3’-脱氧-3’-［~（18）F］-胸腺嘧啶脱氧核苷前体的合成
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摘要
正电子发射断层(PET)是一项强大的医学影像技术,它通过检测正电子-电子湮灭所产生的光子以确定正电子放射性物质的体内分布。氟-18是常用的正电子放射性核素之一,主要用于取代有机分子中的氢原子。氟-18的半衰期有110分钟,比较适合较为复杂的合成过程和较长时间的检测。
3'-脱氧-3'-[18F]-胸(腺嘧啶脱氧核)苷([18F]FLT)是目前最理想的核酸代谢显像剂,在临床上用于评估活体内细胞的增殖情况。
本文参照文献报道的合成路线,并对文献方法作了适当改进,成功地合成了BATH,DMTThy,3'-O-甲磺酰基-胸苷衍生物以及嘧啶环N-叔丁氧羰基保护的类似物等[18F]FLT的标记前体。
同时,本文也对标记前体的[19F]氟化反应作了初步研究。
Positron emission tomography (PET) is a powerful medical imaging method for measuring the distribution of the positron emitter in the human body by co-incidence of the annihilation photons resulting from positron decay. One of the positron emitting isotopes is fluorine-18 that is often used as a substitute for hydrogen in organic molecules with a half-life of 110 minutes, which allows complex synthesis and detailed imaging studies.
3'-deoxy-3'-[18F]fluorothymidine([18F]FLT) appears to be the most promising radiopharmaceutical. It is under clinical evaluation as a metabolic probe for imaging cell proliferation in vivo using positron emission tomography(PET).
In order to improve the [18F]FLT production, according to the reported synthetic route, BATH, DMTThy, 3'-O-mesyl-thymidine derivative and its pyrimidine ring N-BOC-protected analogue as precursors for [18F]FLT were synthesized. The reaction conditions and results were also described in this study.
In addition, the fluorination of the precursors was also discussed.
3'-脱氧-3'-[18F]-胸(腺嘧啶脱氧核)苷([18F]FLT)是目前最理想的核酸代谢显像剂,在临床上用于评估活体内细胞的增殖情况。
本文参照文献报道的合成路线,并对文献方法作了适当改进,成功地合成了BATH,DMTThy,3'-O-甲磺酰基-胸苷衍生物以及嘧啶环N-叔丁氧羰基保护的类似物等[18F]FLT的标记前体。
同时,本文也对标记前体的[19F]氟化反应作了初步研究。
Positron emission tomography (PET) is a powerful medical imaging method for measuring the distribution of the positron emitter in the human body by co-incidence of the annihilation photons resulting from positron decay. One of the positron emitting isotopes is fluorine-18 that is often used as a substitute for hydrogen in organic molecules with a half-life of 110 minutes, which allows complex synthesis and detailed imaging studies.
3'-deoxy-3'-[18F]fluorothymidine([18F]FLT) appears to be the most promising radiopharmaceutical. It is under clinical evaluation as a metabolic probe for imaging cell proliferation in vivo using positron emission tomography(PET).
In order to improve the [18F]FLT production, according to the reported synthetic route, BATH, DMTThy, 3'-O-mesyl-thymidine derivative and its pyrimidine ring N-BOC-protected analogue as precursors for [18F]FLT were synthesized. The reaction conditions and results were also described in this study.
In addition, the fluorination of the precursors was also discussed.
