CN107088228A - The exploitation and application of New video diagnosis and treatment reagent based on tryptophan and its derivative - Google Patents
The exploitation and application of New video diagnosis and treatment reagent based on tryptophan and its derivative Download PDFInfo
- Publication number
- CN107088228A CN107088228A CN201710142906.0A CN201710142906A CN107088228A CN 107088228 A CN107088228 A CN 107088228A CN 201710142906 A CN201710142906 A CN 201710142906A CN 107088228 A CN107088228 A CN 107088228A
- Authority
- CN
- China
- Prior art keywords
- tryptophan
- derivative
- reaction
- new video
- treatment reagent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 title claims abstract description 48
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 20
- 238000003745 diagnosis Methods 0.000 title claims abstract description 14
- 239000002243 precursor Substances 0.000 claims abstract description 15
- 230000002285 radioactive effect Effects 0.000 claims abstract description 14
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 238000011160 research Methods 0.000 claims abstract description 11
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 230000004060 metabolic process Effects 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 4
- 230000026030 halogenation Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 239000000047 product Substances 0.000 claims description 22
- 238000000926 separation method Methods 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 15
- 238000012805 post-processing Methods 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 12
- 230000004224 protection Effects 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 11
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 11
- 239000003208 petroleum Substances 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 10
- 238000002414 normal-phase solid-phase extraction Methods 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- 239000000758 substrate Substances 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 5
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 claims description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 239000004411 aluminium Substances 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 229920001971 elastomer Polymers 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- KCUNTYMNJVXYKZ-JTQLQIEISA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-JTQLQIEISA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 1
- PGXWDLGWMQIXDT-UHFFFAOYSA-N methylsulfinylmethane;hydrate Chemical compound O.CS(C)=O PGXWDLGWMQIXDT-UHFFFAOYSA-N 0.000 claims 1
- 210000000496 pancreas Anatomy 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 5
- 241000699670 Mus sp. Species 0.000 abstract description 4
- 230000002045 lasting effect Effects 0.000 abstract description 4
- 241000699666 Mus <mouse, genus> Species 0.000 abstract description 3
- 238000012879 PET imaging Methods 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 abstract description 3
- 229910052789 astatine Inorganic materials 0.000 abstract description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 229910052801 chlorine Inorganic materials 0.000 abstract description 2
- 238000007689 inspection Methods 0.000 abstract description 2
- 229910052740 iodine Inorganic materials 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 23
- 229960004799 tryptophan Drugs 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 9
- 229910052796 boron Inorganic materials 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 238000012937 correction Methods 0.000 description 7
- -1 indoles amine Chemical class 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000001041 indolyl group Chemical group 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003682 fluorination reaction Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 102000016680 Dioxygenases Human genes 0.000 description 2
- 108010028143 Dioxygenases Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 238000002788 crimping Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical compound [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 2
- 238000009740 moulding (composite fabrication) Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000001243 protein synthesis Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000779 smoke Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000003325 tomography Methods 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- ZTTWHZHBPDYSQB-LBPRGKRZSA-N (2s)-2-amino-3-(1h-indol-3-yl)-2-methylpropanoic acid Chemical compound C1=CC=C2C(C[C@@](N)(C)C(O)=O)=CNC2=C1 ZTTWHZHBPDYSQB-LBPRGKRZSA-N 0.000 description 1
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 1
- GVLISXLTHVQTJN-UHFFFAOYSA-N 2,3-dihydroindole-1,2-dicarboxylic acid Chemical compound C1=CC=C2N(C(O)=O)C(C(=O)O)CC2=C1 GVLISXLTHVQTJN-UHFFFAOYSA-N 0.000 description 1
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 1
- FZGZIHCGKPRSLO-UHFFFAOYSA-N 6,10-dioxaspiro[4.5]decane-7,9-dione Chemical compound O1C(=O)CC(=O)OC11CCCC1 FZGZIHCGKPRSLO-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 1
- 101001037261 Homo sapiens Indoleamine 2,3-dioxygenase 2 Proteins 0.000 description 1
- 101000892398 Homo sapiens Tryptophan 2,3-dioxygenase Proteins 0.000 description 1
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 1
- 102100040062 Indoleamine 2,3-dioxygenase 2 Human genes 0.000 description 1
- 125000002707 L-tryptophyl group Chemical group [H]C1=C([H])C([H])=C2C(C([C@](N([H])[H])(C(=O)[*])[H])([H])[H])=C([H])N([H])C2=C1[H] 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000004020 Oxygenases Human genes 0.000 description 1
- 108090000417 Oxygenases Proteins 0.000 description 1
- 241000736199 Paeonia Species 0.000 description 1
- 235000006484 Paeonia officinalis Nutrition 0.000 description 1
- IOEJYZSZYUROLN-UHFFFAOYSA-M Sodium diethyldithiocarbamate Chemical compound [Na+].CCN(CC)C([S-])=S IOEJYZSZYUROLN-UHFFFAOYSA-M 0.000 description 1
- 102100040653 Tryptophan 2,3-dioxygenase Human genes 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- HKVLOZLUWWLDFP-UHFFFAOYSA-M hydron;tetrabutylazanium;carbonate Chemical compound OC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC HKVLOZLUWWLDFP-UHFFFAOYSA-M 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000012636 positron electron tomography Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Optics & Photonics (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Indole Compounds (AREA)
Abstract
The present invention relates to a kind of exploitation and application of the New video diagnosis and treatment reagent based on tryptophan and its derivative, using the borate of tryptophan and its derivative as radioactive halogenation precursor, by substitution reaction by radioactivity halogen atom (including F, Cl, Br, I, At the 2 of the aromatic ring of tryptophan and its derivative) are incorporated into, 4, 5, 6 or 7, New video diagnosis and treatment reagent is made, so as to carry out NDInondestructire inspection and disease treatment research to organism using it, non-invasi research is carried out including the metabolic processes to organism and chemistry and treatment for radiation-caused disease are carried out to disease.The present invention have selected representative18The fluorotryptophans of F 5 carry out PET imaging experiments in mouse, test result indicates that showing lasting in mice pancreatic and significantly absorbing.
Description
Technical field
The present invention relates to positron emission computerized tomography technical field, and in particular to one kind is based on tryptophan and its derivative
New video diagnosis and treatment reagent exploitation and application.
