~3H和~(14)C标记药物的制备及其质量控制
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摘要
~3H和~(14)C标记药物广泛应用于新药研究和药物残留分析等领域,是用来阐明药物代谢、处置过程及评价药物残留危害的完美工具。~3H和~(14)C标记药物还可用于研究物质的生物化学特性,揭示生物合成途径和酶促反应机制,阐明有机反应机制和解决环境科学领域诸多问题。放射性示踪研究可提供化合物分子及其分解产物、代谢产物、相关物质的定量信息,在新药或待开发药物的药理学与毒理学研究中,拥有不可代替的作用,是利用大部分药物分子中含有H或C原子的特点,用适当标记制备方法,将药物分子中原有的H或C原子用~3H或~(14)C等放射性原子替代,用于后续放射性示踪研究的一种特殊手段。~3H和~(14)C标记药物的制备包括选择、评估和优化放射性标记合成路线和工艺;挑选合适的~3H和~(14)C前导物及中间体;常规合成规模改造成微量合成规模;优化反应条件和收率;最后还要进行放射性标记化合物的结构确证,分析测量其化学纯度、放化纯度、比活度和标记位置以及相关质量控制项目。由于~3H和~(14)C标记药物对药物研发领域的重大影响,本文采用举例讨论方法,对~3H和~(14)C标记药物的制备策略、技术路线选择、合成方法、微量合成改造及其质量控制技术进行了较为详细的论述。
~3H and ~(14)C labeled compounds are excellent investigative tools and widely used to carry out drug metabolism and disposition studies during drug discovery and development stages,and risk evaluation of drug residues.Compounds labeled with ~(14)C or ~3H also have contributed to numerous advances in studies of biochemistry,biosynthetic pathways,enzyme mechanisms,elucidation of organic reaction mechanisms and environmental sciences.The use of radioactivity offers a unique mode of quantitative information of total drug-related molecules,and their decomposition products,metabolites and other substances.Therefore,most of the relevant studies that carry out radioactive tracers use ~3H or ~(14)C instead of H or C of original drug molecules.The preparation of compounds labeled with ~3H and ~(14)C usually involves the design of the preparation,method and apparatus for the identification and characterization of the labeled compounds.Therefore the planning process for syntheses of ~3H and ~(14)C labeled compounds involves evaluation of synthetic pathways,selection of building blocks,modification of microscale synthesis methods,identification of the labeled compounds,analysis of the chemical purity,radiochemical purity,specific activity and position of label.Due to the significant impact of ~3H and ~(14)C labeled compounds on applications in the drug research,this study described strategies for target preparation,preparation of ~3H and ~(14)C labeled compounds and quality control methods of the ~3H and ~(14)C labeled compounds.
~3H and ~(14)C labeled compounds are excellent investigative tools and widely used to carry out drug metabolism and disposition studies during drug discovery and development stages,and risk evaluation of drug residues.Compounds labeled with ~(14)C or ~3H also have contributed to numerous advances in studies of biochemistry,biosynthetic pathways,enzyme mechanisms,elucidation of organic reaction mechanisms and environmental sciences.The use of radioactivity offers a unique mode of quantitative information of total drug-related molecules,and their decomposition products,metabolites and other substances.Therefore,most of the relevant studies that carry out radioactive tracers use ~3H or ~(14)C instead of H or C of original drug molecules.The preparation of compounds labeled with ~3H and ~(14)C usually involves the design of the preparation,method and apparatus for the identification and characterization of the labeled compounds.Therefore the planning process for syntheses of ~3H and ~(14)C labeled compounds involves evaluation of synthetic pathways,selection of building blocks,modification of microscale synthesis methods,identification of the labeled compounds,analysis of the chemical purity,radiochemical purity,specific activity and position of label.Due to the significant impact of ~3H and ~(14)C labeled compounds on applications in the drug research,this study described strategies for target preparation,preparation of ~3H and ~(14)C labeled compounds and quality control methods of the ~3H and ~(14)C labeled compounds.
