. In contrast, [(125/123)I]D-FIAU displayed both sensitivity and selectivity to RG2TK+ tumors. The selective in vivo accumulation of [(123)I]D-FIAU increased with time and the tumor uptake ratios (RG2TK+/RG2TK-) for 2, 4, and 24 hours averaged 6.2, 22.7, and 58.8, respectively. High-resolution SPECT of four nude tumor-bearing mice demonstrated a very high uptake of [(123)I]D-FIAU in the RG2TK+ tumor, while no significant tracer accumulation was observed in the RG2TK- tumor and other organs.


CONCLUSIONS
The data suggest that only the D-isomer of [(123)I]FIAU is useful for imaging HSV1-tk gene expression in mice by high-resolution SPECT imaging.
Choi
Seok Rye
SR
Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, PA 19104, USA.
Zhuang
Zhi-Ping
ZP
Chacko
Ann-Marie
AM
Acton
Paul D
PD
Tjuvajev-Gelovani
Juri
J
Doubrovin
Mikhai
M
Chu
David C K
DC
Kung
Hank F
HF
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives*; D015870:Gene Expression; D015316:Genetic Therapy; D005910:Glioma / Q000000981:diagnostic imaging* / Q000201:enzymology; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009705:Nucleosides; D019275:Radiopharmaceuticals; D051381:Rats; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D015899:Tomography, Emission-Computed, Single-Photon
D007457:Iodine Radioisotopes; D009705:Nucleosides; D019275:Radiopharmaceuticals; D001086:Arabinofuranosyluracil; D013937:Thymidine Kinase