Background technology
Positron emission computerized tomography technology (PET) is as a kind of effective and high imaging technique of sensitivity, by putting
The biomolecule spike of penetrating property mark is received more so as to carry out non-invasi research to the metabolic processes of organism
Carry out more universal concern.
Tryptophan (Trp) is as a kind of particularly important amino acid, and its metabolin be related to cancer, nervous system fail disorderly
A variety of diseases such as random disease and diabetes.For example, except participate in protein synthesis in addition to, tryptophan can in vivo by indoles amine-
The path of the tryptophan 2,3- oxygenases 2 (IDO1/IDO2/TDO2) of 1/ indoles amine -2,3- dioxygenases of 2,3- dioxygenases 2/ point
Solution is into L- kynurenins, and this plays the part of vital role in terms of tumour growth and immune system suppression.Tryptophan is by generation
Thank as serotonin, control various nervous activities and insulin secretion.Obviously, radiolabeled tryptophan and it spread out
The biological metabolic process for the research tryptophan of non-invasi in various diseases provides a kind of possible.
Several classes11The tryptophan derivative of C flag is used to study protein synthesis as PET reagents.Due to11C is marked
The tryptophan derivative half-life period of note is very short (20 minutes), so as to limit its application in multi-center clinical trial, it is impossible to real
Now large-scale production and its commercialization.
The content of the invention
The present invention, by substitution reaction, realizes the tryptophan of borate substitution using tryptophan borate precursor as substrate
2,4,5,6 and No. 7 positions it is radioactive halogen-labeled.The present invention have selected representative18F-5- fluorotryptophans are in mouse
PET imaging experiments are carried out, test result indicates that showing lasting in mice pancreatic and significantly absorbing.
To reach above-mentioned purpose, the technical scheme that the present invention is provided is：
A kind of New video diagnosis and treatment reagent based on tryptophan and its derivative, by tryptophan and its borate of derivative
As the precursor of radioactive halogenation, radioactivity halogen atom (including F, Cl, Br, I, At) is incorporated into by color ammonia by substitution reaction
2,4,5,6 or 7 of the aromatic ring of acid and its derivative, are made New video diagnosis and treatment reagent, so as to enter using it to organism
Row NDInondestructire inspection and disease treatment research, including non-invasi research is carried out and right to the metabolic processes of organism
Disease carries out chemistry and radiotherapy.
The described New video diagnosis and treatment preparation method of reagent thereof based on tryptophan and its derivative specifically includes following steps：
Step 1：Radioactive label
By tryptophan and its borate precursor and Cu (Pyr) of derivative4(OTf)2It is dissolved in DMF；Mixture is in rubber
Barrier film and aluminium crimping cap closure in the reaction tube of Feng Youyi atmospheric air while carry out；By Fluorine source18F-TBAF(18The fourths of F- tetra-
Base ammonium fluoride) MeCN solution be added dropwise by insulin syringe, reaction under the conditions of 110 DEG C stir 20 minutes.
Step 2：Deprotection and post-processing step A
After radioactive label, H is added in rapid product one step up2SO4, and reacted 10 minutes at 140 DEG C, reaction knot
It is cooled to room temperature after beam, reaction solution is neutralized with NaOAc solution, and with aluminum oxide solid-phase extraction column separation and Extraction；
Or, step 2：Deprotection and post-processing step B
After radioactive label, TFA is added in rapid product one step up, and reacted 5 minutes under the conditions of 130 DEG C, reaction
Liquid is heated by batch (-type) and argon gas stream is concentrated.Residue is configured to suspension with KOH, and 5 points are reacted under the conditions of 160 DEG C
Clock；Reaction is neutralized after terminating with 50%AcOH solution, and with aluminum oxide solid-phase extraction column separation and Extraction.
Further, the radioactive source is Fluorine source18F-TBAF。
It is solid by aluminum oxide after object is by radiolabeled general step and deprotection and post-processing step A
Crude product is obtained after phase extraction column, crude product is purified by HPLC and following condition.
The present invention also illustrates tryptophan derivative, and (including the tryptophans that methylate of N- and alpha-methylated tryptophan spread out
It is biological) halogenated precursors synthetic method, synthetic route is：
Concretely comprise the following steps：Under condition of nitrogen gas, Pd (dppf) Cl is loaded in history Ranque tube2, KOAc and B2pin2, and add
Enter the tryptophan methyl ester under anhydrous DMSO and B DEG C of protection, 12h stirred under the conditions of 80 DEG C, reaction is cooled to room temperature after terminating,
Target substrates must be corresponded to by crossing post separation by ethyl acetate/petroleum ether.
Synthetic product includes：
Synthetic reaction has：
Experiment it is initial, we want to confirm whether induction prothetic group (being easily converted to the functional group of halo, such as boron) can be with
It is introduced in each position of tryptophan.As shown in scheme 1A, using the tryptophan derivative of iodo or bromo as substrate, lead to
Miyaura boron glycosylation reactions are crossed, borate group Bpin can successfully be incorporated into 4,5,6 and No. 7 positions of indole ring.In order to
The presence reduction flag rate of N-H groups acid on indoles is prevented, we are protected to nitrogen-atoms with BoC groups.Except
Borate precursor can be fluorinated, and iodonium ylides can also equally realize that electron rich aromatic ring is Radiofluorinated (such as scheme 1B institutes
Show).The synthetic work of borate above and iodonium ylides is to realize that the Radiofluorinated of tryptophan provides the foundation.
The synthesis of the radiolabeled tryptophan derivative of scheme 1
Then, our focuses of work are mainly focused on has been carried out together to the Bpin of 4,5, the 6 and No. 7 positions tryptophans replaced
Position element mark.With anhydrous18F- tetrabutyl ammonium fluorides react progress 20 minutes under 110 degrees Celsius, and then a step as Fluorine source
Deprotection, we respectively obtain 4,5,6,7- with 2.8-8% separation yield (without correction for attenuation)18The tryptophan of F marks.By
Sensitive to alkali in DDTC, tetrabutyl ammonium hydrogen carbonate is largely residued in as phase transfer catalyst18In F- tetrabutyl ammonium fluorides, because
This uses larger amount of18F- tetrabutyl ammonium fluorides on the contrary can reduction flag rate.It may be increased using other weakly alkaline Fluorine sources
Mark rate.Because mark reaction is generally to acid-sensitive, in order to improve reaction yield, we are protected to acid indoles-NH
Shield.However, we are when synthesizing 7-Bpin tryptophan, the BoC protection groups of indoles N atoms are dissociated in building-up process, are pushed away
Survey may due to Bpin groups and BoC protection groups space it is crowded caused by.But we are still isolated with considerable yield18F-
The fluoro- tryptophans of 6- (6.4% separation yield, without correction for attenuation), this shows that the protection to indoles-NH is not necessary.