引文
[1]HANSEN PE.Isotope effect on chemical shifts in hydrogen——bonded systems[J].J Label Compd Radiopharm,2007,50(11-12):967
[2]MAHMUD T.Isotope tracer investigations of natural products biosynthesis:the discovery of novel metabolic pathways[J].J Label Compd Radiopharm,2007,50(11-12):1039
[3]CLELAND WW.The use of isotope effects to determine enzyme mechanisms[J].Arch Biochem Biophys,2005,433(1):2
[4]FITZPATRICK PF.Insights into the mechanisms of flavoprotein oxidases from kinetic isotope effects[J].J Label Compd Radiopharm,2007,50(11-12):1016
[5]HOFF RH,HENGGE AC.The use of isotopes in the study of reactions of acyl,phosphoryl,and sulfurylesters[J].J Label Compd Radiopharm,2007,50(11-12):1026
[6]LLOYD-JONES GC,MU?OZ MP.Isotopic labelling in the study of organic and organometallic mechanism and structure:an account[J].J Label Compd Radiopharm,2010,50(11-12):1072
[7]GERARD P.Applications of deuterium isotope effects to probing aspects of reactions involving oxidative addition and reductive elimination of H-H and C-H bonds[J].J Label Compd Radiopharm,2007,50(11-12):1088
[8]WESTAWAY KC.Determining transition state structure using kinetic isotope effects[J].J Label Compd Radiopharm,2010,50(11-12):989
[9]朱建华,沈鸣华.核药学概论[M].上海:复旦大学出版社,2002ZHU JH,SHEN MH.Introduction of Nuclear Pharmacy[M].Shanghai:Fudan University Press,2002
[10]LEE HN,YANG SD,KIM WH,et al.Separation of 3H,14C,32P,35S,125I,and 131I in radioisotope waste[J].J Radioanal Nucl Chem,2010,284(3):527
[11]ELSINGA PH.Radiopharmaceutical chemistry for positron emission tomography[J].Adv Drug Deliv Rev,2002,62(11):1031
[12]VOGES R,HEYS JR,MOENIUS T.Preparation of compounds labeled with tritium and carbon-14[J].Wiley,2009,26(5):645
[13]SALJOUGHIAN M,WILLIAMS PG.Recent developments in tritium incorporation for radiotracer studies[J].Curr Pharm Des,2000,6(10):1029
[14]斯琴朝克图.氚标记喹赛多的制备及其在大鼠和鸡体内处置研究[D].武汉:华中农业大学,2011HARNUD S.The Synthesis of Tritium Labeled Cyadox and Its Disposition in Rats and Chicken[D].Wuhan:Huazhong Agricultural University,2011
[15]MATLOUBI H,GHANDI M,ZARRINDAST MR,et al.Modified synthesis of 11-[14C]-clozapine[J].Appl Radiat Isot,2001,55(6):789
[16]MARATHE PH,SHYU WC,HUMPHREYS WG.The use of radiolabeled compounds for ADME studies in discovery and exploratory development[J].Curr Pharm Des,2004,10(24):2991
[17]SIDOROV GV,ZVERKOV YB,MYASOEDOV NF.Isotope exchange of azidothymidine with tritium[J].Radiochemistry,2003,45(1):87
[18]SHEVCHENKO V,NAGAEV I,MYASOEDOV N.Optimization of conditions for tritium labeling of organic compounds by isotope exchange with tritium water,based on the concepts of reactions on the catalyst surface[J].Radiochemistry,2005,47(4):403
[19]MIASOEDOV NF,KUZNETSOVA OB,KOZIK VS.Biosynthesis of tritium-labeled S-adenosyl-L-methionine in yeast cells[J].Bioorg Khim,1985,11(7):944
