Preclinical Evaluation of the Penciclovir Analog 9-(4-[18F]Fluoro-3-Hydroxymethylbutyl)Guanine for In Vivo Measurement of Suicide Gene Expression with PET

Journal of Nuclear Medicine

Erlinda M. Gordon¹  Antranik Shahinian¹  James R. Bading¹  Mian M. Alauddin¹  Peter S. Conti¹ 

[1] Department of Radiology, PET Imaging Science Center, University of Southern California, Los Angeles; and Gene Therapy Laboratory, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California Department of Radiology, PET Imaging Science Center, University of Southern California, Los Angeles; and Gene Therapy Laboratory, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California Department of Radiology, PET Imaging Science Center, University of Southern California, Los Angeles; and Gene Therapy Laboratory, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California

关键词: PET;    gene therapy;    [¹⁸F]FHBG;    virus;    colon cancer;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

The gene for herpes simplex virus thymidine kinase (HSV-tk) is widely used as a suicide gene in experimental gene therapy of cancer. 9-(4-Fluoro-3-hydroxymethylbutyl)guanine (FHBG) is an antiviral nucleoside analog that is rapidly phosphorylated by viral thymidine kinase but is a poor substrate for mammalian thymidine kinase. Recently, FHBG labeled in the 4-fluoro position with 18F has shown promise relative to other similar compounds for imaging in vivo expression of HSV-tk using PET. In this study, we evaluated the uptake of [18F]FHBG in vitro and in vivo using transduced and wild-type human colon cancer cells (HT-29). We also imaged [18F]FHBG and measured the radioactivity concentrations of circulating [18F]FHBG and its metabolites in monkeys. Methods: Sterile, pyrogen-free [18F]FHBG was produced routinely in good yields. Cells were transduced with the retroviral vector G1Tk1SvNa containing HSV-tk gene. In vitro uptake studies were performed by incubating cells with [18F]FHBG at 37°C for 1 and 5 h. Biodistribution studies were performed at 2 and 5 h after injection in nude mice bearing tumors grown from wild-type or transduced cells. Sequential, whole-body PET scans of cynomolgus monkeys were obtained over a period of >2 h after intravenous injection of [18F]FHBG. Arterial plasma samples obtained from monkeys 15–120 min after intravenous injection were subjected to acid extraction, and the acid-soluble fractions were analyzed by high-performance liquid chromatography. Results: In vitro studies showed 31 and 71 (P < 0.001) times higher uptake of the probe at 1 and 5 h, respectively, in transduced cells compared with nontransduced cells. In vivo studies in mice showed that tumor uptake of the radiotracer was 4-fold (P < 0.05) and 13-fold (P < 0.001) higher at 2 and 5 h, respectively, in tumors grown from transduced cells compared with control cells. Transduced tumor-to-normal tissue ratios ranged from 2 to 25 at 2 h and from 2 to 22 at 5 h. Recirculating labeled metabolites had only a minor effect on the biodistribution of radiolabel from [18F]FHBG in monkeys. Conclusion: These results indicate that [18F]FHBG may yield high-contrast PET images of HSV-tk expression in tumors and, therefore, it is a very promising radiotracer for monitoring of gene therapy of cancer with PET.

【 授权许可】

Unknown