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Synthesis and Preliminary Evaluation of $9-(4-[^{18}F]Fluoro-3-hydroxymethylbutyl)$ Guanine $([^{18}F]FHBG)$ in HSV1-tk Gene Transduced Hepatoma Cell  

Moon, Byung-Seok (Laboratory of Radiopharmaceuticals, Korea Institute of Radiological and Medical Sciences)
Lee, Tae-Sup (Laboratory of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences)
Lee, Myoung-Keun (Department of Medical Laboratory Science, Yonsei University)
Lee, Kyo-Chul (Laboratory of Radiopharmaceuticals, Korea Institute of Radiological and Medical Sciences)
An, Gwang-Il (Laboratory of Radiopharmaceuticals, Korea Institute of Radiological and Medical Sciences)
Chun, Kwon-Soo (Laboratory of Radiopharmaceuticals, Korea Institute of Radiological and Medical Sciences)
Awh, Ok-Doo (Department of Medical Laboratory Science, Yonsei University)
Chi, Dae-Yoon (Department of Chemistry, Inha University)
Choi, Chang-Woon (Laboratory of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences)
Lim, Sang-Moo (Laboratory of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences)
Cheon, Gi-Jeong (Laboratory of Radiopharmaceuticals, Korea Institute of Radiological and Medical Sciences)
Publication Information
Nuclear Medicine and Molecular Imaging / v.40, no.4, 2006 , pp. 218-227 More about this Journal
Abstract
Purpose: The HSV1-tk reporter gene system is the most widely used system because of its advantage that direct monitoring is possible without the introduction of a separate reporter gene in case of HSV1-tk suicide gene therapy. In this study, we investigate the usefulness of the reporter probe (substrate), $9-(4-[^{18}F]Fluoro-3-hydroxymethylbutyl)$guanine ($[^{18}F]FHBG$) for non-invasive reporter gene imaging using PET in HSV1-tk expressing hepatoma model. Materials and Methods: Radiolabeled FHBG was prepared in 8 steps from a commercially available triester. The labeling reaction was carried out by NCA nucleophilic substitution with $K[^{18}F]/K2.2.2.$ in acetonitrile using N2-monomethoxytrityl-9-14-(tosyl)-3-monomethoxytritylmethylbutyl]guanine as a precursor, followed by deprotection with 1 N HCl. Preliminary biological properties of the probe were evaluated with MCA cells and MCA-tk cells transduced with HSV1-tk reporter gene. In vitro uptake and release-out studies of $[^{18}F]FHBG$ were performed, and was analyzed correlation between $[^{18}F]FHBG$ uptake ratio according to increasing numeric count of MCA-tk cells and degree of gene expression. MicroPET scan image was obtained with MCA and MCA-tk tumor bearing Balb/c-nude mouse model. Results: $[^{18}F]FHBG$ was purified by reverse phase semi-HPLC system and collected at around 16-18 min. Radiothemical yield was about 20-25%) (corrected for decay), radiochemical purity was >95% and specific activity was around >55.5 $GBq/{\mu}\;mol$. Specific accumulation of $[^{18}F]FHBG$ was observed in HSV1-tk gene transduced MCA-tk cells but not in MCA cells, and consecutive 1 hour release-out results showed more than 86% of uptaked $[^{18}F]FHBG$ was retained inside of cells. The uptake of $[^{18}F]FHBG$ was showed a highly significant linear correlation ($R^2=0.995$) with increasing percentage of MCA-tk numeric cell count. In microPET scan images, remarkable difference of accumulation was observed for the two type of tumors. Conclusion: $[^{18}F]FHBG$ appears to be a useful as non-invasive PET imaging substrate in HSV1-tk expressing hepatoma model.
Keywords
$[^{18}F]FHBG$; thymidine kinase; gene therapy; PET;
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