引文
[1] 王世真,分子核医学(第二版),北京:中国协和医科大学出版社,2004
[2] Wahl R. L., Eds. Principles and Practice of Positron Emission Tomography, Philadelphia: Lippincott Williams & Wilkins, 2003
[3] Tamaki N., Kuge, Y., Eds. PET and molecular imaging: state of the art and future perspectives. New York: International Congress Series, 1264. Elsevier Science, 2004
[4] 唐刚华,正电子断层显像与新药研究,药学学报,2001,36(6):470~474
[5] 蔡良,尚玉琨,李舰南,功能与结构融合影像-PET/CT 研究进展,世界肿瘤杂志,2004,3(3),280~282
[6] Wechalekar K., Sharma B., Cook G., PET/CT in oncology—a major advance, Clin. Radiol., 2005, 60(11): 1143~1155
[7] 周克,杨勤,向燕,PET/CT 的基本技术特点及临床应用介绍,西南军医杂志,2005,7(1):58
[8] 李天然,高光荣,钱跟年 等,PET/CT在神经系统中的应用,福州总医院学报,2004,11(3):229~231
[9] 李天然,PET—CT 在冠心病中应用价值的研究进展,实用医技杂志,2004,11(4):529~531
[10] 钟健松,陈萍,PET技术在医学中的应用及其常用药物,九江医学,2003,18(2):123~124
[11] Fowler J. S., Wolf, A. P., Working against Time: Rapid Radiotracer Synthesis and Imaging the Human Brain, Acc. Chem. Res., 1997, 30(4), 181~188
[12] Elsinga P. H., Radiopharmaceutical chemistry for positron emission tomography, Methods, 2002, 27(3): 208~217
[13] Schlyer D. J., PET Tracers and Radiochemistry, Ann. Acad. Med. Singapore, 2004, 33(2): 146~154
[14] Couturier O., Luxen A., Chatal J.-F. etc., Fluorinated tracers for imaging cancer with positron emission tomography, Eur. J. Nucl. Med. Mol. Imaging, 2004, 31(8): 1182~1206
[15] Smart B. E., Fluorine substituent effects (on bioactivity), J. Fluorine Chem., 2001, 109(1): 3~11
[16] 唐志刚,刘正浩,正电子放射性药物的制备与研究进展,基础医学与临床,1999,19(4):6~10
[17] Ding Y.-S., 18F-labeled biomolecules for PET studies in the neurosciences, J. Fluorine Chem., 2000, 101(2): 291~295
[18] Varagnolo L., Stokkel M. P. M., Mazzi, U. etc., 18F-labeled radiopharmaceuticals for PET in oncology, excluding FDG, Nucl. Med. Biol., 2000, 27(2): 103~112
[19] Beuthien-Baumann, B., Hamacher, K., Oberdorfer, F. etc., Preparation of fluorine- 18 labelled sugars and derivatives and their application as tracer for positron- emission- tomography, Carbohydr. Res., 2000, 327(1-2): 107~118
[20] Katzenellenbogen J. A., Steroids labeled with 18F for imaging tumors by positron emission tomography, J. Fluorine Chem., 2001, 109(1): 49~54
[21] Couturier O., Luxen A., Chatal J.-F. etc., Fluorinated tracers for imaging cancer with positron emission tomography, Eur. J. Nucl. Med. Mol. Imaging, 2004, 31(8): 1182~1206
[22] Helus F., Maier-Borst W., Sahm U. etc., F-18 cyclotron production methods, Radiochem. Radioanal. Lett., 1979, 38(3): 395?410
[23] Guillaume M., Luxen A., Nebeling B. etc., Recommendations for fluorine-18 production, Appl. Radiat. Isot., 1991, 42: 749~762
[24] Nickles R. J., Hichwa R. D., Daube M. E. etc., An O -target for the high yield production of 18 F-fluoride182, Appl. Radiat. Isot., 1983, 34(3): 625~629
[25] Shiue C. Y., Salvadori P. A., Wolf A. P. etc., A New Improved Synthesis of 2-Deoxy-2-[18F]Fluoro-D-Glucose from 18F-Labeled Acetyl Hypofluorite, J. Nucl. Med., 1982, 23(10): 899~903
[26] Chirakal R., Firnau G., Schrobilgen G. J. etc., The synthesis of [18]F xenon difluoride from [18]Ffluorine gas, Appl. Radiat. Isot., 1984, 35(5): 401~404