In addition to being easy to synthesis, we do not use optically pure initiation material in the synthesis of all substrates, because we are main
New 18F-PET reagent of the research and utilization radioactive halogenation reaction synthesis based on tryptophan and its derivative.If these reagents
It is synthesized and applies in imaging technique in the future, we can be respectively studied D, L-configuration.
The tryptophan derivative of scheme 2 it is Radiofluorinated
We expand substrate spectrum, have attempted the tryptophan derivative of other substituted bases.As shown in Scheme 3,1- methyl
Replace and can be obtained in indole ring C-5 and the C-6 tryptophan derivative for there are Bpin prothetic groups with synthesizing in high yield, synthesize these examinations
After agent, we select that experiment is marked exemplified by 5-Bpin-1- methyl tryptophans, with high radiochemical purity and 7.9% receipts
Rate is obtained18The fluoro- 1- methyl tryptophans of 5- of F marks.
Synthesis (B) other positions 1- methyl tryptophans precursor (C) 5- of scheme 3 (A) 5-Bpin-1- methyl tryptophans
The labelling experiment of Bpin-1- methyl tryptophans
We use Alpha-Methyl tryptophan as the 3rd class tryptophan reagent, in fact,11C- Alpha-Methyls-L-Trp
(AMT) it is a kind of tryptophan homologue, possesses great potential application in cancer research.However, due to11C is shorter partly to decline
Phase, so as to limit its extensive use in clinical test, it is impossible to realize large-scale production and its commercialization.As shown in Scheme 4,
We are obtained with high radiochemical purity and 7.9% yield18F-5- fluoro-alphas-methyl-L-tryptophan.5-Bpin-AMT precursors can
To be synthesized by two kinds of paths, method synthesis step is relatively fewer shown in scheme 4, but it is Radiofluorinated after deprotection condition
It is harsh.Another method synthesis step is more (as shown in scheme 5), be advantageous in that it is Radiofluorinated after deprotection process condition
Gently.In addition, although we are only tested to 5-Bpin- Alpha-Methyls-L-Trp, the fluorination of other positions can be adopted
With same response strategy.
Scheme 418The synthesis of F- Alpha-Methyls-L-Trp and borate precursor
The 5-Bpin- Alpha-Methyls of scheme 5-another synthesis path of L-Trp
The present invention includes following some association compounds：
Wherein X also includes its radio isotope in addition to representing general halogen atom；The enantiomter of these compounds
Also it is within the scope of the present invention.
Obtain18After the PET reagents of F marks, we select 5- fluorotryptophans to carry out PET imagings in normal mouse.
Beneficial effect：
Find can be by the fluorination reaction of copper participation by studying by the present invention18F is introduced directly into tryptophan aromatic ring
4,5,6 and 7 and indole ring the N- tryptophans and alpha-methylated tryptophan that methylate.F with H close to radius,
On bioactivity influence may be smaller, and half-life period compared with11C length.These18The imaging technique that is embodied as of F fluorinations provides potential answer
With.We select simultaneously18F-5- fluorotryptophans are tested, and are shown lasting in mice pancreatic and are significantly absorbed (Fig. 1), this
Data are provided for the PET reagents research of tryptophan in biochemistry and tryptophan derivative.
Brief description of the drawings
Fig. 1：18The PET images of F-5- fluorotryptophans, show lasting and significantly absorb in mice pancreatic.
Embodiment
With reference to specific embodiment, the invention will be further described.
1) radiolabeled general step
Pinacol borate precursor (5mg) and Cu (Pyr)4(OTf)2(4mg) is dissolved in 50uL DMF.Mixture is in rubber
Glue barrier film and aluminium crimping cap closure in the reaction tube of Feng Youyi atmospheric air while carry out.18F-TBAF(40-50uL MeCN
Solution) it is added dropwise by 0.5mL insulin syringes, reaction is stirred 20 minutes under the conditions of 110 DEG C.
2) deprotection and post-processing step A
After Radiofluorinated, 300uLH is added2SO4(3M), and react 10minutes at 140 DEG C.Reaction terminates rear cold
But to room temperature, reaction solution is neutralized with 450uL 2N NaOAc solution, and (is used with aluminum oxide solid-phase extraction column separation and Extraction
10mLH2O pre-flush).
3) deprotection and post-processing step B
Crude product adds 300uL TFA, and reacts 5minutes under the conditions of 130 DEG C.Reaction solution is heated by batch (-type)
And argon gas stream is concentrated into 50uL.Residue is configured to suspension with 500uLof 5N KOH and reacted under the conditions of 160 DEG C
5minutes.Reaction is neutralized after terminating with 500uL of 50%AcOH, and (is used with aluminum oxide solid-phase extraction column separation and Extraction
10mLH2O pre-flush).
Embodiment 1
Prepare18The fluoro- L-Trps of F-5-
Target product passes through radiolabeled general step (138mCi18F-TBAF in 50uL MeCN) and remove-insurance
Shield and post-processing step A.Carry out purifying the target product for obtaining 11.3mCi (8% radiochemistry receipts by HPLC and following condition
Rate, without correction for attenuation).
Embodiment 2
Prepare18The fluoro- L-Trps of F-6-
Target product passes through radiolabeled general step (38.6mCi18F-TBAF in 40uL MeCN) and it is de-
Protection and post-processing step A.By the crude product that 10mCi is obtained after aluminum oxide solid-phase extraction column.903uCi product passes through
HPLC and following condition purify the target product (2.8% radiochemistry yield, without correction for attenuation) for obtaining 96uCi.
Embodiment 3
Prepare18The fluoro- DL-Trps of F-7-
Target product passes through radiolabeled general step (81.4mCi18F-TBAF in 50uL MeCN) and it is de-
Protection and post-processing step A.By the crude product that 22mCi is obtained after aluminum oxide solid-phase extraction column.2.8mCi product passes through
HPLC and following condition purify the target product (6.4% radiochemistry yield, without correction for attenuation) for obtaining 660uCi.
