A simplified one-pot synthesis of 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine([18F]FHPG) and 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) for gene therapy.
Shiue, Grace G.; Shiue, Ching-Yann; Lee, Roland L.et al.
2001 • In Nuclear Medicine and Biology, 28 (7), p. 875-83
[en] 9-[(3-[18F]Fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG, 2) has been synthesized by nucleophilic substitution of N(2)-(p-anisyldiphenylmethyl)-9-[[1-(p-anisyldiphenylmethoxy)-3-toluenesulfonylox y-2-propoxy]methyl]guanine (1) with potassium [18F]fluoride/Kryptofix 2.2.2 followed by deprotection with 1 N HCl and purification with different methods in variable yields. When both the nucleophilic substitution and deprotection were carried out at 90 degrees C and the product was purified by HPLC (method A), the yield of compound 2 was 5-10% and the synthesis time was 90 min from EOB. However, if both the nucleophilic substitution and deprotection were carried out at 120 degrees C and the product was purified by HPLC, the yield of compound 2 decreased to 2%. When compound 2 was synthesized at 90 degrees C and purified by Silica Sep-Pak (method B), the yield increased to 10-15% and the synthesis time was 60 min from EOB. Similarly, 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG, 4) was synthesized with method A and method B in 9% and 10-15% yield, respectively, in a synthesis time of 90 and 60 min, respectively, from EOB. Compound 2 was relatively unstable in acidic medium at 120 degrees C while compound 4 was stable under the same condition. Both compound 2 and compound 4 had low lipid/water partition coefficient (0.126 +/- 0.022, n=5 and 0.165 +/- 0.023, n=5, respectively). Although it contains non-radioactive ganciclovir ( approximately 5-30 microg) as a chemical by-product, compound 2 synthesized by method B has a similar uptake in 9L glioma cells as that synthesized by method A, and is a potential tracer for imaging herpes simplex virus thymidine kinase gene expression in tumors using PET. Similarly, compound 4 synthesized by method B contains approximately 10-25 microg of penciclovir as a chemical by-product. Thus, the simplified one pot synthesis (method B) is a useful method for synthesizing both compound 2 and compound 4 in good yield for routine clinical use, and the method is readily amenable for automation.
Disciplines :
Radiology, nuclear medicine & imaging
Author, co-author :
Shiue, Grace G.; University of Pennsylvania > Department of Radiology
Shiue, Ching-Yann; University of Pennsylvania > Department of Radiology
Lee, Roland L.; University of Pennsylvania > Department of Radiology
MacDonald, Douglas; University of Pennsylvania > Department of Chemistry
Hustinx, Roland ; Université de Liège - ULiège > Département des sciences cliniques > Médecine nucléaire
Eck, Stephen L.; University of Pennsylvania > Department of Mediciine
Alavi, Abass; University of Pennsylvania > Department of Radiology
Language :
English
Title :
A simplified one-pot synthesis of 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine([18F]FHPG) and 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) for gene therapy.
Alauddin M.M., Conti P.S., Mazza S.M., Hamzeh F.M., Lever J.R. (1996) Synthesis of 9- [3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine (F-18 FHPG): A potential imaging agent of viral infection and gene therapy using PET. Nucl Med Biol 23:787-792.
Alauddin M.M., Shahinian A., Kundu R.K., Gordon E.M., Conti P.S. (1999) Evaluation of 9- [3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine (F-18 FHPG) in vitro and in vivo as a probe for PET imaging of gene incorporation and expression in tumors. Nucl Med Biol 26:371-376.
Alauddin M.M., Conti P.S. (1998) 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. Nucl Med Biol 25:175-180.
Alrabiah F.A., Sacks S.L. (1996) New antiherpesvirus agents. Their targets and therapeutic potential. Drug 52:17-32.
Barrio J.R., Namavari M., Phelps M.E., Satyamurthy N. (1996) Regioselective fluorination of substituted guanines with dilute F2: A facile entry to 8- fluoroguanine derivatives. J Org Chem 61:6084-6085.