[27] Attina M., Cacace F., Walt A., Labeled aryl fluorides from the nucleophilic displacement of activated nitro groups by 18F-F-, J. Label. Compd. Radiopharm., 1983, 20(4): 501~514
[28] Brodack J. W., Dence C. S., Kilbourn M. R. etc., Robotic production of 2-deoxy-2- [18F]fluoro-D-glucose: a routine method of synthesis using tetrabutylammonium [18F]fluoride., Appl. Radiat. Isot., 1988, 39(7): 699~703
[29] Irie T.; Fukushi K.; Ido, T.; Nozaki, T.; Kasida, Y., Appl. Radiat. Isot., 1982, 33: 1449~1452
[30] Luxen, A.; Satyamurthy, N.; Bida, G. T.; Barrio, J. R. Appl. Radiat. Isot., 1986, 37: 409~413
[31] Alavi, A., Reivich, M., Semin. Nucl. Med., 2002, 32(1): 2~5
[32] 魏荣卿，Machulla, H. J.，刘晓宁，检测肿瘤增殖的显像剂18F-FLT，中华核医学杂志，2005，25（1）：59~61
[33] Mier W., Haberkorn U., Eisenhut M., [F]FLT; portrait of a proliferation marker18, Eur. J. Nucl. Med. Mol. Imaging, 2002, 29(2): 165~169
[34] Francis D. L., Visvikis D., Costa D. C. etc., Potential impact of [ 18F]3'-deoxy-3'- fluorothymidine versus [ 18F]fluoro-2-deoxy-d-glucose in positron emission tomography for colorectal cancer, Eur. J. Nucl. Med. Mol. Imaging, 2003, 30(7): 988~994
[35] Dittmann H., Dohmen B. M., Paulsen, F. etc., [ F]FLT PET for diagnosis and staging of thoracic tumours18, Eur. J. Nucl. Med. Mol. Imaging, 2003, 30(10): 1407~1412
[36] Machulla H.-J., Blocher A., Kuntzsch M., Simplified Labeling Approach for Synthesizing 3′-Deoxy-3′-[F]fluorothymidine ([18F]FLT)18, J. Radioanal. Nucl. Chem., 2000, 243(3): 843~846
[37] Buck A. K., Schirrmeister H., Hetzel M. etc., 3-Deoxy-3-[18F] Fluorothymidine- Positron Emission Tomography for Noninvasive Assessment of Proliferation in Pulmonary Nodules, Cancer Res., 2002, 62(12): 3331~3334
[38] Naimi E., Zhou A., Khalili P. etc., Synthesis of 3'- and 5'-Nitrooxy Pyrimidine Nucleoside Nitrate Esters: "Nitric Oxide Donor" Agents for Evaluation as Anticancer and Antiviral Agents, J. Med. Chem. 2003, 46(6): 995~1004
[39] Czernecki S., Vlery J., An efficient synthesis of 3′-azido-3′-deoxythymidine(AZT), Synthesis, 1991, 1991(3): 239~240
[40] Wodarski C., Eisenbarth J., Weber K., Synthesis of 3?-deoxy-3?-[18F]fluoro- thymidine with 2,3?-anhydro-5?-O-(4,4?-dimethoxytrityl)-thymidine, J. Label. Compd. Radiopharm., 2000, 43(12): 1211~1218
[41] Barthel H., Cleij M. C., Collingridge D. R. etc., 3'-Deoxy-3'-[18F] Fluorothymidine as a New Marker for Monitoring Tumor Response to Antiproliferative Therapy in Vivo with Positron Emission Tomography, Cancer Res., 2003, 63(13): 3791~3798
[42] Grierson, J. R., Shields, A. F., Radiosynthesis of 3′-deoxy-3′-[18F] fluorothymidine: [18F]FLT for imaging of cellular proliferation in vivo, Nucl. Med. Bio. 2000, 27(2): 143~156
[43] Ti G. S., Gaffney B. L., Jones R. A., Transient protection: efficient one-flask syntheses of protected deoxynucleosides, J. Am. Chem. Soc. 1982, 104(5): 1316~1319
[44] Martin S . J., Eisenbarth J. A ., Wagner-Utermann U. etc., A new precursor for the radiosynthesis of [18F]FLT, Nucl. Med. Bio., 2002, 29(2): 263~273
