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8-[¹⁸F]Fluoropenciclovir: An Improved Reporter Probe for Imaging HSV1-tk Reporter Gene Expression In Vivo Using PET

Crump Institute for Molecular Imaging; UCLA/Department of Energy Laboratory of Structural Biology and Molecular Medicine; Department of Molecular and Medical Pharmacology, Division of Nuclear Medicine; Molecular Biology Institute; Department of Biomathematics; and UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, California

View larger version (17K): [in a new window]   FIGURE 1. Structures of HSV1-TK reporter gene substrates. FIAU = 5-iodo-2'-fluoro-2'-deoxy-1-ß-D-arabinofuranosyluracil.

View larger version (30K): [in a new window]   FIGURE 2. Cell uptake studies. (A) 8-[3H]GCV (GCV) and 8-[3H]PCV (PCV) net accumulation in C6 control and C6-stb-tk+ cell lines as function of time. (B) FGCV and FPCV net accumulation in C6 control and C6-stb-tk+ cell lines as function of time. Data are expressed as mean ± SE from triplicate samples. 8-[3H]PCV and FPCV show greater accumulation in C6-stb-tk+ cells compared with that of 8-[3H]GCV and FGCV.

View larger version (13K): [in a new window]   FIGURE 3. FPCV metabolites present in livers of mice expressing HSV1-tk. Mouse was injected with 2.0 x 109 pfu of Ad-CMV-HSV1-tk virus, followed by injection of FPCV 48 h later. HPLC analysis of liver sample shows peaks corresponding to 9, 17, and 33 min, which likely represent FPCV mono-, di-, and triphosphates, respectively. Twenty percent of radioactivity retained in liver was present in DNA or RNA fraction (not shown).

View larger version (99K): [in a new window]   FIGURE 4. Adenoviral-mediated HSV1-tk reporter gene expression imaged in living mice. Swiss Webster mice were injected by tail vein with 1.0 x 109 pfu of control virus (A) or 1.0 x 109 pfu of Ad-CMV-HSV1-tk virus (B). For each mouse, whole-body mean coronal projection image of 18F activity distribution is displayed on left. Liver outline, in white, was determined from FPCV signal and cryostat slices. Second images from left are coronal sections, 2 mm thick taken from midthickness of entire coronal sections from microPET. After PET scans were obtained, mice were killed, frozen, and sectioned. Next images are photographs of tissue sections (45-µm thickness) corresponding to approximately midthickness of microPET coronal section. Images on right are DWBA (Autorad) of these tissue sections. Color scale represents FPCV %ID/g tissue. Images are displayed on same quantitative color scale to allow signal intensity comparisons among panels. All microPET images shown used three-dimensional filtered backprojection for reconstruction. FPCV localization is clearly visualized in HSV1-tk liver (%ID/g, 8.8) and only minimal retention is observed in control tumor (%ID/g, 0.02).

View larger version (11K): [in a new window]   FIGURE 5. Hepatic FPCV retention as function of hepatic HSV1-tk levels. Fifteen adult Swiss Webster mice were injected by tail vein with 0–2.0 x 109 pfu of Ad-CMV-HSV1-tk virus and additional control virus to maintain total viral burden at 2.0 x 109 pfu. Forty-eight (±1) hours later animals received tail vein injection of FPCV. Animals were killed 180 min later. Livers were removed and analyzed for 18F accumulation. Viral titer vs. FPCV %ID/g liver (left lobe) is shown. Excellent correlation is observed between FPCV %ID/g liver and amount of virus injected.

View larger version (86K): [in a new window]   FIGURE 6. FPCV vs. FGCV retention in HSV1-tk–expressing tumors. Mouse carrying C6 control and C6-stb-tk+ tumors was injected by tail vein with FDG and scanned. Twenty-four hours later, FGCV was injected by tail vein and second microPET scan was obtained. On third day, mouse was injected with FPCV and scanned again. Images are displayed using same global maximum to allow direct comparison. Quantitative scale is shown at right. Images shown were reconstructed using MAP reconstruction algorithm. FPCV retention in C6-stb-tk+ tumors was significantly greater than that of FGCV (%ID/g tumor, 0.5 and 0.1, respectively).

View larger version (93K): [in a new window]   FIGURE 7. Imaging D2R and HSV1-tk PET reporter genes in same animal. Mouse carrying C6-stb-tk+ tumor (right) and D2R tumor (left) was imaged by microPET for HSV1-tk reporter gene expression (using FPCV) and D2R reporter gene expression (using FESP). Both images are displayed using same global maximum to allow direct comparison. Quantitative scale is shown at right. Images shown were reconstructed with MAP reconstruction algorithm. Highly specific localization of FPCV and FESP was observed in tumors expressing HSV1-tk and D2R genes, respectively.