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-propoxymethyl guanine
[en] 9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine (FHPG) 2 has been labeled with fluorine-18 and evaluated in vitro as a potential radiotracer for mapping gene expression in vivo with positron emission tomography (PET).
Disciplines :
Biotechnology
Author, co-author :
Monclus, Michel
Luxen, André ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse - Centre de recherches du cyclotron
Cool, Vincent
Damhaut, Philippe
Velu, Thierry
Goldman, Serge
Language :
English
Title :
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-propoxymethyl guanine
Culver, K. W.; Ram, Z.; Wallbridge, S.; Ishii, H.; Oldfield, E. H.; Blaese, R. M. Science 1992, 256, 1550.
Tjuvajev, J. G.; Stockhammer, G.; Desai, R.; Uehara, H.; Watanabe, K.; Gansbacher, B.; Blasberg, R. G. Cancer Res. 1995, 55, 6126.
Tjuvajev, J. G.; Finn R.; Watanabe, K.; Joshi, R.; Oku, T.; Kennedy, J.; Beattie, B.; Koutcher, J.; Larson, S.; Blasberg, R. Cancer Res. 1996, 56, 4087.
Barrio, J. R.; Namavari, M.; Phelps, M. E.; Satyamurthy, N. J. Org. Chem. 1996, 61, 6084.
Monclus, M.; Luxen, A.; Van Naemen, J.; Damhaut, P.; Velu, T.; Cool, V.; Goldman, S. J Labelled Compd Radiopharm 1995, 37, 193.
Alauddin, M. M.; Conti, P. S.; Mazza, S. M.; Hamzeh, F. M.; Lever, J. R. Nuclear Medecine & Biology 1996, 23, 787.
Martin, J. C.; McGee, D. P. C.; Jeffry, G. A.; Hobbs, D. W.; Smee, D. F.; Matthews, T. R.; Verheyden, J. P. H. J. Med. Chem. 1986, 29, 1384.
Preparation of 9-{[1,3-di(p-toluenesulfonyloxy)-2-propoxy]methyl}guanine 3. To a suspension of DHPG 1 (255 mg, 1 mmole) in anhydrous pyridine (2 mL) was added with a syringe p-toluenesulfonyl chloride (955 mg, 5 mmoles) previously dissolved in anhydrous pyridine (1 mL). After addition, the suspension was allowed to stand at room temperature for 12 h. The solution was then poured in 1 M HCl/ice and then filtered. The crude material was purified by using column chromatography (SiO2, CH2Cl2/methanol: 9/1 and then CH2Cl2/methanol: 8/2) to afford pure ditosylate 3 (230 mg, 40%) as a solid mp 272-273°C (dec). 1H-NMR (250 MHz, DMSO-d6): δ 2.41 (s, 6H, CH3), 3.88 (dd, J=5.7, 10.6 Hz, 2H, CH2 (5′)), 4.02 (dd, J=3.5, 10.7 Hz, 2H, CH2 (3′)), 4.08-4.12 (m, 1H, CH (4′)), 5.28 (s, 2H, CH2), 6.57 (s, 1H, NH), 7.43 (d, J=8.25 Hz, 2H), 7.65 (d, J=7.8 Hz, 2H); HPLC-MS [M+H]+: 564
Guillaume, M.; Luxen, A.; Nebeling, B.; Argentini, M.; Clark, J. C.; Pike, V. W. Appl. Radiat. Isot. 1991, 42, 749.
Cool, V.; Pirotte, B.; Gérard, C.; Dargent, J.-L.; Baudson, N.; Levivier, M.; Goldman, S.; Hildebrand, J.; Brotchi, J.; Velu, T. Hum. Gen. Ther. 1996, 7, 627.
Ashton, W. T.; Canning, L. F.; Reynolds, G. F.; Tolman, R. L.; Karkas, J. D.; Liou, R.; Davies, M.-E. M.; DeWitt, C. M.; Perry, H. C.; Field, A. K. J. Med. Chem. 1985, 28, 926.
Karkas, J. D.; Germershausen, J.; Tolman, R. L.; MacCoss, M.; Wagner, A. F.; Liou, R.; Bostedor, R. Biochim. Biophys. Acta 1987, 911, 127.
Kohlbrenner, W. E.; Carter, C. D.; Fesik, S. W.; Norbeck, D. W.; Erickson, J. Biochem. Pharmacol. 1990, 40, R5.
Synthesis of R and S enantiomers of FHPG. M. Monclus. Unpublished data.
Elion, G. B.; Furman, P. A.; Fyfe, J. A.; de Miranda, P.; Beauchamp, L.; Schaeffer, H. Proc. Natl. Acad. Sci. USA 1977, 74, 5716.
An authentic sample of FHPG monophosphate was prepared by treating N-acetyl-FHPG with 2-cyanoethyl N,N-diisopropylchlorophosphoramidite. Conversion to the intermediate dicyanoethylphosphoramidite and subsequent oxidation, deprotection and purification by HPLC on a SAX column afforded the desired compound.
Smee, D. F.; Boehme, R.; Chernow, M.; Binko, B. P.; Matthews, T. R. Biochem. Pharmacol. 1985, 34, 1049.