Embodiment 4
Prepare18The fluoro- 1- methyl-L-tryptophans of F-5-
Target product passes through radiolabeled general step (109.7mCi18F-TBAF in 40uL MeCN) and it is de-
Protection and post-processing step A.By the crude product that 36mCi is obtained after aluminum oxide solid-phase extraction column.3.3mCi product passes through
HPLC and following condition purify the target product (7.9% radiochemistry yield, without correction for attenuation) for obtaining 797uCi.
Embodiment 5
Prepare18F-5- fluoro-alphas-methyl-L-tryptophan
Target product passes through radiolabeled general step (55.2mCi18F-TBAF in 50uL MeCN) and it is de-
Protection and post-processing step B.By the crude product that 8.4mCi is obtained after aluminum oxide solid-phase extraction column.4.13mCi product passes through
HPLC and following condition purify the target product (7.6% radiochemistry yield, without correction for attenuation) for obtaining 2.04mCi.
A kind of synthetic method of the fluorinated pre-cursor of tryptophan derivative, synthetic route is：
Concretely comprise the following steps：Under condition of nitrogen gas, Pd (dppf) Cl is loaded in history Ranque tube2, KOAc and B2pin2, and add
Enter the tryptophan methyl ester under anhydrous DMSO and Boc protections, 12h stirred under the conditions of 80 DEG C, reaction is cooled to room temperature after terminating,
Target substrates must be corresponded to by crossing post separation by ethyl acetate/petroleum ether.
Embodiment 6
The fluorinated pre-cursor for the tryptophan derivative that the present invention is synthesized：
(1) 5- pinacols borate-Na- tertbutyloxycarbonyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters
Under condition of nitrogen gas, Pd (dppf) Cl is loaded in Schlenk pipes2(18mg, 0.025mmol, 5mol%), KOAc
(147mg, 1.5mmol, 3.0equiv.) and B2pin2(140mg, 0.55mmol, 1.1equiv.), and it is anhydrous to add 3mL
The iodo- N of DMSO and 5-a- tertbutyloxycarbonyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters (322mg, 0.5mmol,
1.0equiv.), 80℃Under the conditions of stir 12h, reaction is cooled to room temperature, ethyl acetate after terminating：Petroleum ether (1:10) post is crossed
Separate to obtain 5- pinacol borates-Na- tertbutyloxycarbonyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters (79%,
254mg)。
1H NMR(400MHz,CDCl3) δ 8.10 (d, J=7.7Hz, 1H), 7.99 (s, 1H), 7.74 (d, J=8.3Hz,
1H), 7.36 (s, 1H), 5.22 (dd, J=10.4,4.8Hz, 1H), 3.78 (s, 3H), 3.53 (dd, J=14.8,4.6Hz,
1H), (s, the 18H) of 3.38 (dd, J=14.9,10.5Hz, 1H), 1.63 (s, 9H), 1.35 (s, 12H), 1.3113C NMR
(101MHz,CDCl3)δ170.83,151.57,149.42,137.57,130.84,129.98,125.98,124.34,
116.64,114.47,83.61,83.49,82.91,58.10,52.30,28.12,27.70,25.38,24.88,24.84
(carbon adjacent to boron was not observed).IR(KBr)2981,2865,1735,1370,1254,
1142,1054,1033cm-1HRMS(APCI):Calcd.for C33H49BN2O10[M+H]+:645.3553,found
645.3554.
(2) 6- pinacols borate-Na- tertbutyloxycarbonyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters
L-Trp
(4.08g, 20mmol, 1equiv.) and urea (50mg) and 50mL glacial acetic acid wiring solution-formings, 0℃Under the conditions of add
Smoke concentrated nitric acid/acetic acid (0.75mL/3mL) obtains yellow clear solution, 0℃Under the conditions of continue stir, become after suspension heat up
To 15℃, smoke concentrated nitric acid/acetic acid (1.75mL/7mL) is added dropwise, is warmed to room temperature continuation and stirs 18h.Reaction is added after terminating
30mLH2O dilutes, and is then concentrated into 30mL, refrigerator is stood overnight, and filtering can obtain yellow solid for crude product 6- nitro-L- color ammonia
Sour HNO3·1/2H2O (53%, 3.41g).Take crude product 6- nitros-L-Trp HNO3·1/2H2O (2.50g) is dissolved in
In 20mL hot water, 0.42g Na are added2CO3, reaction a moment, which filters, can obtain 6- nitros-L-Trp H2O.6- nitro-L- color ammonia
Sour H2O (687mg, 2.57mmol, 1.0equiv.) and the anhydrous MeOH of 9mL are configured to suspension, 0℃Under the conditions of be carefully added dropwise
Me3SiCl (2.5mL, 19.6mmol, 7.6equiv.), is then warmed to room temperature stirring 18h.Reaction is carefully added into Et after terminating3N
(5mL, 3.6mmol, 1.4equiv.) and (B DEG C)2O(897mg,41.1mmol,1.6equiv.).Whether TLC monitorings reaction
Complete, decompression removes solvent after reaction terminates, and residue adds appropriate H2O, and be extracted with ethyl acetate.Na2SO4Drying is organic
Phase, decompression removes ethyl acetate, and gained solid adds the anhydrous CH of 9mL3CN, DMAP (314mg, 2.57mmol, 1.0equiv.) with
And (B DEG C)2O (1.68g, 7.71mmol, 3equiv.), is stirred at room temperature 12h.Decompression removes reaction dissolvent, acetic acid after reaction terminates
Ethyl ester：Petroleum ether (1:10) cross post separation and obtain 6- nitros-Na- tertbutyloxycarbonyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan first
Ester (68%, 985mg).