Barrio J.R., Namavari M., Phelps M.E., Satyamurthy N. (1996) Elemental fluorine to 8- fluoropurines in one step. J Am Chem Soc 118:10408-10411.
Culver K.W., Ram Z., Wallbridge S., Ishii H., Oldfield E.H., Blease R.M. (1992) In vivo gene transfer with retroviral vector-produced cells for treatment of experimental brain tumors. Science 256:1550-1552.
Dranoff G. (1998) Cancer gene therapy: Connecting basic research with clinical inquiry. J Clin Oncol 16:2548-2556.
Eck S.L., Alavi J.B., Alavi A., Davis A., Hackney D., Judy K., Mollman J., Phillips P.C., Wheeldon E.B., Wilson J.M. (1996) Treatment of advanced CNS malignancies with the recombinant adenovirus H5.010RSVTK: A phase I trial. Hum Gene Ther 7:1465-1482.
Eck S.L. (1998) Gene therapy. Hematology/Oncology Clinics of north america , Philadelphia: W.B. Saunders; 12.
Esandi M.D.C., Someren G.D., Vincent A.J., Van Bekkum D.W., Valerio D., Bout A., Noteboom J.L. (1997) Treatment of malignant mesothelioma in an immunocompetent rat model using a recombinant adenovirus expressing the HSV-tk gene. Hum Gene Ther 4:280-287.
Gambhir S.S., Barrio J.R., Wu L., Iyer M., Namavari M., Satyamurthy N., Bauer E., Parrish C., MacLaren D.C., Borghei A.R., Green L.A., Sharfstein S., Berk A., Cherry S.R., Phelps M.E., Herschman H.R. (1998) Imaging of adenoviral-directed Herpes Simplex virus type 1 thymidine kinase reporter gene expression in mice with radiolabeled ganciclovir. J Nucl Med 39:2003-2011.
Gambhir S.S., Barrio J.R., Phelps M.E., Iyer M., Namavari M., Satyamurthy N., Wu L., Green L.A., Bauer E., MacLaren D.C., Nguyen K., Berk A., Cherry S.R., Herschman H.R. (1999) Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography. Proc Natl Acad Sci 96:2333-2338.
Gambhir S.S., Barrio J.R., Herschman H.R., Phelps M.E. (1999) Assays for noninvasive imaging of reporter gene expression. Nucl Med Biol 26:481-490.
Gambhir S.S., Herschman H.R., Cherry S.R., Barrio J.R., Satyamurthy N., Toyokuni T., Phelps M.E., Larson S.M., Balatoni J., Finn R., Sadelain M., Tjuvajev J., Blasberg R.G. (2000) Imaging transgene expression with radionuclide imaging technologies. Neoplasia 2:118-138.
Germann C., Shields A.F., Grierson J.R., Morr I., Haberkorn U. (1998) 5-Fluoro-1-(2′-deoxy-2′-fluoro-β-D-ribofuranosyl)uracil trapping in Morris Hepatoma cells expressing the Herpes Simplex Virus thymidine kinase gene. J Nucl Med 39:1418-1423.
Goodman S., Monclus M., Cool V., Damhaut P., Luxen A., Levivier M., Brotchi J., Hildebrand J., Velu T. (1996) A novel PET tracer for evaluation of gene therapy. J Nucl Med 37:53.
Haberkorn U., Altmann A., Morr I., Germann C., Oberdorfer F., Van Kaick G. (1997) Multitracer studies during gene therapy of hepatoma cells with herpes simplex virus thymidine kinase and ganciclovir. J Nucl Med 38:1048-1054.
Haberkorn U., Altmann A., Morr I., Knopf K., Germann C., Haeckel R., Oberdorfer F., Van Kaick G. (1997) Monitoring gene therapy with herpes simplex virus thymidine kinase in hepatoma cells: Uptake of specific substrates. J Nucl Med 38:287-294.
Haberkorn U., Oberdorfer F., Gebert J., Morr I., Haack K., Weber K., Lindauer M., Van Kaick G., Schackert H.K. (1996) Monitoring of gene therapy with cytosine deaminase: In vitro studies using 3H-5-fluorocytosine. J Nucl Med 37:87-94.
