JP5618042B2 - アイソトープ標識化合物及びアイソトープ標識化合物前駆体 - Google Patents
アイソトープ標識化合物及びアイソトープ標識化合物前駆体 Download PDFInfo
- Publication number
- JP5618042B2 JP5618042B2 JP2009218247A JP2009218247A JP5618042B2 JP 5618042 B2 JP5618042 B2 JP 5618042B2 JP 2009218247 A JP2009218247 A JP 2009218247A JP 2009218247 A JP2009218247 A JP 2009218247A JP 5618042 B2 JP5618042 B2 JP 5618042B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- isotope
- pet
- labeled compound
- prion
- 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.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims description 76
- 239000002243 precursor Substances 0.000 title claims description 11
- 150000003839 salts Chemical class 0.000 claims description 12
- 150000002430 hydrocarbons Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000003068 molecular probe Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 239000004215 Carbon black (E152) Chemical group 0.000 claims 1
- 229930195733 hydrocarbon Chemical group 0.000 claims 1
- 238000012636 positron electron tomography Methods 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 102000029797 Prion Human genes 0.000 description 27
- 108091000054 Prion Proteins 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 25
- 238000000034 method Methods 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 229940125898 compound 5 Drugs 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 230000000389 anti-prion effect Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 13
- -1 methyloxymethyl Chemical group 0.000 description 13
- 208000024777 Prion disease Diseases 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical class CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 9
- 238000003384 imaging method Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000012879 PET imaging Methods 0.000 description 8
- 230000002159 abnormal effect Effects 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 7
- 229940126214 compound 3 Drugs 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229930040373 Paraformaldehyde Natural products 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229920002866 paraformaldehyde Polymers 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 239000000700 radioactive tracer 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
- 206010062767 Hypophysitis Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical compound I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 210000004560 pineal gland Anatomy 0.000 description 4
- 210000003635 pituitary gland Anatomy 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108010067770 Endopeptidase K Proteins 0.000 description 3
- 101100208721 Mus musculus Usp5 gene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 210000003710 cerebral cortex Anatomy 0.000 description 3
- 210000002987 choroid plexus Anatomy 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000005251 gamma ray Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 2
- VKTQEBSVSIVMSP-UHFFFAOYSA-N 2-iodoaniline;hydrochloride Chemical compound Cl.NC1=CC=CC=C1I VKTQEBSVSIVMSP-UHFFFAOYSA-N 0.000 description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- YFKPQCYLWJULME-UHFFFAOYSA-N 4-[(4-amino-2-methylphenyl)methyl]-3-methylaniline Chemical compound CC1=CC(N)=CC=C1CC1=CC=C(N)C=C1C YFKPQCYLWJULME-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000004952 protein activity Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 210000001913 submandibular gland Anatomy 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- REDSKZBUUUQMSK-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC REDSKZBUUUQMSK-UHFFFAOYSA-N 0.000 description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VKCBXONEZGIOSP-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonylazetidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1CCC1 VKCBXONEZGIOSP-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 1
- YNNKKMKHXXUFLP-UHFFFAOYSA-N 2-pyrrolidin-1-yl-n-[4-[[4-[(2-pyrrolidin-1-ylacetyl)amino]phenyl]methyl]phenyl]acetamide Chemical compound C=1C=C(CC=2C=CC(NC(=O)CN3CCCC3)=CC=2)C=CC=1NC(=O)CN1CCCC1 YNNKKMKHXXUFLP-UHFFFAOYSA-N 0.000 description 1
- WECDUOXQLAIPQW-UHFFFAOYSA-N 4,4'-Methylene bis(2-methylaniline) Chemical compound C1=C(N)C(C)=CC(CC=2C=C(C)C(N)=CC=2)=C1 WECDUOXQLAIPQW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102100034452 Alternative prion protein Human genes 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 241001195836 Cypris Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010064091 Iatrogenic infection Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 102100025818 Major prion protein Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 108050001286 Somatostatin Receptor Proteins 0.000 description 1
- 102000011096 Somatostatin receptor Human genes 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- MGSKVZWGBWPBTF-UHFFFAOYSA-N aebsf Chemical compound NCCC1=CC=C(S(F)(=O)=O)C=C1 MGSKVZWGBWPBTF-UHFFFAOYSA-N 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 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 description 1
- 238000007664 blowing Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
- G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
- G01T1/16—Measuring radiation intensity
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Nuclear Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Physics & Mathematics (AREA)
- High Energy & Nuclear Physics (AREA)
- Molecular Biology (AREA)
- Spectroscopy & Molecular Physics (AREA)
Description
また、ステップ1における原料として、ベンゼン環に対する置換基の位置の異なる異性体を用いることによって、配位位置が有機スズ化合物4と異なる異性体を合成することもできる。
まず、o-トルイジンと2-ヨードアニリンとをパラホルムアルデヒドを用いてカップリングし、下記化合物1’を合成した。
1H NMR (CDCl3): δ 2.13 (s, 3H), 3.51 (s, 2H), 3.70 (s, 2H), 3.95 (s, 2H), 6.60 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.84 (s, 1H), 6.94 (dd, J = 1.7, 8.1 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H).