In 18mLCH2Cl2Middle addition 6- nitros-Na- tertbutyloxycarbonyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters
(862mg, 1.53mmol) and zinc powder (5.0g), 0℃Under the conditions of 1.4mL HOAc are slowly added dropwise.It is warmed to room temperature after completion of dropwise addition
Continue to stir 20min.Reaction end is filtered to get filtrate, and saturation NaHCO is used respectively3, H2O, saturation NaCl solution washing, is used in combination
Na2SO4Dry.Decompression removes solvent gained residue and is dissolved in THF (11.2mL), H2In O (7.9mL) and 5%HCl (4.3mL),
0℃Under the conditions of be slowly added to NaNO2(116mg, 1.68mmol, 1.1equiv.), 0℃Stir after 5min, in above-mentioned mixed liquor
Middle addition is by NaI (1.43g, 9.52mmol, 6.2equiv.), I2(388mg 1.53mmol) and H2It is molten that O (150mL) is prepared
Liquid, continues to stir 1.0h.Reaction uses saturation NaHCO after terminating3Aqueous solution regulation pH 7-8, EtOAc extractions, collect organic phase point
Saturation NaHSO is not used3The aqueous solution, H2O and the washing of the saturation NaCl aqueous solution, Na2SO4Dry.Decompression removes solvent, and uses acetic acid
Ethyl ester：Petroleum ether (1:10) cross post separation and obtain the iodo- N of 6-a- tertbutyloxycarbonyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters
(76%, 748mg).7
Under condition of nitrogen gas, Pd (dppf) Cl is loaded in Schlenk pipes2(11mg, 0.015mmol, 5mol%), KOAc
(88mg, 0.9mmol, 3.0equiv.) and B2pin2(84mg, 0.33mmol, 1.1equiv.), and it is anhydrous to add 1.5mL
The iodo- N of DMSO and 5-a- tertbutyloxycarbonyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters (193mg, 0.3mmol,
1.0equiv.), 80℃Under the conditions of stir 12h, reaction is cooled to room temperature, ethyl acetate after terminating：Petroleum ether (1:10) post is crossed
Separate to obtain 6- pinacol borates-Na- tertbutyloxycarbonyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters (74%,
143mg)。
1H NMR(400MHz,CDCl3) δ 8.61 (s, 1H), 7.65 (d, J=7.8Hz, 1H), 7.51 (d, J=7.8Hz,
1H), 7.42 (s, 1H), 5.19 (dd, J=10.2,4.8Hz, 1H), 3.76 (s, 3H), 3.51 (dd, J=15.0,4.7Hz,
1H), (s, the 18H) of 3.35 (dd, J=14.9,10.2Hz, 1H), 1.64 (s, 9H), 1.33 (s, 12H), 1.3113C NMR
(101MHz,CDCl3)δ170.75,151.67,149.31,135.18,132.86,128.47,125.32,121.69,
118.10,116.39,83.53,83.28,82.92,58.09,52.27,28.05,27.67,25.44,24.83,24.81
(carbon adjacent to boron was not observed).IR(KBr)2981,2844,1644,1386,1055,
1033,1016cm-1.HRMS(ESI):Calcd.for C33H49BN2O10[M+Na]+:667.3372,found 667.3373.
(3) 4- pinacols borate-Na- tertbutyloxycarbonyl-Nb,Nb- two tertbutyloxycarbonyl-D, L-Trp methyl esters
Synthetic method is with reference to 5-BPin-Trp.
1H NMR(400MHz,CDCl3) δ 8.31 (d, J=8.1Hz, 1H), 7.77 (d, J=7.3Hz, 1H), 7.31 (s,
1H), 7.27 (s, 1H), 7.24 (d, J=7.5Hz, 1H), 5.53 (dd, J=11.5,4.2Hz, 1H), 3.97 (dd, J=14.2,
4.1Hz, 1H), 3.75 (s, 3H), 3.24 (dd, J=14.1,11.7Hz, 1H), 1.61 (s, 9H), 1.35 (s, 6H), 1.31 (s,
6H),1.22(s,18H).
13C NMR(101MHz,CDCl3)δ171.19,151.42,149.18,135.83,133.43,131.83,
126.48,123.20,118.00,117.49,83.75,83.24,82.33,58.04,51.85,28.03,27.53,24.92,
24.70,24.38(carbon adjacent to boron was not observed).IR(KBr)2981,1733,1631,
1397,1260,1135,1105cm-1.HRMS(ESI):Calcd.for C33H49BN2O10[M+Na]+:667.3372,found
667.3362.
(4) 7- pinacols borate-Nb,Nb- two tertbutyloxycarbonyl-D, L-Trp methyl esters
Synthetic method is with reference to 5-BPin-Trp.Indole ring N- tertbutyloxycarbonyls protection group is deprotected in boron glycosylation reaction.
1H NMR(400MHz,CDCl3) δ 9.07 (s, 1H), 7.70 (d, J=7.8Hz, 1H), 7.60 (d, J=6.6Hz,
1H), 7.09 (t, J=7.5Hz, 1H), 7.05 (d, J=1.9Hz, 1H), 5.15 (dd, J=10.2,4.8Hz, 1H), 3.74 (s,
3H), 3.59 (dd, J=14.8,4.8Hz, 1H), 3.41 (dd, J=14.8,10.2Hz, 1H), 1.35 (s, 12H), 1.26 (s,
18H).
13C NMR(101MHz,CDCl3)δ170.90,151.47,141.23,128.99,126.35,122.90,
122.11,118.69,110.87,83.52,82.48,59.01,51.95,27.46,25.61,24.78,24.67(carbon
adjacent to boron was not observed).IR(KBr)2981,1748,1456,1387,1123,1057,
1033,1015cm-1.HRMS(ESI):Calcd.for C28H41BN2O8[M+Na]+:567.2848,found 567.2843.
(5)
6,10-dioxaspiro[4.5]decane-7,9-dion-{Dimethyl(2S,3aR,8aS)-8-acetyl-1,
2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-1,2-dicarboxylate-5-iodonium}ylide
NaBO3Dimethyl (2S, 3aR, 8aS) -8- is added portionwise in (385mg, 2.5mmol, 10.0equiv.)
acetyl-5-iodo-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-1,2-dicarboxylate
In glacial acetic acid (1.67mL) solution of (111mg, 0.25mmol, 1.0equiv), 12h is stirred at 50 DEG C.Reaction adds after terminating
Enter appropriate H2O is quenched, and is extracted with DCM, organic phase Na2SO4Dry, it is standby that filtering and concentrating obtains crude product.6,10-
Dioxaspiro [4.5] decane-7,9-dione (43mg, 0.25mmol, 1.0equiv.) and 10%Na2CO3(w/v,
0.75mL, 0.33M) wiring solution-forming, 1mL EtOH are added, and add standby crude product immediately.Above-mentioned mixed solution is acutely stirred
Mix 12h, reaction, which terminates rear MeOH, crosses post separation and obtain 6,10-dioxaspiro [4.5] decane-7,9-dion- { Dimethyl
(2S,3aR,8aS)-8-acetyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-1,2-
Dicarboxylate-5-iodonium } ylide (51%, 78mg).