Huber B.E., Richard C.A., Krenitski T.A. (1991) Retroviral mediated gene therapy for the treatment of hepatocellular carcinoma. An innovative approach for cancer therapy. Proc Natl Acad Sci USA 88:8039-8043.
Hustinx R., Eck S.L., Alavi A. (1999) Potential applications of PET imaging in developing novel cancer therapies. J Nucl Med 40:995-1002.
Hustinx R., Shiue C.Y., Alavi A.A., McDonald D., Shiue G.G., Zhuang H., Lanuti M., Lambright E., Karp J.S., Eck S.L. (2001) Imaging in vivo herpes simplex virus thymidine kinase gene transfer to tumor-bearing rodents using positron emission tomography and [18F]FHPG. Eur J Nucl Med 28:5-12.
Iyer M., Barrio J.R., Namavari M., Bauer E., Satyamurthy N., Nguyen K., Toyokuni T., Phelps M.E., Herschman H.R., Gambhir S.S. (2001) 8-[18F]Fluoropenciclovir: An improved reporter probe for imaging HSV1-tk reporter gene expression in vivo using PET. J Nucl Med 42:96-105.
Larson S.M., Tjuvajev J., Blasberg R. (1997) Triumph over mischance: A role for nuclear medicine in gene therapy. J Nucl Med 38:1230-1233.
Martin J.C., McGee D.P., Jeffrey G.A., Hobbs D.W., Smee D.F., Matthews T.R., Verheyden J.P. (1986) Synthesis and anti-herpes-virus activity of acyclic 2′-deoxyguanosine analogues related to 9-[1,3-dihydroxy-2-propoxy)methyl]guanine. J Med Chem 29:1384-1389.
Monclus M., Luxen A., Cool V., Damhault P., Velu T., Goldman S. (1997) Development of a positron emission tomography radiopharmaceutical for imaging thymidine kinase gene expression: Synthesis and in vitro evaluation of 9-[3-[18F]Fluoro-1-hydroxy-2-propoxy)methyl]guanine. Bioorg Med Chem Letters 7:1879-1882.
Monclus M., Luxen A., Cool V., Damhaut P., Schurins A.L., Havet K., Baudson N., Van Naemen J., Velu T., Goldman S. (1997) S, Synthesis of R-and S-9-[3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine: Radiopharmaceuticals for gene therapy. XII International Symposium on Radiopharmaceutical Chemistry Uppsala , Sweden, June 15-19; 20-22.
Moolten F.L., Wells J.M. (1990) Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 82:297-300.
Moolten F.L., Wells J.M., Heyman R.A., Evans R.M. (1990) Lymphoma regression induced by ganciclovir in mice bearing a herpes thymidine kinase transgene. Hum Gene Ther 1:125-134.
Morin K.W., Knaus E.E., Wiebe L.I. (1997) Non-invasive scintigraphic monitoring of gene expression in a HSV-1 thymidine kinase gene therapy model. Nucl Med Comm 18:599-605.
Namavari M., Barrio J.R., Toyokuni T., Gambhir S.S., Cherry S.R., Herschman H.R., Phelps M.E. (2000) Satyamurthy N Synthesis of 8-[18F]fluoroguanine derivatives: In vivo probes for imaging gene expression with positron emission tomography. Nucl Med Biol 27:157-162.
Oldfield E.H., Ram Z., Culver K.W., Blease R.M., DeVroom H.L., Anderson W.F. (1993) Clinical protocols: Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. Hum Gene Ther 4:36-69.
Phelps M.E., Mazziotta J.C., Schelbert H.R. Positron emission tomography and autoradiography- Principle and applications for the brain and heart, N. Y.: Raven Press; 1986.
Schaeffer H.J., Bauchamp L., De Miranda P., Elion G. (1978) 9-(2-Hydroxyethyloxmethyl)guanine activity against viruses of the herpes group. Nature 272:583-585.
Shiue C.Y., Shiue G.G., MacDonald D., Eck S.L., Alavi A.A. (1998) Simplified one-pot synthesis of 9-[3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine (F-18 FHPG) for gene therapy. J Nucl Med 39:231.