[45] Yun M., Oh S. J., Ha H. J. etc., High radiochemical yield synthesis of 3′-deoxy-3′- [18F]fluorothymidine using (5′-O-dimethoxytrityl-2′-deoxy-3′-O-nosyl- β-D-threo pentofuranosyl) thymine and its 3-N-BOC-protected analogue as a labeling precursor, Nucl. Med. Bio. 2003, 30(2): 151~157
[46] Lzsó G., Huszthy P., Lempert K. etc., Reactions of some p-substituted triphenylmethyl chlorides with alcohols, alkali-metal alcoholates, and tributylamine, J. Chem. Soc. Perkin Trans. II. 1989(7): 769~778
[47] Moon B. S., Lee K. C., An G. I. etc., Preparation of 3?-deoxy-3?-[18F]fluoro- thymidine([18F]FLT) in ionic liquid, [bmim][OTf], J. Label. Compd. Radiopharm., 2006, 49(3): 287~293
[48] Marjima T., Pac C., Nakasone A. etc., Redox-photosensitized reactions. 7. Aromatic hydrocarbon-photosensitized electron-transfer reactions of furan, methylated furans, 1,1-diphenylethylene, and indene with p-dicyanobenzene, J. Am. Chem. Soc. 1981, 103(15): 4499~4508
[49] Smyth T. P., Carey A., Hodnett B. K., Inexpensive, active KF for nucleophilic aromatic displacement reactions, Tetrahedron. 1995, 51(22): 6363~6376
[50] Wilson I. K., Chatterjee S., Wolf W., Synthesis of 3′-fluoro-3′-deoxythymidine and studies of its 18F-radiolabeling, as a tracer for the noninvasive monitoring of the biodistribution of drugs against AIDS, J. Fluorine Chem. 1991, 55(3): 283~289
[51] Kimura Y., Suzuki H., Freeze-dried potassium fluoride: Synthetic utility as a fluorinating agent, Tetrahedron Lett. 1989, 30(10): 1271~1272
[2] Wahl R. L., Eds. Principles and Practice of Positron Emission Tomography, Philadelphia: Lippincott Williams & Wilkins, 2003
[3] Tamaki N., Kuge, Y., Eds. PET and molecular imaging: state of the art and future perspectives. New York: International Congress Series, 1264. Elsevier Science, 2004
[4] 唐刚华,正电子断层显像与新药研究,药学学报,2001,36(6):470~474
[5] 蔡良,尚玉琨,李舰南,功能与结构融合影像-PET/CT 研究进展,世界肿瘤杂志,2004,3(3),280~282
[6] Wechalekar K., Sharma B., Cook G., PET/CT in oncology—a major advance, Clin. Radiol., 2005, 60(11): 1143~1155
[7] 周克,杨勤,向燕,PET/CT 的基本技术特点及临床应用介绍,西南军医杂志,2005,7(1):58
[8] 李天然,高光荣,钱跟年 等,PET/CT在神经系统中的应用,福州总医院学报,2004,11(3):229~231
[9] 李天然,PET—CT 在冠心病中应用价值的研究进展,实用医技杂志,2004,11(4):529~531
[10] 钟健松,陈萍,PET技术在医学中的应用及其常用药物,九江医学,2003,18(2):123~124
[11] Fowler J. S., Wolf, A. P., Working against Time: Rapid Radiotracer Synthesis and Imaging the Human Brain, Acc. Chem. Res., 1997, 30(4), 181~188
[12] Elsinga P. H., Radiopharmaceutical chemistry for positron emission tomography, Methods, 2002, 27(3): 208~217
[13] Schlyer D. J., PET Tracers and Radiochemistry, Ann. Acad. Med. Singapore, 2004, 33(2): 146~154
[14] Couturier O., Luxen A., Chatal J.-F. etc., Fluorinated tracers for imaging cancer with positron emission tomography, Eur. J. Nucl. Med. Mol. Imaging, 2004, 31(8): 1182~1206
[15] Smart B. E., Fluorine substituent effects (on bioactivity), J. Fluorine Chem., 2001, 109(1): 3~11
[16] 唐志刚,刘正浩,正电子放射性药物的制备与研究进展,基础医学与临床,1999,19(4):6~10