1H NMR(400MHz,CDCl3) δ 7.92 (d, J=9.1Hz, 1H), 7.67 (s, 1H), 7.66 (s, 1H), 6.20 (t,
J=12.4Hz, 1H), 4.56 (s, 1H), 4.06 (s, 1H), 3.67 (s, 3H), 3.17 (s, 3H), 2.59 (s, 2H), 2.58-
(m, the 4H) of 2.50 (m, 3H), 2.07 (t, J=7.3Hz, 4H), 1.77-1.7013C NMR(101MHz,CDCl3)δ170.88,
164.33,154.84,146.29,137.39,135.62,134.38,134.29,129.18,121.00,113.90,106.95,
78.52,59.31,57.62,53.15,52.37,52.20,39.55,37.21,23.22.IR(KBr)2951,1712,1655,
1391,1342,1054,1033cm-1.HRMS(APCI):Calcd.for C24H25IN2O9[M+H]+:613.0677,found
613.0665.
(6) 5- pinacols borate-Na- methyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters
Under the conditions of 0 DEG C, the iodo- N of 5-bThe dry DMF of-methoxycarbonyl group-L-Trp methyl esters (563mg, 1.4mmol, 1.0equiv.)
NaH (62mg, 1.54mmol, 1.1equiv., 60%) dry DMF (4.2mL) suspension is slowly added dropwise in (2.8mL) solution,
Completion of dropwise addition continues under the conditions of 0 DEG C to stir after 30minutes, be added dropwise MeI (219mg, 95 μ L, 1.54mmol,
1.1equiv.), reaction is warmed to room temperature stirring 2h.Reaction uses saturation NH after terminating4Reaction, ethyl acetate extraction is quenched in Cl solution
Aqueous phase, collects organic phase and is washed with saturation NaCl (5mL), Na2SO4Dry, filtering is spin-dried for standby.Add in above-mentioned residue
Enter CH3CN (6mL) and TMSI (422mg, 2.1mmol, 1.5equiv.) flow back 1h under a nitrogen atmosphere.It is cooled to after room temperature,
Add 1mL MeOH and reaction is quenched, being spin-dried for solvent, to obtain light tan solid standby.
Above-mentioned light tan solid and THF/H2O (2/1) is made into suspension, 0℃Under the conditions of add appropriate Na2CO3And (B
℃)2O (611mg, 2.8mmol, 2equiv.), is warmed to room temperature stirring 2h.Reaction terminates rear EtOAc and extracts and use saturation respectively
NH4Cl,H2O and saturation NaCl washing organic phases, Na2SO4Dry and be spin-dried for standby.Added in above-mentioned residue appropriate
CH3CN, DMAP (172mg, 1.4mmol, 1.0equiv.) and (B DEG C)2O (917mg, 4.2mmol, 3.0equiv.), in room temperature
Under be stirred overnight.EtOAc dilute reaction solutions simultaneously use saturation NH respectively4Cl,H2O and saturation NaCl washing organic phases.Decompression is removed
Solvent, and use ethyl acetate：Petroleum ether (1:10) cross post separation and obtain the iodo- N of 5-a- methyl-Nb,Nb- two tertbutyloxycarbonyl-L- color ammonia
Sour methyl esters (61%, 477mg).
5- pinacol borates-N can be obtained with reference to 5-BPin-Trpa- methyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan first
Ester (81%)
1H NMR(400MHz,CDCl3) δ 8.08 (s, 1H), 7.64 (d, J=8.3Hz, 1H), 7.23 (d, J=8.3Hz,
1H), 6.83 (s, 1H), 5.17 (dd, J=10.3,4.7Hz, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.61 (dd, J=
14.9,4.7Hz, 1H), 3.37 (dd, J=14.8,10.4Hz, 1H), 1.35 (s, 12H), 1.27 (s, 18H)13C NMR
(101MHz,CDCl3)δ171.02,151.37,138.85,127.91,127.77,127.66,126.54,110.82,
108.40,83.25,82.66,59.01,52.08,32.53,27.59,25.54,24.84,24.76(carbon adjacent
to boron was not observed).IR(KBr)2980,1640,1386,1260,1141,cm-1.HRMS(ESI):
Calcd.for C29H43BN2O8[M+Na]+:581.3005,found581.3004.
(7) 6- pinacols borate-Na- methyl-Nb,Nb- two tert-butoxycarbonyl-l-l-tryptophan methyl esters
Target product can be synthesized with reference to above-mentioned similar synthesis step.
1H NMR(400MHz,CDCl3) δ 7.75 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.52 (d, J=8.0Hz,
1H), 6.92 (s, 1H), 5.13 (dd, J=10.0,4.8Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.58 (dd, J=
14.9,4.8Hz, 1H), 3.35 (dd, J=14.9,10.1Hz, 1H), 1.36 (s, 12H), 1.28 (s, 18H)13C NMR
(101MHz,CDCl3)δ171.01,151.55,136.52,130.49,129.19,124.79,118.01,116.03,
110.15,83.41,82.70,59.07,52.10,32.68,27.61,25.61,24.95,24.80(carbon adjacent
to boron was not observed).IR(KBr)2981,2844,1748,1688,1387,1055,1033,1013cm- 1.HRMS(ESI):Calcd.for C29H43BN2O8[M+Na]+:581.3005,found 581.3002.