Smee D.F., Boehme R., Chernow M., Binko B.P., Matthews T.R. (1985) Intracellular metabolism and enzymatic phosphorylation of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and acyclovir in herpes simplex virus infected and uninfected cells. Biochem Pharmacol 34:1049-1056.
Smee D.F., Campbell N.J., Matthews T.R. (1985) Comparative anti-herpes virus activities of the 9-(1,3-dihydroxy-2-propoxymethyl)guanine, acyclovir, and two 2′-fluoropyrimidine nucleosides. Antiviral Res 5:259-267.
Smee D.F., Martin J.C., Verheyden J.P.H., Matthews T.R. (1983) Anti-herpes virus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine. Antimicrob Agents Chemother 23:676-682.
Smith K.O., Galloway K.S., Kennell W.L., Ogilvie K.K., Radatus B.K. (1982) A new nucleoside analogue, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]-methyl]guanine, highly active in vitro against herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 22:55-61.
Sterman D.H., Treat J., Litzky L.A., Amin K.M., Molnar-Limber K.L., Wilson J.M., Albelda S.M., Kaiser L.R. (1998) Adenovirus-mediated herpes simplex virus thymidine kinase gene delivery in patients with localized malignancy: Results of a phase 1 clinical trial in malignant mesothelioma. Hum Gene Ther 9:2121-2133.
Takamiya Y., Short M.P., Ezzedine Z.D., Moolten F.L., Breakfield X.O., Martuzza R.L. (1992) Gene therapy of malignant brain tumors: A rat glioma line bearing the herpes simplex virus type 1-thymidine kinase with wild type retrovirus kills other tumor cells. J Neurosci Sci 33:493-503.
Tjuvajev J.G., Stockhammer G., Desai R., Uehara H., Gansbacher B., Watanabe K., Blasberg R. (1995) Imaging gene transfer and expression in vivo. Cancer Res 55:6121-6135.
Tjuvajev J.G., Finn R., Watababe K., Joshi R., Oku T., Kennedy J., Beattie B., Koutcher J., Larson S.M., Blasberg R. (1996) Noninvasive imaging of herpes virus thymidine kinase gene transfer and expression: A potential method for monitoring clinical gene therapy. Cancer Res 56:4087-4095.
Tjuvajev J.G., Avril N., Oku T., Sasajima T., Miyagawa T., Joshi R., Safer M., Beattie B., DiResta G., Daghighian F., Augensen F., Koutcher J., Zweit J., Humm J., Larson S.M., Finn R., Blasberg R. (1998) Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. Cancer Res 58:4333-4341.
Vile R.G., Hart I.R. (1993) Use of tissue specific expression of the herpes simplex virus thymidine gene to inhibit growth of established murine melanomas following direct intramural injection of DNA. Cancer Res 53:3860-3864.
Vincent A.J., Esandi M.D.C., Van Someren G., Noteboom J.L., Avezaat C.J., Vecht C., Sillevis Smitt P.S., Van Bekkum D.W., Valerio D., Hoogerbrugge P.M., Bout A. (1996) Treatment of leptomeningeal metastases in a rat model using a recombinant adenovirus containing the HSV-tk gene. J Neurosurg 85:648-654.
Vincent A.J., Vogels R., Van Someren G., Esandi M.D.C., Noteboom J.L., Avezaat C.J., Vecht C., Van Bekkum D.W., Valerio D., Bout A., Hoogerbrugge P.M. (1996) Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors. Hum Gene Ther 7:197-205.
Vincent A.J., Esandi M., Avezaat C.J.J., Vecht C., Sillevis Smitt P.S., Van Bekkum D.W., Valerio D., Hoogerbrugge P.M., Bout A. (1997) Preclinical testing of recombinant adenoviral herpes simplex virus-thymidine kinase gene therapy for central nervous system malignancies. Neurosurg 41:442-452.
Wiebe L.I., Morin K.W., Knaus E.E. (1997) Radiopharmaceuticals to monitor gene transfer. Quart J Nucl Med 41:79-89.
