Herpes simplex virus thymidine kinase imaging in mice with (1-(2'-deoxy-2'-[18F]fluoro-1-β-D-arabinofuranosyl)-5-iodouracil) and metabolite (1-(2'-deoxy-2'-[18F]fluoro-1-β-D-arabinofuranosyl)-5-uracil).
OBJECTIVE
FIAU, (1-(2'-deoxy-2'-fluoro-1-β-D-arabinofuranosyl)-5-iodouracil) has been used as a substrate for herpes simplex virus thymidine kinases (HSV-TK and HSV-tk, for protein and gene expression, respectively) and other bacterial and viral thymidine kinases for noninvasive imaging applications. Previous studies have reported the formation of a de-iodinated metabolite of 18F-FIAU. This study reports the dynamic tumor uptake, biodistribution, and metabolite contribution to the activity of 18F-FIAU seen in HSV-tk gene expressing tumors and compares the distribution properties with its de-iodinated metabolite 18F-FAU.


METHODS
CD-1 nu/nu mice with subcutaneous MH3924A and MH3924A-stb-tk+ xenografts on opposite flanks were used for the biodistribution and imaging studies. Mice were injected IV with either 18F-FIAU or 18F-FAU. Mice underwent dynamic imaging with each tracer for 65 min followed by additional static imaging up to 150 min post-injection for some animals. Animals were sacrificed at 60 or 150 min post-injection. Samples of blood and tissue were collected for biodistribution and metabolite analysis. Regions of interest were drawn over the images obtained from both tumors to calculate the time-activity curves.


RESULTS
Biodistribution and imaging studies showed the highest uptake of 18F-FIAU in the MH3924A-stb-tk+ tumors. Dynamic imaging studies revealed a continuous accumulation of 18F-FIAU in HSV-TK expressing tumors over 60 min. The mean biodistribution values (SUV ± SE) for MH3924A-stb-tk+ were 2.07 ± 0.40 and 6.15 ± 1.58 and that of MH3924A tumors were 0.19 ± 0.07 and 0.47 ± 0.06 at 60 and 150 min, respectively. In 18F-FIAU injected mice, at 60 min nearly 63% of blood activity was present as its metabolite 18F-FAU. Imaging and biodistribution studies with 18F-FAU demonstrated no specific accumulation in MH3924A-stb-tk+ tumors and SUVs for both the tumors were similar to those observed with muscle.


CONCLUSIONS
18F-FIAU shows a continuous accumulation of activity in HSV-TK expressing tumors. 18F-FAU does not show any preferential accumulation in HSV-TK expressing tumors. In the 18F-FIAU treated mice, the 18F-FAU contribution to the total uptake seen in HSV-TK positive tumors is minimal.
Nimmagadda
Sridhar
S
Karmanos Cancer Institute, Wayne State University, 4100 John R, 4 HWCRC, Detroit, MI 48201-2013, USA.
Mangner
Thomas J
TJ
Lawhorn-Crews
Jawana M
JM
Haberkorn
Uwe
U
Shields
Anthony F
AF
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D001692:Biological Transport; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D051381:Rats; D018139:Simplexvirus / Q000201:enzymology*; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000378:metabolism*
C558662:1-(2'-deoxy-2'-fluoro-1-arabinofuranosyl)-5-uracil; C457880:2'-fluorodeoxyuracil-arabinofuranoside; D005462:Fluorine Radioisotopes; D001086:Arabinofuranosyluracil; C043457:fialuridine; D013937:Thymidine Kinase