13C NMR (CDCl3): δ 17.4, 39.6, 84.5, 114.8, 115.1, 122.6, 127.2, 129.9, 130.9, 131.3, 133.9, 138.8, 142.7, 144.7.
MS (EI): m/z 338 (M+).
Anal. Calcd for C14H15IN2: C, 49.72; H, 4.47; N, 8.28. Found: C, 49.62; H, 4.57, N, 8.12.
1H NMR (CDCl3): δ 0.88 (t, J = 7.3 Hz, 9H), 1.05-1.08 (m, 6H), 1.32 (sextet, J = 7.3 Hz, 6H), 1.49-1.55 (m, 6H), 2.12 (s, 3H), 3.48 (s, 2H), 3.50 (s, 2H), 3.74 (s, 2H), 6.591 (d, J = 8.3 Hz, 1H), 6.593 (d, J = 8.1 Hz, 1H), 6.83-6.87 (m, 2H), 6.91 (dd, J = 2.2, 8.1 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H).
MS (EI) m/z: 502 (M+).
Anal. Calcd for C26H42N2Sn: C, 62.29; H, 8.44; N, 5.59. Found: C, 62.13; H, 8.45, N, 5.56.
1H NMR (CDCl3): δ 0.87 (t, J = 7.3 Hz, 9H), 1.08-1.12 (m, 6H), 1.31 (sextet, J = 7.5 Hz, 6H), 1.46-1.53 (m, 6H), 2.26 (s, 3H), 3.91 (s, 2H), 4.20 (s, 2H), 4.23 (s, 2H), 7.03 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 7.15 (dd, J = 2.0, 8.1 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 8.07 (s, 1H), 8.17 (s, 1H).
MS (EI) m/z: 597 [(M-Bu)+].
Anal. Calcd for C30H44Cl2N2O2Sn: C, 55.07; H, 6.78; N, 4.28. Found: C, 55.17; H, 6.72, N, 4.32.
1H NMR (CDCl3): δ 0.87 (t, J = 7.3 Hz, 9H), 1.07-1.10 (m, 6H), 1.30 (sextet, J = 7.4 Hz, 6H), 1.46-1.52 (m, 6H), 1.83-1.86 (m, 8H), 2.21 (s, 3H), 2.70-2.72 (m, 8H), 3.28 (s, 2H), 3.31 (s, 2H), 3.87 (s, 2H), 6.98 (s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.13 (dd, J = 2.0, 8.3 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 8.86 (s, 1H), 9.21 (s, 1H).
MS (EI) m/z: 667 [(M-Bu)+].
Anal. Calcd for C38H60N4O2Sn・0.5(H2O): C, 62.30; H, 8.39; N, 7.65. Found: C, 62.51; H, 8.33, N, 7.68.