[17] Ding Y.-S., 18F-labeled biomolecules for PET studies in the neurosciences, J. Fluorine Chem., 2000, 101(2): 291~295
[18] Varagnolo L., Stokkel M. P. M., Mazzi, U. etc., 18F-labeled radiopharmaceuticals for PET in oncology, excluding FDG, Nucl. Med. Biol., 2000, 27(2): 103~112
[19] Beuthien-Baumann, B., Hamacher, K., Oberdorfer, F. etc., Preparation of fluorine- 18 labelled sugars and derivatives and their application as tracer for positron- emission- tomography, Carbohydr. Res., 2000, 327(1-2): 107~118
[20] Katzenellenbogen J. A., Steroids labeled with 18F for imaging tumors by positron emission tomography, J. Fluorine Chem., 2001, 109(1): 49~54
[21] Couturier O., Luxen A., Chatal J.-F. etc., Fluorinated tracers for imaging cancer with positron emission tomography, Eur. J. Nucl. Med. Mol. Imaging, 2004, 31(8): 1182~1206
[22] Helus F., Maier-Borst W., Sahm U. etc., F-18 cyclotron production methods, Radiochem. Radioanal. Lett., 1979, 38(3): 395?410
[23] Guillaume M., Luxen A., Nebeling B. etc., Recommendations for fluorine-18 production, Appl. Radiat. Isot., 1991, 42: 749~762
[24] Nickles R. J., Hichwa R. D., Daube M. E. etc., An O -target for the high yield production of 18 F-fluoride182, Appl. Radiat. Isot., 1983, 34(3): 625~629
[25] Shiue C. Y., Salvadori P. A., Wolf A. P. etc., A New Improved Synthesis of 2-Deoxy-2-[18F]Fluoro-D-Glucose from 18F-Labeled Acetyl Hypofluorite, J. Nucl. Med., 1982, 23(10): 899~903
[26] Chirakal R., Firnau G., Schrobilgen G. J. etc., The synthesis of [18]F xenon difluoride from [18]Ffluorine gas, Appl. Radiat. Isot., 1984, 35(5): 401~404
[27] Attina M., Cacace F., Walt A., Labeled aryl fluorides from the nucleophilic displacement of activated nitro groups by 18F-F-, J. Label. Compd. Radiopharm., 1983, 20(4): 501~514
[28] Brodack J. W., Dence C. S., Kilbourn M. R. etc., Robotic production of 2-deoxy-2- [18F]fluoro-D-glucose: a routine method of synthesis using tetrabutylammonium [18F]fluoride., Appl. Radiat. Isot., 1988, 39(7): 699~703
[29] Irie T.; Fukushi K.; Ido, T.; Nozaki, T.; Kasida, Y., Appl. Radiat. Isot., 1982, 33: 1449~1452
[30] Luxen, A.; Satyamurthy, N.; Bida, G. T.; Barrio, J. R. Appl. Radiat. Isot., 1986, 37: 409~413
[31] Alavi, A., Reivich, M., Semin. Nucl. Med., 2002, 32(1): 2~5
[32] 魏荣卿，Machulla, H. J.，刘晓宁，检测肿瘤增殖的显像剂18F-FLT，中华核医学杂志，2005，25（1）：59~61
[33] Mier W., Haberkorn U., Eisenhut M., [F]FLT; portrait of a proliferation marker18, Eur. J. Nucl. Med. Mol. Imaging, 2002, 29(2): 165~169
[34] Francis D. L., Visvikis D., Costa D. C. etc., Potential impact of [ 18F]3'-deoxy-3'- fluorothymidine versus [ 18F]fluoro-2-deoxy-d-glucose in positron emission tomography for colorectal cancer, Eur. J. Nucl. Med. Mol. Imaging, 2003, 30(7): 988~994
[35] Dittmann H., Dohmen B. M., Paulsen, F. etc., [ F]FLT PET for diagnosis and staging of thoracic tumours18, Eur. J. Nucl. Med. Mol. Imaging, 2003, 30(10): 1407~1412
[36] Machulla H.-J., Blocher A., Kuntzsch M., Simplified Labeling Approach for Synthesizing 3′-Deoxy-3′-[F]fluorothymidine ([18F]FLT)18, J. Radioanal. Nucl. Chem., 2000, 243(3): 843~846