[20]REN S,HESK D,MCNAMARA P,et al.Syntheses of 3H-labeled,14C-labeled,and 2H4-labeled SCH 444877,phosphodiesterase type5 inhibitors[J].J Label Compd Radiopharm,2013,56(9-10):480
[21]EGAN JA,LASETER AG,FILER CN.Tritium labelling and characterization of the antimalarial drug(+/-)-chloroquine by several methods[J].Appl Radiat Isot,2002,57(3):343
[22]KOVALAINEN JT,MORIMOTO H,WILLIAMS PG,et al.Synthesis of a tritium labelled antihistaminic drug[3H]-N,N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethaneamine·HCl[J].J Label Compd Radiopharm,1995,36(12):1147
[23]BAGSHAW CR.Kinetic Isotope Effects[J].Springer Berlin Heidelberg,2013,3(236):1200
[24]PAAREN HE,FIVIZZANI MA,SCHNOES HK,et al.Preparation of tritium-or deuterium-labeled vitamin D analogs by a convenient general method[J].Proc Nat Acad Sci USA,1981,78(10):6173
[25]EGMOND MR,VLIEGENTHART JFG,BOLDINGH J.Synthesis of ii(n-8)ls,tritium-labelled linoleic acid[J].Biochim Biophys Acta,1973,316(1):1
[26]HESK D,BORGES S,HENDERSHOT S,et al.Synthesis of 3H,2H4,and 14C-SCH 417690(vicriviroc)[J].J Label Compd Radiopharm,2016,59(5):190
[27]MATLOUBI H,SHAFIEE A,SAEMIAN N,et al.Synthesis of carbon-14 analogue of 1,5 diaryl-5-[14C]-1,2,3-triazoles[J].Appl Radiat Isot,2004,60(5):665
[28]AGRAWAL N,KOHEN A.Microscale synthesis of 2-tritiated isopropanol and 4R-tritiated reduced nicotinamide adenine dinucleotide phosphate[J].Anal Biochem,2003,322(2):179
[29]ICHINOSE K,LEEPER FJ,BATTERSBY AR.Preparation of[4R-3H]NADH,[4R-3H]NADPH and the corresponding 4S-isomers all with substantial specific activities[J].J Chem Soc,Perkin Trans,1993,11(11):1213
[30]PARNES H,KECZER SD.Microscale synthesis of volatile,14C‐labelled acid chlorides[J].J Label Compd Radiopharm,2010,22(3):287
[31]FILER CN.Isotopic fractionation of organic compounds in chromatography[J].J Label Compd Radiopharm,1999,42(2):169
[32]HEYS JR.High performance liquid chromatographic studies of p H dependence in the isotopic fractionation of deuterated benzazepines[J].J Chromatogr A,1987,407:37
[33]HONG B,KOHEN A.Microscale synthesis of isotopically labeled6R‐N5,N10-methylene-5,6,7,8-tetrahydrofolate[J].J Label Compd Radiopharm,2010,48(10):759
[34]KOVALAINEN JT,MORIMOTO H,WILLIAMS PG,et al.Synthesis of a tritium labelled antihistaminic drug[3H]-N,N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethaneamine·HCl[J].J Label Compd Radiopharm,1995,36(12):1147
[35]折冬梅,曲哲,黄啟良等.杀菌剂氟吗啉的14C标记合成[J].核农学报,2007,21(2):206SHE DM,QU Z,HUANG QL,et al.Preparation of C-14 labeled flumorph[J].J Nucl Agric Sci,2007,21(2):206
[36]FILER CN.The analysis of 14C and 3H labeled compounds[J].Appl Radiat Isot,1988,39(6):530
[37]HESK D,BORGES S,DUMPIT R,et al.Synthesis of 3H,13C,2H3,15N and 14C-labelled SCH 466036,a histamine 3 receptor antagonist[J].J Label Compd Radiopharm,2015,58(2):36
[38]FILER CN,HAINLEY C,NUGENT RP.Tritiation of dopaminergic ligands(-)-lisuride and(+/-)-nomifensine[J].J Radioanal Nucl Chem,2006,267(2):345
