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Evaluation of ⁷⁶Br-FBAU as a PET Reporter Probe for HSV1-tk Gene Expression Imaging Using Mouse Models of Human Glioma

¹ NeuroOncology Branch, National Cancer Institute and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
² PET Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
³ Institute of Radiology Sciences, Universita’ degli studi di Milano, Milan, Italy
⁴ Nuclear Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland

The utility of 5-⁷⁶Br-bromo-2'-fluoro-2'-deoxyuridine (⁷⁶Br-FBAU), a uracil analog, as a PET reporter probe for use with the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene system for gene expression imaging was evaluated in vivo and in vitro using human and rat glioma cells. Methods: Human glioma cell lines U87 and U251 were transduced with replication-defective adenovirus constitutively expressing HSV1-tk (Ad.TK) or a control expressing green fluorescent protein (Ad.GFP). These cells were incubated with ⁷⁶Br-FBAU for 20–120 min to determine the percentage of total dose uptake. In vitro uptake of equimolar concentrations (1.8 x 10^–8 mol/L) of ⁷⁶Br-FBAU and 2'-fluoro-2'-deoxy-5-iodouracil-ß-D-arabinofuranoside (¹⁴C-FIAU) was also determined in RG2-TK rat glioma cells stably expressing HSV1-tk and in control RG2 cells at 30–120 min. In vivo uptake of ⁷⁶Br-FBAU was determined in subcutaneous U87 tumor intratumorally transduced with Ad.TK by ex vivo biodistribution. Uptake in intracranial U87 tumors transduced with Ad.TK expressing HSV1-tk was measured by brain autoradiography. In vivo PET was performed on subcutaneous and intracranial U87 tumors transduced with Ad.TK and on subcutaneous and intracranial stably expressing RG2-TK tumors. Results: U87 and U251 cells transduced with Ad.TK had significantly increased uptake of ⁷⁶Br-FBAU compared with cells transduced with Ad.GFP over 20–120 min. In stably expressing cells at 120 min, ¹⁴C-FIAU uptake in RG2-TK tumor cells was 11.3 %ID (percentage injected dose) and in RG2 control cells was 1.7 %ID, and ⁷⁶Br-FBAU uptake in RG2-TK tumor cells was 14.2 %ID and in RG2 control cells was 1.5 %ID. Ex vivo biodistribution of subcutaneous U87 tumors transduced with Ad.TK accumulated ⁷⁶Br-FBAU significantly more than in the control Ad.GFP transduced tumor and normal tissue, with the lowest uptake in brain. Autoradiography showed localized uptake in intracranial U87 and U251 cells transduced with Ad.TK. PET image analyses of mice with RG2-TK tumors resulted in an increased tumor-to-background ratio of 13 and 26 from 2 to 6 h after injection, respectively, in intracranial tumors. Conclusion: ⁷⁶Br-FBAU accumulates in glioma cells constitutively expressing HSV1-tk by either adenoviral transduction or in stably expressing cell lines both in vitro and in vivo. ⁷⁶Br-FBAU shows promise as a PET reporter probe for use with the HSV1-tk in vivo gene expression imaging system.

Key Words: herpes simplex virus type 1 thymidine kinase • ⁷⁶Br-FBAU • glioma • small-animal PET

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