[37] Buck A. K., Schirrmeister H., Hetzel M. etc., 3-Deoxy-3-[18F] Fluorothymidine- Positron Emission Tomography for Noninvasive Assessment of Proliferation in Pulmonary Nodules, Cancer Res., 2002, 62(12): 3331~3334
[38] Naimi E., Zhou A., Khalili P. etc., Synthesis of 3'- and 5'-Nitrooxy Pyrimidine Nucleoside Nitrate Esters: "Nitric Oxide Donor" Agents for Evaluation as Anticancer and Antiviral Agents, J. Med. Chem. 2003, 46(6): 995~1004
[39] Czernecki S., Vlery J., An efficient synthesis of 3′-azido-3′-deoxythymidine(AZT), Synthesis, 1991, 1991(3): 239~240
[40] Wodarski C., Eisenbarth J., Weber K., Synthesis of 3?-deoxy-3?-[18F]fluoro- thymidine with 2,3?-anhydro-5?-O-(4,4?-dimethoxytrityl)-thymidine, J. Label. Compd. Radiopharm., 2000, 43(12): 1211~1218
[41] Barthel H., Cleij M. C., Collingridge D. R. etc., 3'-Deoxy-3'-[18F] Fluorothymidine as a New Marker for Monitoring Tumor Response to Antiproliferative Therapy in Vivo with Positron Emission Tomography, Cancer Res., 2003, 63(13): 3791~3798
[42] Grierson, J. R., Shields, A. F., Radiosynthesis of 3′-deoxy-3′-[18F] fluorothymidine: [18F]FLT for imaging of cellular proliferation in vivo, Nucl. Med. Bio. 2000, 27(2): 143~156
[43] Ti G. S., Gaffney B. L., Jones R. A., Transient protection: efficient one-flask syntheses of protected deoxynucleosides, J. Am. Chem. Soc. 1982, 104(5): 1316~1319
[44] Martin S . J., Eisenbarth J. A ., Wagner-Utermann U. etc., A new precursor for the radiosynthesis of [18F]FLT, Nucl. Med. Bio., 2002, 29(2): 263~273
[45] Yun M., Oh S. J., Ha H. J. etc., High radiochemical yield synthesis of 3′-deoxy-3′- [18F]fluorothymidine using (5′-O-dimethoxytrityl-2′-deoxy-3′-O-nosyl- β-D-threo pentofuranosyl) thymine and its 3-N-BOC-protected analogue as a labeling precursor, Nucl. Med. Bio. 2003, 30(2): 151~157
[46] Lzsó G., Huszthy P., Lempert K. etc., Reactions of some p-substituted triphenylmethyl chlorides with alcohols, alkali-metal alcoholates, and tributylamine, J. Chem. Soc. Perkin Trans. II. 1989(7): 769~778
[47] Moon B. S., Lee K. C., An G. I. etc., Preparation of 3?-deoxy-3?-[18F]fluoro- thymidine([18F]FLT) in ionic liquid, [bmim][OTf], J. Label. Compd. Radiopharm., 2006, 49(3): 287~293
[48] Marjima T., Pac C., Nakasone A. etc., Redox-photosensitized reactions. 7. Aromatic hydrocarbon-photosensitized electron-transfer reactions of furan, methylated furans, 1,1-diphenylethylene, and indene with p-dicyanobenzene, J. Am. Chem. Soc. 1981, 103(15): 4499~4508
[49] Smyth T. P., Carey A., Hodnett B. K., Inexpensive, active KF for nucleophilic aromatic displacement reactions, Tetrahedron. 1995, 51(22): 6363~6376
[50] Wilson I. K., Chatterjee S., Wolf W., Synthesis of 3′-fluoro-3′-deoxythymidine and studies of its 18F-radiolabeling, as a tracer for the noninvasive monitoring of the biodistribution of drugs against AIDS, J. Fluorine Chem. 1991, 55(3): 283~289
[51] Kimura Y., Suzuki H., Freeze-dried potassium fluoride: Synthetic utility as a fluorinating agent, Tetrahedron Lett. 1989, 30(10): 1271~1272