(8) 5- pinacols borate-Na- tertbutyloxycarbonyl-Nb- tertbutyloxycarbonyl-Alpha-Methyl-L-Trp methyl esters
Under condition of nitrogen gas, addition Dimethyl (2S, 3aR, 8aS) -8-acetyl-1 in anhydrous THF (25mL), 2,3,
3a,8,8a–hexahydropyrrolo[2,3-b]indole-1,2-dicarboxylate(2.07g,6.50mmol,
1.0equiv.), temperature is down to after -78 DEG C, carefully be added dropwise lithium diisopropylamine (LDA) THF (5.2mL, 10.4mmol,
1.6equiv.2M) solution, after completion of dropwise addition, continues to stir 90minutes at -78 DEG C, MeI (1.01g, 445 μ is then added dropwise
L, 2.53mmol, 1.1equiv.), reaction solution is warmed to room temperature after stirring 5h, uses saturation NH4Reaction, acetic acid second is quenched in the Cl aqueous solution
Ester aqueous layer extracted, collects organic phase and is washed with saturated sodium-chloride water solution (5mL) and use Na2SO4Dry.It is spin-dried for using ethyl acetate：
Petroleum ether (1:1) cross post separation and obtain Dimethyl (2S) -8-acetyl-2-methyl-3,3a, 8,8a-
Tetrahydropyrrolo [2,3-b] indole-1,2 (2H)-dicarboxylate (40%, 861mg).In Dimethyl
(2S)-8-acetyl-2-methyl-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-
CH is added in dicarboxylate (798mg, 2.40mmol, 1.0equiv.)2Cl2(12mL) and add ICl (1M in
CH2Cl2, 9.6mL, 9.6mmol, 4.0equiv.) and NaHCO3(806mg, 9.6mmol, 4.0equiv.), gained peony
2h is stirred at room temperature in solution.Reaction solution is poured into 10%Na by reaction after terminating2S2O3And 10%NaHCO3(1:1,30mL) mixed
Close in solution, acutely rock until red is taken off.CHCl3It is extracted twice collection organic phase and uses Na2SO4Dry, be spin-dried for using acetic acid
Ethyl ester：Petroleum ether (1:2) cross post separation and obtain Dimethyl (2S) -8-acetyl-5-iodo-2-methyl-3,3a, 8,8a-
Tetrahydropyrrolo [2,3-b] indole-1,2 (2H)-dicarboxylate (79%, 2.9g).
Dimethyl(2S)-8-acetyl-5-iodo-2-methyl-3,3a,8,8a-tetrahydropyrrolo[2,
3-b] indole-1,2 (2H)-dicarboxylate (825g, 1.8mmol, 1.0equiv.) adds to H2SO4In/MeOH, in room
The lower stirring 3h of temperature.Reaction solution is poured into water (40mL) and extracted with EtOAc, collects organic phase and uses 5%NaHCO respectively3And saturation
NaCl is washed, Na2SO4Organic phase is dried, is spin-dried for using ethyl acetate：Petroleum ether (1:3) cross post separation and obtain the iodo- N of 5-b- methoxy carbonyl
Base-Alpha-Methyl-L-Trp methyl esters (87%, 362mg).Residue can refer to above-mentioned similar step synthesising target compound.
1H NMR(400MHz,CDCl3) δ 8.11 (d, J=7.4Hz, 1H), 7.93 (s, 1H), 7.72 (d, J=8.3Hz,
1H), 7.33 (s, 1H), 5.38 (s, 1H), 3.72 (s, 3H), 3.57 (d, J=12.6Hz, 1H), 3.34 (d, J=14.4Hz,
1H), (d, J=3.3Hz, the 13H) of 1.64 (s, 9H), 1.47 (s, 9H), 1.3413C NMR(101MHz,CDCl3)δ174.44,
154.21,149.38,137.25,130.60,130.34,126.14,124.89,115.32,114.44,83.55,59.80,
52.58,28.42,28.13,24.93,24.77.
IR(KBr)2981,2889,1748,1457,1381,1252,1151,1072,954cm-1.HRMS(ESI):
Calcd.for C29H43BN2O8[M+Na]+:581.3005,found 581.3001.
(9) 5- pinacols borate-Na- methyl-Nb- tertbutyloxycarbonyl-Alpha-Methyl-L-Trp methyl esters
Target product can be synthesized with reference to above-mentioned similar synthesis step.
1H NMR(400MHz,CDCl3) δ 8.03 (s, 1H), 7.64 (d, J=8.3Hz, 1H), 7.26 (d, J=8.2Hz,
1H), 6.83 (s, 1H), 5.29 (s, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.52 (d, J=18.7Hz, 1H), 3.37 (d, J
=14.4Hz, 1H), 1.47 (s, 9H), 1.36 (s, 6H), 1.35 (s, 6H)
13C NMR(101MHz,CDCl3)δ174.76,154.44,138.56,128.45,128.09,127.65,
126.79,109.37,108.51,83.29,60.13,52.46,32.67,28.41,26.87,24.95,24.79.IR(KBr)
2980,2889,1748,1457,1386,1260,1150,1088,953cm-1.HRMS(ESI):Calcd.for C25H37BN2O6
[M+Na]+:495.2637,found 495.2641.
It is described above, only it is presently preferred embodiments of the present invention, any formal limitation not is made to the present invention, it is any ripe
Professional and technical personnel is known, it is without departing from the scope of the present invention, real to more than according to the technical spirit of the present invention
Apply any simple modification, equivalent substitution that example made and improve etc., still fall within technical solution of the present invention protection domain it
It is interior.
Claims (6)
1. a kind of New video diagnosis and treatment reagent based on tryptophan and its derivative, it is characterised in that：By tryptophan and its derivative
Radioactivity halogen atom is incorporated into tryptophan and its derivative by the borate of thing as the precursor of radioactive halogenation by substitution reaction
2,4,5,6 or 7 of the aromatic ring of thing, are made New video diagnosis and treatment reagent, so as to carry out non-invasi to organism using it
Check and disease treatment research, including non-invasi research is carried out to the metabolic processes of organism and chemistry is carried out to disease
And treatment for radiation-caused disease.
2. the New video diagnosis and treatment reagent according to claim 1 based on tryptophan and its derivative, it is characterised in that：System
Preparation Method comprises the following steps：
Step 1：Radioactive label
By tryptophan and its borate precursor and Cu (Pyr) of derivative4(OTf)2It is dissolved in DMF；Mixture is in diaphragm of rubber
Cap closure is crimped with aluminium while being carried out in the reaction tube of Feng Youyi atmospheric air；The MeCN solution of radioactive source is passed through into pancreas islet
Plain syringe is added dropwise, and reaction is stirred 20 minutes under the conditions of 110 DEG C；
Step 2：Deprotection and post-processing step A
After radioactive label, H is added in rapid product one step up2SO4, and reacted 10 minutes at 140 DEG C, after reaction terminates
It is cooled to room temperature, reaction solution is neutralized with NaOAc solution, and with aluminum oxide solid-phase extraction column separation and Extraction；
Or, step 2：Deprotection and post-processing step B
After radioactive label, TFA is added in rapid product one step up, and is reacted 5 minutes under the conditions of 130 DEG C, reaction solution leads to
Cross batch (-type) heating and the concentration of argon gas stream；Residue is configured to suspension with KOH, is reacted 5 minutes under the conditions of 160 DEG C；Instead
Neutralized after should terminating with 50%AcOH solution, and with aluminum oxide solid-phase extraction column separation and Extraction.
