Direct Comparison of Radiolabeled Probes FMAU, FHBG, and FHPG as PET Imaging Agents for HSV1-tk Expression in a Human Breast Cancer Model

2′-Deoxy-2′-fluoro-5-methyl-1-β-d-arabinofuranosyluracil (FMAU), 9-(4-fluoro-3-hydroxy-methyl-butyl)guanine (FHBG) and 9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]-guanine (FHPG) have been evaluated in a human breast cancer model as potential radiotracers for PET imaging of HSV1-tk gene expression. In vitro accumulation of [14C]FMAU, [18F]FHBG, and [18F]FHPG in HSV1-tk-expressing cells was 14- to 16-fold (p < .001), 9- to 13-fold (p < .001), and 2- to 3-fold (p < .05) higher than tk-negative control cells, respectively, between 30 and 240 min. Accumulation of FMAU and FHBG in vector-transduced cells was 10- to 14-fold and 6- to 10-fold higher than wild-type cells, respectively. At 2 hr, uptake of [14C]FMAU in tk-positive cells was 6.3-fold and 60-fold higher than [18F]FHBG and [18F]FHPG, respectively. In vivo, tumor uptake of [14C]FMAU in HSV1-tk-expressing cells was 3.7-fold and 5.5-fold (p < .001) higher than tk-negative control cells at 1 and 2 hr, respectively. Tumor uptake of [18F]FHBG was 4.2-fold and 12.6-fold higher (p < .001) than tk-negative cells at the same time points. Incorporation of [14C]FMAU in tk-positive tumor was 18-fold and 24-fold higher (p < .001) than [18F]FHBG at 1 and 2 hr, respectively. Micro-PET images support the biodistribution results and indicate that both [18F]FMAU and [18F]FHBG are useful for imaging HSV1-tk expression in breast cancer. Although FMAU demonstrates higher total incorporation (%dose/g) in tumor tissue compared with the other tracers, FHBG is superior in terms of specific accumulation in transfected cells at later time points.

[1]  S. Gambhir,et al.  Comparison of [18F]FHBG and [14C]FIAU for imaging of HSV1-tk reporter gene expression: adenoviral infection vs stable transfection , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[2]  P. Conti,et al.  Synthesis of [18F]‐labeled 2′‐deoxy‐2′‐fluoro‐5‐methyl‐1‐β‐D‐arabinofuranosyluracil ([18F]‐FMAU) , 2002 .

[3]  P. Conti,et al.  Evaluation of 2′-Deoxy-2′-Flouro-5-Methyl-1-β-d-Arabinofuranosyluracil as a Potential Gene Imaging Agent for HSV-tk Expression In Vivo , 2002 .

[4]  J. Bading,et al.  Preclinical evaluation of the penciclovir analog 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl)guanine for in vivo measurement of suicide gene expression with PET. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[5]  S. Cherry,et al.  Quantification of target gene expression by imaging reporter gene expression in living animals , 2000, Nature Medicine.

[6]  J. Bading,et al.  Pharmacokinetics of the thymidine analog 2'-fluoro-5-[(14)C]-methyl-1-beta-D-arabinofuranosyluracil ([(14)C]FMAU) in rat prostate tumor cells. , 2000, Nuclear medicine and biology.

[7]  R. Blasberg,et al.  Imaging adenoviral-mediated herpes virus thymidine kinase gene transfer and expression in vivo. , 1999, Cancer research.

[8]  J. Barrio,et al.  Assays for noninvasive imaging of reporter gene expression. , 1999, Nuclear medicine and biology.

[9]  P. Conti,et al.  Evaluation of 9-[(3-18F-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]-FHPG) in vitro and in vivo as a probe for PET imaging of gene incorporation and expression in tumors. , 1999, Nuclear medicine and biology.

[10]  S. Cherry,et al.  Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Humm,et al.  Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. , 1998, Cancer research.

[12]  P. Conti,et al.  Synthesis and preliminary evaluation of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG): a new potential imaging agent for viral infection and gene therapy using PET. , 1998, Nuclear medicine and biology.

[13]  Z. Ram,et al.  Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells , 1997, Nature Medicine.

[14]  G. van Kaick,et al.  Monitoring gene therapy with herpes simplex virus thymidine kinase in hepatoma cells: uptake of specific substrates. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[15]  P. Conti,et al.  9-[(3-[18F]-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]-FHPG): a potential imaging agent of viral infection and gene therapy using PET. , 1996, Nuclear medicine and biology.

[16]  R. Blasberg,et al.  Imaging the expression of transfected genes in vivo. , 1995, Cancer research.

[17]  Y. Chiang,et al.  An improved retroviral vector encoding the herpes simplex virus thymidine kinase gene increases antitumor efficacy in vivo. , 1995, Cancer gene therapy.

[18]  W F Anderson,et al.  Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. , 1993, Human gene therapy.

[19]  G. Maga,et al.  L-thymidine is phosphorylated by herpes simplex virus type 1 thymidine kinase and inhibits viral growth. , 1992, Journal of medicinal chemistry.

[20]  Z. Ram,et al.  In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. , 1992, Science.

[21]  J. Urbain.  Reporter genes and imagene. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[22]  N. Satyamurthy,et al.  8-[18F]Fluoropenciclovir: an improved reporter probe for imaging HSV1-tk reporter gene expression in vivo using PET. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  R. Evans,et al.  Lymphoma regression induced by ganciclovir in mice bearing a herpes thymidine kinase transgene. , 1990, Human gene therapy.

[24]  K. Watanabe,et al.  Nucleosides. 110. Synthesis and antiherpes virus activity of some 2'-fluoro-2'-deoxyarabinofuranosylpyrimidine nucleosides. , 1979, Journal of medicinal chemistry.