[2]MAHMUD T.Isotope tracer investigations of natural products biosynthesis:the discovery of novel metabolic pathways[J].J Label Compd Radiopharm,2007,50(11-12):1039
[3]CLELAND WW.The use of isotope effects to determine enzyme mechanisms[J].Arch Biochem Biophys,2005,433(1):2
[4]FITZPATRICK PF.Insights into the mechanisms of flavoprotein oxidases from kinetic isotope effects[J].J Label Compd Radiopharm,2007,50(11-12):1016
[5]HOFF RH,HENGGE AC.The use of isotopes in the study of reactions of acyl,phosphoryl,and sulfurylesters[J].J Label Compd Radiopharm,2007,50(11-12):1026
[6]LLOYD-JONES GC,MU?OZ MP.Isotopic labelling in the study of organic and organometallic mechanism and structure:an account[J].J Label Compd Radiopharm,2010,50(11-12):1072
[7]GERARD P.Applications of deuterium isotope effects to probing aspects of reactions involving oxidative addition and reductive elimination of H-H and C-H bonds[J].J Label Compd Radiopharm,2007,50(11-12):1088
[8]WESTAWAY KC.Determining transition state structure using kinetic isotope effects[J].J Label Compd Radiopharm,2010,50(11-12):989
[9]朱建华,沈鸣华.核药学概论[M].上海:复旦大学出版社,2002ZHU JH,SHEN MH.Introduction of Nuclear Pharmacy[M].Shanghai:Fudan University Press,2002
[10]LEE HN,YANG SD,KIM WH,et al.Separation of 3H,14C,32P,35S,125I,and 131I in radioisotope waste[J].J Radioanal Nucl Chem,2010,284(3):527
[11]ELSINGA PH.Radiopharmaceutical chemistry for positron emission tomography[J].Adv Drug Deliv Rev,2002,62(11):1031
[12]VOGES R,HEYS JR,MOENIUS T.Preparation of compounds labeled with tritium and carbon-14[J].Wiley,2009,26(5):645
[13]SALJOUGHIAN M,WILLIAMS PG.Recent developments in tritium incorporation for radiotracer studies[J].Curr Pharm Des,2000,6(10):1029
[14]斯琴朝克图.氚标记喹赛多的制备及其在大鼠和鸡体内处置研究[D].武汉:华中农业大学,2011HARNUD S.The Synthesis of Tritium Labeled Cyadox and Its Disposition in Rats and Chicken[D].Wuhan:Huazhong Agricultural University,2011
[15]MATLOUBI H,GHANDI M,ZARRINDAST MR,et al.Modified synthesis of 11-[14C]-clozapine[J].Appl Radiat Isot,2001,55(6):789
[16]MARATHE PH,SHYU WC,HUMPHREYS WG.The use of radiolabeled compounds for ADME studies in discovery and exploratory development[J].Curr Pharm Des,2004,10(24):2991
[17]SIDOROV GV,ZVERKOV YB,MYASOEDOV NF.Isotope exchange of azidothymidine with tritium[J].Radiochemistry,2003,45(1):87
[18]SHEVCHENKO V,NAGAEV I,MYASOEDOV N.Optimization of conditions for tritium labeling of organic compounds by isotope exchange with tritium water,based on the concepts of reactions on the catalyst surface[J].Radiochemistry,2005,47(4):403
[19]MIASOEDOV NF,KUZNETSOVA OB,KOZIK VS.Biosynthesis of tritium-labeled S-adenosyl-L-methionine in yeast cells[J].Bioorg Khim,1985,11(7):944
[20]REN S,HESK D,MCNAMARA P,et al.Syntheses of 3H-labeled,14C-labeled,and 2H4-labeled SCH 444877,phosphodiesterase type5 inhibitors[J].J Label Compd Radiopharm,2013,56(9-10):480