3. the New video diagnosis and treatment reagent according to claim 2 based on tryptophan and its derivative, it is characterised in that：Institute
It is to include to state radioactive source18Radioactivity halogen source including F-TBAF.
4. the New video diagnosis and treatment reagent according to claim 2 based on tryptophan and its derivative, it is characterised in that：Mesh
Mark thing is obtained after crude product by radiolabeled general step and deprotection and post-processing step A or B separation and Extraction, slightly
Product is further purified by HPLC.
5. the synthetic method of the halogenated precursors of tryptophan derivative, it is characterised in that：Synthetic route is：
Reactions steps are：Under condition of nitrogen gas, Pd (dppf) Cl is loaded in history Ranque tube2, KOAc and B2pin2, and add nothing
Tryptophan methyl ester under water DMSO and Boc protection, stirs 12h under the conditions of 80 DEG C, and reaction is cooled to room temperature after terminating, passed through
Ethyl acetate/petroleum ether, which crosses post separation, must correspond to target substrates.
6. the New video diagnosis and treatment reagent according to claim 5 based on tryptophan and its derivative, it is characterised in that：Close
Include into borate：
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710142906.0A CN107088228A (en) | 2017-03-10 | 2017-03-10 | The exploitation and application of New video diagnosis and treatment reagent based on tryptophan and its derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710142906.0A CN107088228A (en) | 2017-03-10 | 2017-03-10 | The exploitation and application of New video diagnosis and treatment reagent based on tryptophan and its derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107088228A true CN107088228A (en) | 2017-08-25 |
Family
ID=59646551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710142906.0A Pending CN107088228A (en) | 2017-03-10 | 2017-03-10 | The exploitation and application of New video diagnosis and treatment reagent based on tryptophan and its derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107088228A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019041588A (en) * | 2017-08-29 | 2019-03-22 | 大陽日酸株式会社 | Process for producing labeled proteins, process for producing labeled peptides and kits |
| WO2022186273A1 (en) * | 2021-03-03 | 2022-09-09 | 国立大学法人千葉大学 | Radioactive compound |
-
2017
- 2017-03-10 CN CN201710142906.0A patent/CN107088228A/en active Pending
Non-Patent Citations (6)
| Title |
|---|
| BENJAMIN C. GIGLIO ET AL: "Synthesis of 5-[18F]Fluoro-α-methyl Tryptophan: New Trp Based PET Agents", 《THERANOSTICS》 * |
| DAVID M. TAYLOR ET AL: "Generic models for radionuclide dosimetry: 11C-, 18F- or 75Se-labelled amino acids", 《APPLIED RADIATION AND ISOTOPES》 * |
| DOMINIQUE SCHÄFER ET AL: "Preparation of No-Carrier-Added 6-[18F]Fluoro-L-tryptophan via Cu-Mediated Radiofluorination", 《EUR. J. ORG. CHEM.》 * |
| H. L. ATKINS ET AL: "Organic radiopharmaceuticals labeled with isotopes of short half-life. V. 18 Flabeled 5- and 6-fluorotryptophan", 《JOURNAL OF NUCLEAR MEDICINE》 * |
| JOHANNES ZISCHLER ET AL: "Alcohol-Enhanced Cu-Mediated Radiofluorination", 《CHEM. EUR. J.》 * |
| PHILIPP S. WEISS ET AL: "Radiosynthesis of 4-[18F]fluoro-L-tryptophan by isotopic exchange on carbonyl-activated precursors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019041588A (en) * | 2017-08-29 | 2019-03-22 | 大陽日酸株式会社 | Process for producing labeled proteins, process for producing labeled peptides and kits |
| WO2022186273A1 (en) * | 2021-03-03 | 2022-09-09 | 国立大学法人千葉大学 | Radioactive compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5341136B2 (en) | Amino acid analogs for tumor imaging | |
| JP5635225B2 (en) | Precursor compounds of radioactive halogen-labeled organic compounds | |
| JP4370162B2 (en) | Solid phase nucleophilic fluorination | |
| CN101443307B (en) | Method for preparing radioactive fluorine labeled organic compound | |
| EP2070897B1 (en) | Method of rapid methylation, kit for preparing pet tracer and method of producing pet tracer | |
| JP7455429B2 (en) | Boron carrier integrated with tumor diagnosis and treatment, its preparation method and use | |
| CN109803973B (en) | Chelating PSMA inhibitors | |
| CN107501393B (en) | Method and kit for synthesizing 18F-labeled amino acid polypeptide drug | |
| CN107088228A (en) | The exploitation and application of New video diagnosis and treatment reagent based on tryptophan and its derivative | |
| CN107522673B (en) | 1,2,4, 5-tetrazine compound for bioorthogonal reaction and preparation method and application thereof | |
| CN102712603A (en) | Radioiodination method | |
| CN109608464B (en) | Radioiodine-labeled Larotrectinib compound and preparation method and application thereof | |
| CN109982722A (en) | Precursor for radiofluorination | |
| US20100292478A1 (en) | Process of preparing a radioactive compound containing a fluorine-18 isotope | |
| Ranyuk et al. | A new approach for the synthesis of 18 F-radiolabelled phthalocyanines and porphyrins as potential bimodal/theranostic agents | |
| CN101723850B (en) | Novel 18F labeled aromatic amino acids, preparation method and application thereof in tumor imaging | |
| JP5594742B2 (en) | 18F labeled azide compound, 18F labeling reagent, and 18F labeling method for alkyne compound using the same | |
| Kimura et al. | Microwave-assisted synthesis of organometallic complexes of 99mTc (CO) 3 and Re (CO) 3: its application to radiopharmaceuticals | |
| CN113105432B (en) | Carbon-11 (C)11C) Radiopharmaceutical, preparation method and application thereof | |
| CN112390760B (en) | FAK-targeting compound and preparation method and application thereof | |
| CN114075167B (en) | Novel positron medicine [ TSPO ] of targeting translocation protein 18 F]TPO1 development | |
| CN106631908A (en) | Radioactive iodine labeling method | |
| WO2021243337A1 (en) | Methods for rapid formation of chemicals including positron emission tomography biomarkers | |
| CN109320500B (en) | A kind of18F-labeled benzimidazole compound and preparation method and application thereof | |
| KR20080074145A (en) | Process for production of compound labeled with radioactive fluorine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170825 |