11Cで標識したアイソトープ標識化合物5’の合成では、以下の装置及び試薬を用いた。
標識用合成装置は、理化学研究所 分子イメージング科学研究センターに設置してある標準型標識用自動合成装置を用いた。化学薬品は市販のものをそのまま用いた。高速液体クロマトグラフィー用アセトニトリル(ナカライ社製)、脱水N,N-ジメチルホロムアミド(DMF)(関東化学社製)、脱水N-メチル-2-ピロリジノン(NMP)(関東化学社製)、トリス(ジベンジリデンアセトン)ジパラジウム(0)(Aldrich社製)、トリ-o-トリルホスフィン(Aldrich社製)、塩化銅(和光社製)、炭酸カリウム(和光社製)、重炭酸アンモニウム(東京化成社製)を使用した。
11C核の製造は住友重機械工業社製サイクロトロンCYPRIS HM-12Sを使用し、14N(p,α)11Cの核反応により製造した。[11C]ヨウ化メチルの合成は専用の標識用合成装置を用いて、11CO2ガスを出発物質として、11CO2→11CH3OH→11CH3Iの順に変換して調製した。
トリスジベンジリデンアセトンジパラジウム(1.6 mg, 1.7 μmol)および、トリ-o-トリルホスフィン(2.1 mg, 6.8μmol)のNMP溶液(0.3 mL)を標識用合成装置の反応容器(A)に準備し、室温に設置した。反応容器(A)中の溶液は、[11C]ヨウ化メチルを吹き込む10-20分前に設置した。また、スズ前駆体4’(2.3 mg, 3.2 μmol)、CuCl(1.7 mg, 17.5 μmol)、およびK2CO3(1.2 mg, 8.8 μmol)のNMP溶液(80 μL)を反応容器(B)に準備し、室温に設置した。続いて反応容器(A)に[11C]ヨウ化メチルを60-80 mL/minのガス流量で吹き込み、その後1分間静置した。得られた溶液を反応容器(B)に移送し、さらに反応容器(A)の内部を少量のNMP溶液(60 μL)を用いて洗浄して、この洗浄液も反応容器(B)に移送した。続いて、反応容器(B)中の混合溶液を80 ℃で5分間加熱した。得られた反応溶液を0.3 mLの洗浄液(アセトニトリル:水=4:1溶液)で希釈した後、綿栓あるいはフィルターを用いてろ過し、分取HPLCにて分取した。分取用カラムはPhenomenex 社製Gemini 5μ C18 110A 10mm×250mm、ガードカラムはPhenomenex 社製 Semiprep Guard Cartridge System (AJO-7220)およびSUMIKA社製スミパックスフイルター PG-ODSを使用した。流量は5ml/minで、移動層は100mM NH4HCO3(pH=7.8):CH3CN(5% H2O添加)=40:60を使用した。UV検出波長254 nmおよびγ線検出器で測定した結果、アイソトープ標識化合物5’の保持時間は約14.3分であった(図1)。分取したアイソトープ標識化合物5’を含むフラクションをエバポレーターを用いて減圧濃縮した。濃縮液は臨床用投与溶液(生理食塩水:4ml、propylene glycol:0.3 ml、Tween80:0.05 ml)を用いて希釈し、無菌バイアルに入れた。
本溶液の一部(20μL)を分析HPLCに供して、目的化合物の同定、純度検定、および比放射能の算出を行った。分析カラムはPhenomenex 社製Gemini 4.6mm×150mm を使用し、カラム温度30℃で分析を行った。流量は1ml/minで、移動層は100mM NH4HCO3(pH=7.8):CH3CN=40:60を使用した。UV検出波長254 nmおよびγ線検出器で測定した結果、アイソトープ標識化合物5’の保持時間は約8.0分であった。なお、アイソトープ標識化合物5’の同定はアイソトープ標識化合物5’の非標識体(5’(a))を用いて行った。アイソトープ標識化合物5’の総放射能は0.5−2.0GBq、[11C]ヨウ化メチルに基づく崩壊補正放射化学収率は20%であった。合成時間は43分、放射化学純度は95%以上で、化学的純度は82%−92%、比放射能は 98−110GBq/μmolであった。
1H NMR (CDCl3): δ 1.85 (quint, J = 3.3 Hz, 8H), 2.20 (s, 6H), 2.72 (br, 8H), 3.30 (s, 4H), 3.85 (s, 2H), 6.97 (s, 2H), 7.04 (dd, J = 1.7, 8.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 9.21 (s, 2H).
13C NMR (CDCl3): δ 17.5, 24.1, 40.8, 54.5, 59.5, 121.4, 127.3, 127.7, 130.8, 133.8, 137.3, 168.9.