[21]EGAN JA,LASETER AG,FILER CN.Tritium labelling and characterization of the antimalarial drug(+/-)-chloroquine by several methods[J].Appl Radiat Isot,2002,57(3):343
[22]KOVALAINEN JT,MORIMOTO H,WILLIAMS PG,et al.Synthesis of a tritium labelled antihistaminic drug[3H]-N,N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethaneamine·HCl[J].J Label Compd Radiopharm,1995,36(12):1147
[23]BAGSHAW CR.Kinetic Isotope Effects[J].Springer Berlin Heidelberg,2013,3(236):1200
[24]PAAREN HE,FIVIZZANI MA,SCHNOES HK,et al.Preparation of tritium-or deuterium-labeled vitamin D analogs by a convenient general method[J].Proc Nat Acad Sci USA,1981,78(10):6173
[25]EGMOND MR,VLIEGENTHART JFG,BOLDINGH J.Synthesis of ii(n-8)ls,tritium-labelled linoleic acid[J].Biochim Biophys Acta,1973,316(1):1
[26]HESK D,BORGES S,HENDERSHOT S,et al.Synthesis of 3H,2H4,and 14C-SCH 417690(vicriviroc)[J].J Label Compd Radiopharm,2016,59(5):190
[27]MATLOUBI H,SHAFIEE A,SAEMIAN N,et al.Synthesis of carbon-14 analogue of 1,5 diaryl-5-[14C]-1,2,3-triazoles[J].Appl Radiat Isot,2004,60(5):665
[28]AGRAWAL N,KOHEN A.Microscale synthesis of 2-tritiated isopropanol and 4R-tritiated reduced nicotinamide adenine dinucleotide phosphate[J].Anal Biochem,2003,322(2):179
[29]ICHINOSE K,LEEPER FJ,BATTERSBY AR.Preparation of[4R-3H]NADH,[4R-3H]NADPH and the corresponding 4S-isomers all with substantial specific activities[J].J Chem Soc,Perkin Trans,1993,11(11):1213
[30]PARNES H,KECZER SD.Microscale synthesis of volatile,14C‐labelled acid chlorides[J].J Label Compd Radiopharm,2010,22(3):287
[31]FILER CN.Isotopic fractionation of organic compounds in chromatography[J].J Label Compd Radiopharm,1999,42(2):169
[32]HEYS JR.High performance liquid chromatographic studies of p H dependence in the isotopic fractionation of deuterated benzazepines[J].J Chromatogr A,1987,407:37
[33]HONG B,KOHEN A.Microscale synthesis of isotopically labeled6R‐N5,N10-methylene-5,6,7,8-tetrahydrofolate[J].J Label Compd Radiopharm,2010,48(10):759
[34]KOVALAINEN JT,MORIMOTO H,WILLIAMS PG,et al.Synthesis of a tritium labelled antihistaminic drug[3H]-N,N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethaneamine·HCl[J].J Label Compd Radiopharm,1995,36(12):1147
[35]折冬梅,曲哲,黄啟良等.杀菌剂氟吗啉的14C标记合成[J].核农学报,2007,21(2):206SHE DM,QU Z,HUANG QL,et al.Preparation of C-14 labeled flumorph[J].J Nucl Agric Sci,2007,21(2):206
[36]FILER CN.The analysis of 14C and 3H labeled compounds[J].Appl Radiat Isot,1988,39(6):530
[37]HESK D,BORGES S,DUMPIT R,et al.Synthesis of 3H,13C,2H3,15N and 14C-labelled SCH 466036,a histamine 3 receptor antagonist[J].J Label Compd Radiopharm,2015,58(2):36
[38]FILER CN,HAINLEY C,NUGENT RP.Tritiation of dopaminergic ligands(-)-lisuride and(+/-)-nomifensine[J].J Radioanal Nucl Chem,2006,267(2):345