MS (EI) m/z: 448 (M+).
Anal. Calcd for C27H36N4O2・0.25(H2O): C, 71.57; H, 8.12; N, 12.37. Found: C, 71.63; H, 7.85, N, 12.33.
50 mLナス型フラスコにm-トルイジン塩酸塩 (1.43 g, 10.0 mmol)、メタノール (10 mL) を、m-トルイジン(1.43 g, 10.0 mmol)、パラホルムアルデヒド (0.30 g, 10.0 mmol) を順に加え、加熱還流下で2日間撹拌した。室温に戻したのち、減圧濃縮した。得られた残渣に蒸留水(10 mL)を加え、1N水酸化ナトリウム水溶液を用いて中和した。ジクロロメタン(10 mL×4)で抽出し、有機層を蒸留水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別し、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (シリカゲル 250 g, 展開溶媒;ヘキサン/酢酸エチル = 1/1) で精製し、茶色結晶の(6)(518 mg, 22.9%) を得た。
TLC Rf 0.30 (ヘキサン/酢酸エチル = 1/1)
1H NMR (400 MHz, CDCl3): δ 2.17 (s, 6H, CH 3), 3.51 (br s, 4H, NH 2), 3.70 (s, 2H, CH 2), 6.45 (dd, J = 2.4, 8.3 Hz, 2H, Ar-H), 6.55 (d, J = 2.4 Hz, 2H, Ar-H), 6.68 (d, J = 8.3 Hz, 2H, Ar-H).
10 mL 二口ナス型フラスコにアルゴン雰囲気下で、化合物(6) (283 mg, 1.25 mmol) 、4-ジメチルアミノピリジン (15 mg, 0.13 mmol) を加え、脱水ジクロロメタン (7 mL) に溶解した。脱水ピリジン (243 mL, 3.01 mmol) を加え、得られた混合溶液を0 °Cに冷却し、臭化ブロモアセチル (239 mL, 2.76 mmol) を滴下し、10分間撹拌した後、室温に戻し5時間撹拌した。析出した固体を濾取し、ジクロロメタン (30 mL)およびジエチルエーテル (20 mL) で洗浄し、白色結晶の化合物(7) (453 mg, 77.3%) を得た。
1H NMR (400 MHz, CD3SOCD3,): δ 2.17 (s, 6H, CH 3), 3.80 (s, 2H, CH 2), 4.00 (s, 4H, CH 2), 6.77 (d, J = 8.3 Hz, 2H, Ar-H,), 7.28 (dd, J = 2.0, 8.3 Hz, 2H, Ar-H,), 7.42 (d, J = 2.0 Hz, 2H, Ar-H,), 10.27 (s, 2H, NH).
TLC Rf 0.35 (ジクロロメタン/メタノール = 10/1)
1H NMR (400 MHz, CDCl3,): δ 1.84-1.87 (m, 8H, CH 2), 2,25 (s, 6H, CH 3), 2.60-2.69 (m, 8H, CH 2), 3.27 (s, 4H, NH 2), 3.83 (s, 2H, CH 2), 6.84 (d, J = 8.2Hz, 2H, Ar-H), 7.28 (dd, J = 1.9, 8.2 Hz, 2H, Ar-H), 7.44 (d, J = 1.9 Hz, 2H, Ar-H), 9.00 (s, 2H, NH).
[培養細胞]
マウス視床下部神経細胞系列GT1は、マウスプリオンに感染し得る。化合物の抗プリオン作用を評価する目的で、我々はGTFK-1細胞系列を用いた(N. Nishida et al., J. Virol, 74, 320-325 (2000))。これらはGSS由来の(O. Milhavet et al., Proc. Natl. Acad. Sci. U. S. A., 97, 13937-13942 (2000))マウス適合プリオンFukuoka-1株である。
GT1-7細胞は、ペニシリンおよびストレプトマイシンを含むDMEM培地(Invitrogen社製)で培養した。3〜4日ごとに、細胞をトリプシン処理し、1:5に希釈して継代した。安定にFukuoka-1または22L株に感染したGT1-7細胞については、O.Milhavet et al., Proc. Natl. Acad. Sci. U.S.A. 97, 13937-13942 (2000)に記載されている。化合物のストック溶液は、10mMのDMSO中に調製し室温で保存した。使用前に、化合物を培地で希釈した。対照細胞を溶媒のみを含む(0.1%)培地で処理した。約2×105の細胞を6ウェルプレートの各ウェルに入れ、15時間後に化合物を添加して薬剤処理を開始した。72時間のインキュベーションの後に、細胞を回収した。
回収した細胞を、1×Triton/DOC溶解バッファー(0.5% TritonX-100, 0.5% deoxycholic acid, 150mM NaCl, 50mM Tris HCl[pH7.5])150μl中に溶解させた。タンパク質濃度をBCAプロテインアッセイキット(Pierce社製)で測定し、各細胞溶解液を2mg/mlに標準化した。感染型プリオンタンパク質の産生を分析するため、タンパク質1mgあたり20μgの濃度のプロテイナーゼKを用いて30分間37℃で消化した。消化を阻害剤AEBSF(3mM)で止めた後、サンプルについて15% ポリアクリルアミドゲルを用いてSDS-PAGEを行った。次いで、タンパク質をPVDF膜(Immobilon-P, ミリポア社製)に転写した。ウェスタンブロットによるタンパク質のバンド検出に、抗マウスPrP抗体M-20(SANTA CRUZ社製)を一次抗体として用いた。バンドのシグナルはSuper Signal(Pierce社製)で可視化し、曝露およびシグナルの定量は、膜をLAS-1000 UVmini(富士フイルム社製)でスキャンすることにより行った。
(PET撮影1)
PET撮影1では、健常ラット頭頚部のPET撮像を行った。以下に詳細を示す。
なお、撮像結果からの画像の再構成はASIPro(SIEMENS社製のソフトウェア)を用いて次のように行った。PETプローブの投与直後は当該PETプローブが拡散中である。よって、投与後5分程度の間に撮像した画像で見られるPETプローブの集積は、ソマトスタチン受容体と特異的結合したものよりも血中にある未結合のPETプローブの影響が強い。このため、PETプローブの投与後5分から90分までに得られたデータをMaximum a Posteriori Expectation Maximization法(MAP-EM法:参考文献/Qi J, Leahy R, Resolution and noise properties of MAP reconstruction for fully 3-D PET, IEEE Trans Med Imag vol 19, 493-506(2000))にて画像再構成を行った。再構成した画像を図2及び図3に示す。
PET撮影2では、健常ラットでのEx Vivo オートラジオグラフィー(Ex Vivo ARG)を行った。詳細を以下に示す。
PET撮影1から得られたtTACにより、組織に十分取り込ませるのに必要な時間が分かっていたため、投与後40分間PETプローブを取りこませることとした。その後、安楽死させ脱血灌流後に脳を取り出し、2mm厚のスライス切片を作って、イメージングプレート(BAS-SR2040、FUJIFILM社製)に20分間露光させた。イメージングプレートをイメージアナライザー(FLA-7000,FUJIFILM社製)にセットし、PETプローブの集積部位を検出した。
Claims (4)
- 下記一般式(a)(式中、R0は11CH3、CH2 18F及びCF2 18Fのいずれかであり、R1及びR2は同一又は異なって、水素原子又は炭化水素基を示す。)、又はその薬学上許容される塩、水和物、若しくは溶媒和物からなることを特徴とするアイソトープ標識化合物。
- 下記一般式(b)(式中、R 1 及びR 2 は同一又は異なって、水素原子又は炭化水素基を示す。)で示される請求項1記載のアイソトープ標識化合物。
- 下記有機スズ化合物(c)(式中、R 1 及びR 2 は同一又は異なって、水素原子又は炭化水素基を示し、Rはアルキル基を示す。)からなることを特徴とするアイソトープ標識化合物前駆体。
- 請求項1又は2に記載のアイソトープ標識化合物を含有することを特徴とするPET用分子プローブ。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009218247A JP5618042B2 (ja) | 2009-09-21 | 2009-09-21 | アイソトープ標識化合物及びアイソトープ標識化合物前駆体 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009218247A JP5618042B2 (ja) | 2009-09-21 | 2009-09-21 | アイソトープ標識化合物及びアイソトープ標識化合物前駆体 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2011063574A JP2011063574A (ja) | 2011-03-31 |
JP5618042B2 true JP5618042B2 (ja) | 2014-11-05 |
Family
ID=43950202
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009218247A Expired - Fee Related JP5618042B2 (ja) | 2009-09-21 | 2009-09-21 | アイソトープ標識化合物及びアイソトープ標識化合物前駆体 |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP5618042B2 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015119111A1 (ja) * | 2014-02-10 | 2015-08-13 | 国立大学法人岐阜大学 | 抗プリオン化合物のマレイン酸塩及びその製造方法、並びにその医薬組成物 |
US20240141875A1 (en) | 2023-04-10 | 2024-05-02 | Energy Vault, Inc. | Energy storage and delivery system and method |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2004035522A1 (ja) * | 2002-08-30 | 2006-02-16 | 株式会社 ビーエフ研究所 | プリオン蛋白蓄積性疾患の診断プローブおよび治療薬ならびにプリオン蛋白の染色剤 |
JP2005120002A (ja) * | 2003-10-15 | 2005-05-12 | Kazuo Kuwata | アミロイド前駆体特殊構造形成阻害剤 |
US8288604B2 (en) * | 2006-08-25 | 2012-10-16 | Gifu University | Method of rapid methylation, kit for preparing PET tracer and method of producing PET tracer |
JP2009013126A (ja) * | 2007-07-06 | 2009-01-22 | Gifu Univ | プリオンタンパク質構造変換抑制剤 |
WO2009072417A1 (ja) * | 2007-12-07 | 2009-06-11 | Nagasaki University | プリオン病診断用組成物 |
-
2009
- 2009-09-21 JP JP2009218247A patent/JP5618042B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JP2011063574A (ja) | 2011-03-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6524046B2 (ja) | Psma結合剤及びその使用 | |
Zhang et al. | F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Aβ aggregates in the brain | |
Rong et al. | Radiochemistry for positron emission tomography | |
JP2015061842A (ja) | 灌流造影を含む適用のための造影剤 | |
JP2009532328A (ja) | 5−ht1b受容体の放射性リガンド | |
JP6987840B2 (ja) | Ido1酵素イメージングのための放射性リガンド | |
WO2015060365A1 (ja) | タウイメージングプローブ | |
JP2013542254A (ja) | タウ病理のイメージングプローブとしての複素環式化合物 | |
Matsumura et al. | Synthesis and biological evaluation of novel styryl benzimidazole derivatives as probes for imaging of neurofibrillary tangles in Alzheimer’s disease | |
BRPI0808503A2 (pt) | Composto, e, uso de um composto | |
Hostetler et al. | [18F] Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey | |
JP2002525325A (ja) | 放射標識化ニューロキニン−1受容体拮抗薬 | |
AU2014337102B2 (en) | Imaging histone deacetylases with a radiotracer using positron emission tomography | |
Nguyen et al. | IBETA: A new aβ plaque positron emission tomography imaging agent for Alzheimer’s disease | |
BRPI0917147B1 (pt) | Composto ou sal deste, uso de um composto ou sal deste, e, processo para fabricar um composto | |
JP5618042B2 (ja) | アイソトープ標識化合物及びアイソトープ標識化合物前駆体 | |
JP2023184564A (ja) | 新規化合物 | |
EP2711026A1 (en) | Radioactive fluorine-labeled quinoxaline compound | |
CA2911307C (en) | Use of fluorinated derivatives of 4-aminopyridine in therapeutics and medical imaging | |
US20070092442A1 (en) | F-18-fluorinated phosphonium cation imaging agents and methods of synthesis | |
WO2023098622A1 (zh) | α-突触核蛋白聚集体的小分子结合配体、其制备方法及用途 | |
WO2023104148A1 (zh) | 结合α-突触核蛋白聚集体的小分子探针及其用途 | |
WO2023109745A1 (zh) | 用于α-突触核蛋白聚集体成像的小分子探针 | |
JP2021116238A (ja) | 新規化合物、およびその利用 | |
US20140348748A1 (en) | Beta-amyloid imaging agents, methods of manufacture, and methods of use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20120914 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20120914 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20120914 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20140123 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140128 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140328 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140624 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140714 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140812 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140902 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5618042 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |