JP5048655B2 - 新規アミロイド親和性化合物 - Google Patents
新規アミロイド親和性化合物 Download PDFInfo
- Publication number
- JP5048655B2 JP5048655B2 JP2008513252A JP2008513252A JP5048655B2 JP 5048655 B2 JP5048655 B2 JP 5048655B2 JP 2008513252 A JP2008513252 A JP 2008513252A JP 2008513252 A JP2008513252 A JP 2008513252A JP 5048655 B2 JP5048655 B2 JP 5048655B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- carbon
- hydroxyphenyl
- mmol
- solution
- 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 abstract description 95
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 61
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 41
- 230000002285 radioactive effect Effects 0.000 claims abstract description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 18
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000000032 diagnostic agent Substances 0.000 claims abstract description 11
- 229940039227 diagnostic agent Drugs 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical group 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 12
- -1 triphenylstannyl substituent Chemical group 0.000 claims description 11
- 231100000053 low toxicity Toxicity 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical group OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 231100000299 mutagenicity Toxicity 0.000 abstract description 7
- 230000007886 mutagenicity Effects 0.000 abstract description 7
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 125000005843 halogen group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 121
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
- 239000000243 solution Substances 0.000 description 98
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 72
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 68
- 238000006243 chemical reaction Methods 0.000 description 56
- 210000004556 brain Anatomy 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 230000015572 biosynthetic process Effects 0.000 description 39
- 239000000203 mixture Substances 0.000 description 39
- 238000003786 synthesis reaction Methods 0.000 description 38
- 239000002904 solvent Substances 0.000 description 37
- 239000002244 precipitate Substances 0.000 description 32
- LJYOFQHKEWTQRH-UHFFFAOYSA-N 2-bromo-1-(4-hydroxyphenyl)ethanone Chemical compound OC1=CC=C(C(=O)CBr)C=C1 LJYOFQHKEWTQRH-UHFFFAOYSA-N 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 238000010992 reflux Methods 0.000 description 24
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 22
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 22
- 239000000126 substance Substances 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- 239000011259 mixed solution Substances 0.000 description 20
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 18
- 239000003480 eluent Substances 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- 238000009825 accumulation Methods 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 14
- 239000003643 water by type Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 11
- 238000003384 imaging method Methods 0.000 description 11
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 10
- 230000035772 mutation Effects 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 239000002504 physiological saline solution Substances 0.000 description 10
- 239000012488 sample solution Substances 0.000 description 10
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- DJAPVDCXTHRTAM-UHFFFAOYSA-N 4-(6-bromoimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(Br)C=C2)C2=N1 DJAPVDCXTHRTAM-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 238000000211 autoradiogram Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- SZSBJKUORKLYBS-UHFFFAOYSA-N 4-(6-tributylstannylimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound C=1N2C=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=1C1=CC=C(O)C=C1 SZSBJKUORKLYBS-UHFFFAOYSA-N 0.000 description 8
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
- KPMVHELZNRNSMN-UHFFFAOYSA-N chembl1985849 Chemical compound N1=CC=C2NCCN21 KPMVHELZNRNSMN-UHFFFAOYSA-N 0.000 description 8
- 229940125773 compound 10 Drugs 0.000 description 8
- 238000003745 diagnosis Methods 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000011630 iodine Substances 0.000 description 8
- 229910052740 iodine Inorganic materials 0.000 description 8
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 8
- 238000002372 labelling Methods 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 238000010186 staining Methods 0.000 description 8
- 235000010323 ascorbic acid Nutrition 0.000 description 7
- 229960005070 ascorbic acid Drugs 0.000 description 7
- 239000011668 ascorbic acid Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- FVAUCKIRQBBSSJ-VVUPZWBASA-M sodium;iodine-123(1-) Chemical compound [Na+].[123I-] FVAUCKIRQBBSSJ-VVUPZWBASA-M 0.000 description 7
- 208000037259 Amyloid Plaque Diseases 0.000 description 6
- 241000700157 Rattus norvegicus Species 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 238000012856 packing Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 235000009518 sodium iodide Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- KXVNPTXWXIWCDV-UHFFFAOYSA-N 4-(6-bromoimidazo[1,2-a]pyrimidin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(Br)C=N2)C2=N1 KXVNPTXWXIWCDV-UHFFFAOYSA-N 0.000 description 5
- JGGPCIBRNWAFCI-UHFFFAOYSA-N 4-(6-tributylstannylimidazo[1,2-a]pyrazin-2-yl)phenol Chemical compound N1=C2C=NC([Sn](CCCC)(CCCC)CCCC)=CN2C=C1C1=CC=C(O)C=C1 JGGPCIBRNWAFCI-UHFFFAOYSA-N 0.000 description 5
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000000945 filler Substances 0.000 description 5
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 238000009206 nuclear medicine Methods 0.000 description 5
- 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 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 5
- LLEVBSPEOUODSV-UHFFFAOYSA-N 2-(4-hydroxyphenyl)imidazo[1,2-a]pyridin-6-ol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(O)C=C2)C2=N1 LLEVBSPEOUODSV-UHFFFAOYSA-N 0.000 description 4
- XSXUDIYFRDEABR-UHFFFAOYSA-N 4-(6-fluoroimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(F)C=C2)C2=N1 XSXUDIYFRDEABR-UHFFFAOYSA-N 0.000 description 4
- BZEKKGFLKRGAHN-UHFFFAOYSA-N 4-(6-iodoimidazo[1,2-a]pyrazin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(I)N=C2)C2=N1 BZEKKGFLKRGAHN-UHFFFAOYSA-N 0.000 description 4
- YBOCOHMLQZAQQZ-UHFFFAOYSA-N 4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(I)C=C2)C2=N1 YBOCOHMLQZAQQZ-UHFFFAOYSA-N 0.000 description 4
- GLKDFGAOWZETRP-UHFFFAOYSA-N 4-(6-iodoimidazo[1,2-a]pyrimidin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(I)C=N2)C2=N1 GLKDFGAOWZETRP-UHFFFAOYSA-N 0.000 description 4
- FKWHXDDWWVEVJB-UHFFFAOYSA-N 4-(6-nitroimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(C=C2)[N+]([O-])=O)C2=N1 FKWHXDDWWVEVJB-UHFFFAOYSA-N 0.000 description 4
- FOWQPXNDIGOLLB-UHFFFAOYSA-N 4-(6-tributylstannylimidazo[1,2-a]pyrimidin-2-yl)phenol Chemical compound C=1N2C=C([Sn](CCCC)(CCCC)CCCC)C=NC2=NC=1C1=CC=C(O)C=C1 FOWQPXNDIGOLLB-UHFFFAOYSA-N 0.000 description 4
- JWBYSUDXMOHHKN-UHFFFAOYSA-N 4-(8-tributylstannylimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound N1=C2C([Sn](CCCC)(CCCC)CCCC)=CC=CN2C=C1C1=CC=C(O)C=C1 JWBYSUDXMOHHKN-UHFFFAOYSA-N 0.000 description 4
- ZWIARAQZLULYPG-NSCUHMNNSA-N 4-[(e)-2-[4-(methylamino)phenyl]ethenyl]phenol Chemical compound C1=CC(NC)=CC=C1\C=C\C1=CC=C(O)C=C1 ZWIARAQZLULYPG-NSCUHMNNSA-N 0.000 description 4
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 4
- 108010090849 Amyloid beta-Peptides Proteins 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
- 206010002022 amyloidosis Diseases 0.000 description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 4
- 230000008499 blood brain barrier function Effects 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000010191 image analysis Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- IAVCEBMLYVGBLA-UHFFFAOYSA-N 2-[1-[6-[2-fluoroethyl(methyl)amino]naphthalen-2-yl]ethylidene]propanedinitrile Chemical compound C1=C(C(C)=C(C#N)C#N)C=CC2=CC(N(CCF)C)=CC=C21 IAVCEBMLYVGBLA-UHFFFAOYSA-N 0.000 description 3
- SDSBDQCXPSOHTP-UHFFFAOYSA-N 2-iodoimidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC(I)=CN21 SDSBDQCXPSOHTP-UHFFFAOYSA-N 0.000 description 3
- DMVUOKSPXGUFKC-UHFFFAOYSA-N 4-[6-(3-fluoropropoxy)imidazo[1,2-a]pyridin-2-yl]phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(OCCCF)C=C2)C2=N1 DMVUOKSPXGUFKC-UHFFFAOYSA-N 0.000 description 3
- UHRHPPKWXSNZLR-UHFFFAOYSA-N 5-bromopyrimidin-2-amine Chemical compound NC1=NC=C(Br)C=N1 UHRHPPKWXSNZLR-UHFFFAOYSA-N 0.000 description 3
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- ZMXDDKWLCZADIW-YYWVXINBSA-N DMF-d7 Substances [2H]C(=O)N(C([2H])([2H])[2H])C([2H])([2H])[2H] ZMXDDKWLCZADIW-YYWVXINBSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-AHCXROLUSA-N Iodine-123 Chemical compound [123I] ZCYVEMRRCGMTRW-AHCXROLUSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 3
- 235000010724 Wisteria floribunda Nutrition 0.000 description 3
- LWFOGUFUFSGJTC-UHFFFAOYSA-L [I-].[Na+].[I+].[I-] Chemical compound [I-].[Na+].[I+].[I-] LWFOGUFUFSGJTC-UHFFFAOYSA-L 0.000 description 3
- 210000004727 amygdala Anatomy 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 230000003920 cognitive function Effects 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 229960003279 thiopental Drugs 0.000 description 3
- LYAHJFZLDZDIOH-VURMDHGXSA-N (Z)-2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide Chemical compound C=1C=COC=1/C(C(=O)N)=C/C1=CC=C([N+]([O-])=O)O1 LYAHJFZLDZDIOH-VURMDHGXSA-N 0.000 description 2
- VNHWPVLQRKKKRY-UHFFFAOYSA-N 1-bromo-3-fluoropropane Chemical compound FCCCBr VNHWPVLQRKKKRY-UHFFFAOYSA-N 0.000 description 2
- ZKEAOLVGPKCNCT-UHFFFAOYSA-N 2-bromo-3-methoxy-6-nitropyridine Chemical compound COC1=CC=C([N+]([O-])=O)N=C1Br ZKEAOLVGPKCNCT-UHFFFAOYSA-N 0.000 description 2
- PDOWLYNSFYZIQX-UHFFFAOYSA-N 2-bromo-3-methoxypyridine Chemical compound COC1=CC=CN=C1Br PDOWLYNSFYZIQX-UHFFFAOYSA-N 0.000 description 2
- CITPFMBCYSGMIV-UHFFFAOYSA-N 4-(6-bromoimidazo[1,2-a]pyrazin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(Br)N=C2)C2=N1 CITPFMBCYSGMIV-UHFFFAOYSA-N 0.000 description 2
- RAQFZCMVVMGRPO-UHFFFAOYSA-N 4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=CC=C2Br)C2=N1 RAQFZCMVVMGRPO-UHFFFAOYSA-N 0.000 description 2
- YJTXQLYMECWULH-UHFFFAOYSA-N 5-fluoropyridin-2-amine Chemical compound NC1=CC=C(F)C=N1 YJTXQLYMECWULH-UHFFFAOYSA-N 0.000 description 2
- XJKJHILCYUUVSJ-UHFFFAOYSA-N 5-methoxypyridin-2-amine Chemical compound COC1=CC=C(N)N=C1 XJKJHILCYUUVSJ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 238000010953 Ames test Methods 0.000 description 2
- 231100000039 Ames test Toxicity 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 208000036632 Brain mass Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- YCSBALJAGZKWFF-UHFFFAOYSA-N anthracen-2-amine Chemical compound C1=CC=CC2=CC3=CC(N)=CC=C3C=C21 YCSBALJAGZKWFF-UHFFFAOYSA-N 0.000 description 2
- 210000000702 aorta abdominal Anatomy 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002059 diagnostic imaging Methods 0.000 description 2
- 238000002224 dissection Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 102000034240 fibrous proteins Human genes 0.000 description 2
- 108091005899 fibrous proteins Proteins 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- YCKRFDGAMUMZLT-BJUDXGSMSA-N fluorine-18 atom Chemical compound [18F] YCKRFDGAMUMZLT-BJUDXGSMSA-N 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000012636 positron electron tomography Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- FVAUCKIRQBBSSJ-FXMLPJBTSA-M sodium;iodine-125(1-) Chemical compound [Na+].[125I-] FVAUCKIRQBBSSJ-FXMLPJBTSA-M 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- HFHIRXFGKJJNIT-UHFFFAOYSA-N (4-acetylphenyl) benzoate Chemical compound C1=CC(C(=O)C)=CC=C1OC(=O)C1=CC=CC=C1 HFHIRXFGKJJNIT-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical class C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- ZQAQXZBSGZUUNL-BJUDXGSMSA-N 2-[4-(methylamino)phenyl]-1,3-benzothiazol-6-ol Chemical compound C1=CC(N[11CH3])=CC=C1C1=NC2=CC=C(O)C=C2S1 ZQAQXZBSGZUUNL-BJUDXGSMSA-N 0.000 description 1
- ZQAQXZBSGZUUNL-UHFFFAOYSA-N 2-[4-(methylamino)phenyl]-1,3-benzothiazol-6-ol Chemical compound C1=CC(NC)=CC=C1C1=NC2=CC=C(O)C=C2S1 ZQAQXZBSGZUUNL-UHFFFAOYSA-N 0.000 description 1
- YKHQFTANTNMYPP-UHFFFAOYSA-N 2-bromopyridin-3-ol Chemical compound OC1=CC=CN=C1Br YKHQFTANTNMYPP-UHFFFAOYSA-N 0.000 description 1
- FDRCIXUKBBBOPH-UHFFFAOYSA-N 2-ethenyl-1,3-benzoxazole Chemical class C1=CC=C2OC(C=C)=NC2=C1 FDRCIXUKBBBOPH-UHFFFAOYSA-N 0.000 description 1
- CCZWSTFVHJPCEM-UHFFFAOYSA-N 2-iodopyridine Chemical compound IC1=CC=CC=N1 CCZWSTFVHJPCEM-UHFFFAOYSA-N 0.000 description 1
- APWCDYSPTMTDOA-UHFFFAOYSA-N 3-[2-(4-hydroxyphenyl)imidazo[1,2-a]pyridin-6-yl]oxypropyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCCOC1=CN2C=C(C=3C=CC(O)=CC=3)N=C2C=C1 APWCDYSPTMTDOA-UHFFFAOYSA-N 0.000 description 1
- QPXUOSWLWHLJGH-UHFFFAOYSA-N 3-bromo-1,2,4-triazin-6-amine Chemical compound NC1=CN=C(Br)N=N1 QPXUOSWLWHLJGH-UHFFFAOYSA-N 0.000 description 1
- RBCARPJOEUEZLS-UHFFFAOYSA-N 3-bromopyridin-2-amine Chemical compound NC1=NC=CC=C1Br RBCARPJOEUEZLS-UHFFFAOYSA-N 0.000 description 1
- UZZOZUQVHHJNTR-UHFFFAOYSA-N 4-(1,3-benzothiazol-2-yl)-2-iodoaniline Chemical compound C1=C(I)C(N)=CC=C1C1=NC2=CC=CC=C2S1 UZZOZUQVHHJNTR-UHFFFAOYSA-N 0.000 description 1
- WKRCOZSCENDENK-UHFFFAOYSA-N 4-(1,3-benzothiazol-2-yl)aniline Chemical compound C1=CC(N)=CC=C1C1=NC2=CC=CC=C2S1 WKRCOZSCENDENK-UHFFFAOYSA-N 0.000 description 1
- FGQRNGPGBIJMET-UHFFFAOYSA-N 4-(6-iodo-1,3-benzothiazol-2-yl)-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1C1=NC2=CC=C(I)C=C2S1 FGQRNGPGBIJMET-UHFFFAOYSA-N 0.000 description 1
- ZDGRIJNRIGFCGI-UHFFFAOYSA-N 4-(6-iodo-1,3-benzoxazol-2-yl)-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1C1=NC2=CC=C(I)C=C2O1 ZDGRIJNRIGFCGI-UHFFFAOYSA-N 0.000 description 1
- HEFZAAWRNDUFSO-UHFFFAOYSA-N 4-(6-iodo-6-tributylstannyl-5H-imidazo[1,2-a]pyrimidin-2-yl)phenol Chemical compound N1=C2N=CC([Sn](CCCC)(CCCC)CCCC)(I)CN2C=C1C1=CC=C(O)C=C1 HEFZAAWRNDUFSO-UHFFFAOYSA-N 0.000 description 1
- RCVUDYJMEJWTNN-ONEGZZNKSA-N 4-[(e)-2-(4-iodophenyl)ethenyl]-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1\C=C\C1=CC=C(I)C=C1 RCVUDYJMEJWTNN-ONEGZZNKSA-N 0.000 description 1
- DMVUOKSPXGUFKC-SJPDSGJFSA-N 4-[6-(3-(18F)fluoranylpropoxy)imidazo[1,2-a]pyridin-2-yl]phenol Chemical compound [18F]CCCOC=1C=CC=2N(C=1)C=C(N=2)C1=CC=C(C=C1)O DMVUOKSPXGUFKC-SJPDSGJFSA-N 0.000 description 1
- XTZDIUGVJZDRGY-UHFFFAOYSA-N 4-imidazo[1,2-a]pyridin-2-ylphenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=CC=C2)C2=N1 XTZDIUGVJZDRGY-UHFFFAOYSA-N 0.000 description 1
- GSZMUPHKOPBPPS-UHFFFAOYSA-N 5-[2-[6-(2-fluoroethoxy)-1,3-benzoxazol-2-yl]ethenyl]-n,n-dimethyl-1,3-thiazol-2-amine Chemical compound S1C(N(C)C)=NC=C1C=CC1=NC2=CC=C(OCCF)C=C2O1 GSZMUPHKOPBPPS-UHFFFAOYSA-N 0.000 description 1
- KRRTXVSBTPCDOS-UHFFFAOYSA-N 5-bromopyrazin-2-amine Chemical compound NC1=CN=C(Br)C=N1 KRRTXVSBTPCDOS-UHFFFAOYSA-N 0.000 description 1
- MAXBVGJEFDMHNV-UHFFFAOYSA-N 5-chloropyridin-2-amine Chemical compound NC1=CC=C(Cl)C=N1 MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 description 1
- IVILGUFRMDBUEQ-UHFFFAOYSA-N 5-iodopyridin-2-amine Chemical compound NC1=CC=C(I)C=N1 IVILGUFRMDBUEQ-UHFFFAOYSA-N 0.000 description 1
- HAFKCGZQRIIADX-UHFFFAOYSA-N 5-iodopyrimidin-2-amine Chemical compound NC1=NC=C(I)C=N1 HAFKCGZQRIIADX-UHFFFAOYSA-N 0.000 description 1
- UGSBCCAHDVCHGI-UHFFFAOYSA-N 5-nitropyridin-2-amine Chemical compound NC1=CC=C([N+]([O-])=O)C=N1 UGSBCCAHDVCHGI-UHFFFAOYSA-N 0.000 description 1
- ZTWYBFHLUJUUDX-UHFFFAOYSA-N 6-aminopyridin-3-ol Chemical compound NC1=CC=C(O)C=N1 ZTWYBFHLUJUUDX-UHFFFAOYSA-N 0.000 description 1
- JECUQJPFGTUNCJ-UHFFFAOYSA-N 6-bromo-2-phenylimidazo[1,2-a]pyridine Chemical compound C=1N2C=C(Br)C=CC2=NC=1C1=CC=CC=C1 JECUQJPFGTUNCJ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 230000007082 Aβ accumulation Effects 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YYZLUDJZIZPGPJ-UHFFFAOYSA-N CCN(CC(C=C1)Br)C1N Chemical compound CCN(CC(C=C1)Br)C1N YYZLUDJZIZPGPJ-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 0 OCc1cccc(-c2c[n](****3)c3n2)c1 Chemical compound OCc1cccc(-c2c[n](****3)c3n2)c1 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- GKPQAXNEUSDRJJ-UHFFFAOYSA-N [4-(2-bromoacetyl)phenyl] benzoate Chemical compound C1=CC(C(=O)CBr)=CC=C1OC(=O)C1=CC=CC=C1 GKPQAXNEUSDRJJ-UHFFFAOYSA-N 0.000 description 1
- ZQFKHCJMZIZJBI-UHFFFAOYSA-N [4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl] benzoate Chemical compound C=1N2C=C(OC)C=CC2=NC=1C(C=C1)=CC=C1OC(=O)C1=CC=CC=C1 ZQFKHCJMZIZJBI-UHFFFAOYSA-N 0.000 description 1
- CUWCXPCLKLAPJW-UHFFFAOYSA-L [F-].[Na+].[I+].[F-] Chemical compound [F-].[Na+].[I+].[F-] CUWCXPCLKLAPJW-UHFFFAOYSA-L 0.000 description 1
- SEYCZVIQKZIEDQ-UHFFFAOYSA-O [NH3+]C(N=C1)=CCC1Br Chemical compound [NH3+]C(N=C1)=CCC1Br SEYCZVIQKZIEDQ-UHFFFAOYSA-O 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- KRHYYFGTRYWZRS-BJUDXGSMSA-M fluorine-18(1-) Chemical compound [18F-] KRHYYFGTRYWZRS-BJUDXGSMSA-M 0.000 description 1
- 238000005558 fluorometry Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 description 1
- INSWZAQOISIYDT-UHFFFAOYSA-N imidazo[1,2-a]pyrimidine Chemical compound C1=CC=NC2=NC=CN21 INSWZAQOISIYDT-UHFFFAOYSA-N 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000012332 laboratory investigation Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- OEOPVJYUCSQVMJ-UHFFFAOYSA-N n,n-dimethyl-4-(6-methyl-1,3-benzothiazol-2-yl)aniline Chemical compound C1=CC(N(C)C)=CC=C1C1=NC2=CC=C(C)C=C2S1 OEOPVJYUCSQVMJ-UHFFFAOYSA-N 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000006824 pyrimidine synthesis Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical class C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 150000001629 stilbenes Chemical class 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- XXSLZJZUSYNITM-UHFFFAOYSA-N tetrabutylammonium tribromide Chemical compound Br[Br-]Br.CCCC[N+](CCCC)(CCCC)CCCC XXSLZJZUSYNITM-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
-
- 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
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- 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
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
-
- 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
-
- 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
- C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Optics & Photonics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Carbon And Carbon Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
このような脳内アミロイド画像診断用プローブの多くは、アミロイドに対する親和性が高く、かつ脳移行性の高い疎水性の低分子化合物を、種々の放射性核種、例えば11C、18F及び123I等で標識した化合物である。具体例として、6−ヨード−2−[4’−(N,N−ジメチルアミノ)フェニル]ベンゾチアゾール(以下、TZDMという)や6−ヒドロキシ−2−[4’−(N−メチルアミノ)フェニル]ベンゾチアゾール(以下、6−OH−BTA−1という)を始めとする種々のチオフラビン誘導体(特許文献1、非特許文献3)、(E)−4−メチルアミノ−4’―ヒドロキシスチルベン(以下、SB−13という)や(E)−4−ジメチルアミノ−4’―ヨードスチルベン(以下、m−I−SBという)を初めとするスチルベン化合物(特許文献2、非特許文献4,非特許文献5)、6−ヨード−2−[4’−(N,N−ジメチルアミノ)フェニル]ベンゾオキサゾール(以下、IBOXという)、6−[2−(フルオロ)エトキシ]−2−[2−(2−ジメチルアミノチアゾール−5−イル)エテニル]ベンゾオキサゾールを初めとするベンゾオキサゾール誘導体(非特許文献6,非特許文献7)、2−(1−{6−[(2−フルオロエチル)(メチル)アミノ]−2−ナフチル}エチリデン)マロノニトリル(以下、FDDNPという)を初めとするDDNP誘導体(特許文献4、非特許文献8)及び6−ヨード−2−[4’−(N,N−ジメチルアミノ)フェニル]イミダゾ[1,2−a]ピリジン(以下、IMPYという)を初めとするイミダゾピリジン誘導体(特許文献3、非特許文献9)等を11Cや放射性ハロゲンで標識した化合物が報告されている。さらに、これらの画像診断用プローブの一部については、ヒトイメージング研究が実施され、AD患者において健常例とは明らかに異なる脳への放射能集積を示すことが報告されている(非特許文献10、非特許文献11)。
TZDM、IBOX及びm−I−SBのヨードを[125I]で標識した化合物は、正常マウスを用いた実験の結果、投与後2分点において、いずれも脳内への移行が認められている。しかしこれらの化合物は、正常組織からのクリアランスが十分ではなく、投与後の時間経過に伴い、徐々に脳内に集積する傾向を示している(特表2005−512945号公報、Zhi-Ping Zhuang et al.,Nuclear Medicine and Biology, 2001, 28, p.887-894、H. F. Kung et al.,J. Am. Chem. Soc., 2001, 123, p.12740-12741)。正常組織からのクリアランスが十分でないと、アミロイド集積部位において十分なコントラストが得られないといった問題がある。SB−13を[11C]で標識した化合物については、ラットを用いた実験より正常組織からのクリアランスを有することが示されているが、そのクリアランス速度は十分に速いとはいえない(Masahiro Ono et al., Nuclear Medicine and Biology, 2003, 30, p.565-571)。
FDDNPについても、復帰突然変異試験にて陽性を示すことが、報告されている。(国際公開第03/106439号パンフレット)
R1は放射性ハロゲン置換基、mは0〜4の整数、nは0又は1である。放射性ハロゲンとしては種々の元素を用いることができ、好ましくは18F、76Br、123I、124I、125I及び131Iからなる群より選択されるハロゲン、より好ましくは18F、123I及び125Iからなる群より選択されるハロゲンを用いることができる。なお、式(1)中、n=0の場合、m=0〜4であることが好ましく、n=1の場合、m=1〜4であることが好ましい。
mは0〜4の整数、nは0又は1であり、R2は、m=n=0のとき、非放射性ハロゲン置換基、ニトロ置換基、炭素数3〜12のトリアルキルスタニル置換基又はトリフェニルスタニル置換基、m≠0及び/又はn≠0のとき、非放射性ハロゲン置換基、メタンスルホン酸置換基、トリフルオロメタンスルホン酸置換基又は芳香族スルホン酸置換基である。非放射性ハロゲン置換基としては、放射性フッ素を用いた求核置換反応における標的となりうるハロゲン又は放射性ヨウ素との間の同位体交換反応の標的となりうるハロゲンを用いることができ、好ましくはヨウ素、臭素又は塩素を用いることができる。トリアルキルスタニル置換基としては種々の置換基を用いることができ、トリメチルスタニル置換基及びトリブチルスタニル置換基を好ましく用いることができる。なお、式(2)中、n=0の場合、m=0〜4であることが好ましく、n=1の場合、m=1〜4であることが好ましい。
上記式(1)においてA1、A2、A3及びA4のうちA1を窒素とした化合物、並びに、上記式(2)においてA5、A6、A7及びA8のうちA5を窒素とした化合物は、例えば、図1の工程2において2−アミノ−5−ブロモピリジンの代わりに2−アミノ−5−ブロモピリミジンを用いる以外上記の方法に準じて製造することができる。
上記式(1)においてA1、A2、A3及びA4のうちA2及びA4を窒素とした化合物、並びに、上記式(2)においてA5、A6、A7及びA8のうちA6及びA8を窒素とした化合物は、例えば、図1の工程2において2−アミノ−5−ブロモピリジンの代わりに6−アミノ−3−ブロモ−1,2,4−トリアジンを用いる以外上記の方法に準じて製造することができる。
酸化剤は、反応液中のヨウ素を酸化させることができるものであれば特に限定する必要はなく、好ましくは過酸化水素又は過酢酸を用いることができる。酸化剤の添加量は、反応溶液中のヨウ素を酸化させるのに十分な量であれば良い。
なお、下記実施例において、実験に供する各化合物の名称を、表1の様に定義した。
1H−NMR(溶媒:重クロロホルム、共鳴周波数:500MHz):δ8.01-7.94 ( m, 1H ), 7.71-7.67 ( m, 2H ), 7.70-7.67 ( m, 1H ), 7.64-7.60 ( m, 1H ), 7.20-7.11 ( m, 1H ), 6.89-6.85 ( m, 2H ), 1.62-1.46 ( m, 6H ), 1.34 ( sext, J = 7.3 Hz, 6H ), 1.18-1.03 ( m, 6H ), 0.90 ( t, J = 7.3 Hz, 9H )。
カラム:Phenomenex Luna C18(商品名、Phenomenex社製、サイズ:4.6×150mm)
移動相:0.1%トリフルオロ酢酸/アセトニトリル=20/80→0/100(17分、直線グラジエント)
流速:1.0 mL/分
検出器:紫外可視吸光光度計(検出波長:282nm)及び放射線検出器 (形式:STEFFI型、raytest社製)
TLCプレート:RP−18F254(製品名、メルク社製)
展開相:メタノール/水=20/1
検出器:バイオイメージングアナライザー,BAS−2500(形式:BAS−2500、富士写真フィルム株式会社製)
1H−NMR(溶媒:重ジメチルスルホキシド、共鳴周波数:500MHz):δ9.54 ( br. s, 1H ), 8.83-8.81 ( m, 1H ), 8.17 ( s, 1H ), 7.79-7.74 ( m, 2H ), 7.51 ( d, J = 9.6 Hz, 1H ), 7.30 ( dd, J = 9.6, 1.8 Hz, 1H ), 6.86-6.81 ( m, 2H )。
1H−NMR(溶媒:重ジメチルスルホキシド、共鳴周波数:500MHz):δ8.86-8.84 ( m, 1H ), 8.14 ( s, 1H ), 7.78-7.74 ( m, 2H ), 7.40-7.35 ( m, 2H ), 6.86-6.82 ( m, 2H )。
1H−NMR(溶媒:重ジメチルホルムアミド、共鳴周波数:500MHz):δ9.80 ( br. s, 1H ), 9.35 ( d, J = 2.3 Hz, 1H ), 8.60 ( d, J = 2.3 Hz, 1H ), 8.23 ( s, 1H ), 7.94-7.90 ( m, 2H ), 6.98-6.94 ( m, 2H )。
1H−NMR(溶媒:重ジメチルスルホキシド、共鳴周波数:270MHz):δ9.52 ( s, 1H ), 8.22 ( d, J = 2.2 Hz, 1H ), 8.08 ( s, 1H ), 7.75-7.65 ( m, 2H ), 7.44 ( d, J = 9.6 Hz, 1H ), 6.99 ( dd, J = 9.6, 2.2 Hz, 1H ), 6.85-6.75 ( m, 2H ), 4.62 ( dt, 2JHF = 47.0 Hz, J = 6.0 Hz, 2H ), 4.05 ( t, J = 6.0 Hz, 2H ), 2.13 ( dquint, 3JHF = 25.9 Hz, J = 6.0 Hz, 2H )。
1H−NMR(溶媒:重ジメチルスルホキシド、共鳴周波数:500MHz):δ9.56 ( br. s, 1H ), 9.21 ( d, J = 2.5 Hz, 1H ), 8.46 ( d, J = 2.5 Hz, 1H ), 8.09 ( s, 1H ), 7.79-7.75 ( m, 2H ), 6.83-6.79 ( m, 2H )。
1H−NMR(溶媒:重ジメチルスルホキシド、共鳴周波数:500MHz):δ9.45 ( br. s, 1H ), 8.65 ( ddd, 3JHF = 4.6 Hz, J = 2.5, 0.7 Hz, 1H ), 8.16-8.15 ( m, 1H ), 7.75-7.69 ( m, 2H ), 7.56-7.51 ( m, 1H ), 7.23 ( ddd, 3JHF = 8.4 Hz, J = 9.9, 2.5 Hz, 1H ), 6.82-6.76 ( m, 2H )。
1H−NMR(溶媒:重ジメチルスルホキシド、共鳴周波数:500MHz):δ9.74-9.72 ( m, 1H ), 9.59 ( br. s, 1H ), 8.39 ( s, 1H ), 7.87 ( dd, J = 9.9, 2.3 Hz, 1H ), 7.79-7.74 ( m, 2H ), 7.65-7.61 ( m, 1H ), 6.84-6.80 ( m, 2H )。
1H−NMR(溶媒:重クロロホルム、共鳴周波数:500MHz):δ8.41 ( s, 1H ), 8.23 ( s, 1H ), 7.80 ( d, J = 8.7 Hz, 2H ), 7.63 ( s, 1H ), 6.93 ( d, J = 8.7 Hz, 2H ), 1.57-1.51 ( m, 6H ), 1.37-1.23 ( m, 6H ), 1.16-1.12 ( m, 6H ), 0.88 ( d, J = 7.3 Hz, 9H )。
1H−NMR(溶媒:重クロロホルム、共鳴周波数:500MHz):δ9.21 ( s, 1H ), 7.95 ( s, 1H ), 7.79 ( d, J = 8.7 Hz, 2H ), 7.77 ( s, 1H ), 6.91 ( d, J = 8.7 Hz, 2H ), 1.70-1.55 ( m, 6H ), 1.38-1.31 ( m, 6H ), 1.18-1.15 ( m, 6H ), 0.89 ( d, J = 7.3 Hz, 9H )。
1H−NMR(溶媒:重ジメチルホルムアミド、共鳴周波数:500MHz):δ9.89 ( s, 1H ), 9.01 ( s, 1H ), 8.82, ( s, 1H ), 8.42 ( s, 1H ), 7.92 ( d, J = 8.7 Hz, 2H ), 6.93 ( d, J = 8.7 Hz, 2H )。
1H−NMR(溶媒:重クロロホルム、共鳴周波数:500MHz):δ8.01( d, J = 6.4 Hz, 1H ), 7.87 ( d, J = 8.7 Hz, 2H ), 7.70 ( s, 1H ), 7.17 ( d, J = 6.4 Hz, 1H ), 6.87 ( d, J = 8.7 Hz, 2H ), 6.68-6.66 ( m, 1H ), 1.69-1.56 ( m, 6H ), 1.38-1.30 ( m, 6H ), 1.28-1.16 ( m, 6H ), 0.88 ( t, J = 7.3 Hz, 9H )。
(実施例II-5)[123I]−2−(4’−ヒドロキシフェニル)−6−ヨードイミダゾ[1,2−a]ピリミジンの合成
TLCプレート:TLCプレート:Silica Gel 60 F254(製品名、メルク社製)
展開相:クロロホルム/メタノール/トリエチルアミン=100/1/2
検出器:Rita Star(製品名、raytest社製)
[123I]−2−(4’−ヒドロキシフェニル)−8−ヨードイミダゾ[1,2−a]ピリジンの合成
本発明化合物のアミロイド親和性を、以下のin vitro結合試験により評価した。
各時間点において、実施例I-16及び比較例I-7ともに2匹の動物を用いて実験を行った。
この結果より、化合物6は、脳内アミロイドに集積する性能を有し、脳内アミロイドの描出能を有することが示唆された。
なお、実験は、各時間点において、3匹の動物を用いて行った。
Claims (12)
- A1、A2、A3及びA4のうち、少なくとも3つが炭素である、請求項1記載の化合物又はその塩。
- A1、A2、A3及びA4が全て炭素である、請求項2記載の化合物又はその塩。
- R1が、18F、76Br、123I、124I、125I及び131Iからなる群より選択される、請求項1〜3のいずれか1項に記載の化合物又はその塩。
- A5、A6、A7及びA8のうち、少なくとも3つが炭素である、請求項5記載の化合物又はその塩。
- A5、A6、A7及びA8が全て炭素である、請求項6記載の化合物又はその塩。
- R2が、ヨウ素、シュウ素、トリメチルスタニル置換基、トリブチルスタニル置換基、トリフルオロメタンスルホン酸置換基及びトリフェニルスタニル置換基からなる群より選択されたものである、請求項5〜7のいずれか1項に記載の化合物又はその塩。
- A1、A2、A3及びA4のうち、少なくとも3つが炭素である、請求項9に記載の低毒性アルツハイマー病診断剤。
- A1、A2、A3及びA4が全て炭素である、請求項10に記載の低毒性アルツハイマー病診断剤。
- R1が、18F、76Br、123I、124I、125I又は131Iからなる群より選択される、請求項9〜11のいずれか1項に記載の低毒性アルツハイマー病診断剤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008513252A JP5048655B2 (ja) | 2006-04-28 | 2007-04-26 | 新規アミロイド親和性化合物 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006124811 | 2006-04-28 | ||
JP2006124811 | 2006-04-28 | ||
JP2008513252A JP5048655B2 (ja) | 2006-04-28 | 2007-04-26 | 新規アミロイド親和性化合物 |
PCT/JP2007/059048 WO2007125988A1 (ja) | 2006-04-28 | 2007-04-26 | 新規アミロイド親和性化合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2007125988A1 JPWO2007125988A1 (ja) | 2009-09-10 |
JP5048655B2 true JP5048655B2 (ja) | 2012-10-17 |
Family
ID=38655513
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008513252A Expired - Fee Related JP5048655B2 (ja) | 2006-04-28 | 2007-04-26 | 新規アミロイド親和性化合物 |
Country Status (16)
Country | Link |
---|---|
US (2) | US8022207B2 (ja) |
EP (1) | EP2022792B1 (ja) |
JP (1) | JP5048655B2 (ja) |
KR (1) | KR20080112343A (ja) |
CN (1) | CN101472923A (ja) |
AT (1) | ATE493410T1 (ja) |
AU (1) | AU2007244313B2 (ja) |
CA (1) | CA2657312A1 (ja) |
DE (1) | DE602007011601D1 (ja) |
ES (1) | ES2355079T3 (ja) |
IL (1) | IL194889A0 (ja) |
NO (1) | NO20084897L (ja) |
NZ (1) | NZ572741A (ja) |
RU (1) | RU2008147002A (ja) |
TW (1) | TW200803903A (ja) |
WO (1) | WO2007125988A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2009057575A1 (ja) * | 2007-10-30 | 2011-03-10 | 日本メジフィジックス株式会社 | 新規アミロイド親和性化合物の使用及び製造方法 |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE535527T1 (de) | 2006-05-19 | 2011-12-15 | Nihon Mediphysics Co Ltd | Verbindung mit affinität zu amyloid |
CN101535309A (zh) * | 2006-11-17 | 2009-09-16 | 日本医事物理股份有限公司 | 对淀粉状蛋白具有亲和性的新化合物 |
NZ577511A (en) | 2006-11-30 | 2012-04-27 | Nihon Mediphysics Co Ltd | 2-Phenyl-imidazo[1,2-a]pyridine derivatives substituted with a radioactive halogen substituent |
CN101903381A (zh) * | 2007-10-24 | 2010-12-01 | 日本医事物理股份有限公司 | 对淀粉样蛋白具有亲和性的新化合物 |
CN101903383A (zh) * | 2007-10-26 | 2010-12-01 | 日本医事物理股份有限公司 | 对淀粉样蛋白具有亲和性的新化合物 |
EP2218464A1 (en) * | 2009-02-11 | 2010-08-18 | Technische Universität München | Compounds for non-invasive measurement of aggregates of amyloid peptides |
US9926316B2 (en) * | 2016-03-03 | 2018-03-27 | The Cleveland Clinic Foundation | Antitumor derivatives for differentiation therapy |
CN108822105A (zh) * | 2018-08-14 | 2018-11-16 | 河南师范大学 | 一种由乙苯类化合物合成2-芳基咪唑并[1,2-a]吡啶类化合物的方法 |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4727145A (en) * | 1986-09-22 | 1988-02-23 | Ortho Pharmaceutical Corporation | 2- Or 3- aryl substituted imidazo [1,2-a]pyridines |
US4871745A (en) * | 1986-09-22 | 1989-10-03 | Ortho Pharmaceutical Corporation | 2- or 3-aryl substituted imidazo(1,2-A)pyridines and their use as antisecretory agents |
US4791117A (en) * | 1986-09-22 | 1988-12-13 | Ortho Pharmaceutical Corporation | 2- or 3-aryl substituted imidazo[1,2-a]pyridines and their use as calcium channel blockers |
US4833149A (en) * | 1986-09-22 | 1989-05-23 | Ortho Pharmaceutical Corporation | 2- or 3-aryl substituted imidazo[1,2-a]pyridines |
BR9611047A (pt) * | 1995-10-17 | 2000-03-08 | Searle & Co | Processo de deteção de ciclo oxigenase-2 |
US6812327B1 (en) * | 1996-10-25 | 2004-11-02 | Human Genome Sciences, Inc. | Neutrokine-alpha polypeptides |
CA2340394A1 (en) | 1998-08-20 | 2000-03-02 | Jorge R. Barrio | Methods for labeling .beta.-amyloid plaques and neurofibrillary tangles |
US20010051632A1 (en) * | 2000-03-31 | 2001-12-13 | Wenying Chai | Phenyl-substituted indolizines and tetrahydroindolizines |
US6514969B2 (en) * | 2000-08-16 | 2003-02-04 | Boehringer Ingelheim Pharma Kg | β-amyloid inhibitors, processes for preparing them, and their use in pharmaceutical compositions |
DE10040016A1 (de) | 2000-08-16 | 2002-02-28 | Boehringer Ingelheim Pharma | Neue beta-Amyloid Inhibitoren, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
RU2324686C2 (ru) * | 2000-08-24 | 2008-05-20 | Юнивесити Оф Питсбэг | ПРОИЗВОДНЫЕ ТИОФЛАВИНА, СВЯЗЫВАЮЩИЕ АМИЛОИД, СПОСОБ ОБНАРУЖЕНИЯ in vivo ОТЛОЖЕНИЙ АМИЛОИДА И СПОСОБ РАСПОЗНАВАНИЯ БОЛЕЗНИ АЛЬЦГЕЙМЕРА |
IL157359A0 (en) * | 2001-02-26 | 2004-02-19 | Bristol Myers Squibb Pharma Co | A radiopharmaceutical composition containing an ascorbic acid analog |
US6596731B2 (en) * | 2001-03-27 | 2003-07-22 | Hoffmann-La Roche Inc. | Substituted imidazo[1,2-A] pyridine derivatives |
JP4317955B2 (ja) | 2001-04-23 | 2009-08-19 | ザ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・ペンシルバニア | アミロイド斑凝集阻害剤および診断用造影剤 |
JP4436928B2 (ja) | 2001-08-27 | 2010-03-24 | ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア | スチルベン誘導体、およびアミロイド斑の結合および画像化のためのその使用 |
GB0205281D0 (en) * | 2002-03-06 | 2002-04-17 | Novartis Ag | Organic compounds |
EP1356827A1 (en) * | 2002-04-24 | 2003-10-29 | Mallinckrodt Inc. | Method for obtaining a 2-18F-fluor-2-deoxy-D-glucose (18F-FDG)-solution |
AU2003242233A1 (en) | 2002-06-12 | 2003-12-31 | Bf Research Institute, Inc. | Probe compound for image diagnosis of disease with amyloid accumulation, compound for staining age spots/diffuse age spots, and remedy for disease with amyloid accumulation |
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 |
GB0229695D0 (en) * | 2002-12-20 | 2003-01-29 | Amersham Plc | Solid-phase preparation of 18F-labelled amino acids |
EP1699799B1 (en) * | 2003-12-31 | 2007-05-16 | Schering-Plough Ltd. | Control of parasites in animals by the use of imidazo [1,2-b]pyridazine derivatives |
ATE535527T1 (de) * | 2006-05-19 | 2011-12-15 | Nihon Mediphysics Co Ltd | Verbindung mit affinität zu amyloid |
EP2042501B1 (en) * | 2006-06-21 | 2017-04-12 | Nihon Medi-Physics Co., Ltd. | Compound having affinity for amyloid |
CN101535309A (zh) * | 2006-11-17 | 2009-09-16 | 日本医事物理股份有限公司 | 对淀粉状蛋白具有亲和性的新化合物 |
NZ577511A (en) | 2006-11-30 | 2012-04-27 | Nihon Mediphysics Co Ltd | 2-Phenyl-imidazo[1,2-a]pyridine derivatives substituted with a radioactive halogen substituent |
CN101903381A (zh) * | 2007-10-24 | 2010-12-01 | 日本医事物理股份有限公司 | 对淀粉样蛋白具有亲和性的新化合物 |
CN101903383A (zh) * | 2007-10-26 | 2010-12-01 | 日本医事物理股份有限公司 | 对淀粉样蛋白具有亲和性的新化合物 |
CN101909659A (zh) * | 2007-10-30 | 2010-12-08 | 日本医事物理股份有限公司 | 对淀粉样蛋白具有亲和性的新化合物的应用及制备方法 |
-
2007
- 2007-04-24 TW TW096114488A patent/TW200803903A/zh unknown
- 2007-04-26 RU RU2008147002/04A patent/RU2008147002A/ru not_active Application Discontinuation
- 2007-04-26 EP EP07742483A patent/EP2022792B1/en not_active Not-in-force
- 2007-04-26 ES ES07742483T patent/ES2355079T3/es active Active
- 2007-04-26 JP JP2008513252A patent/JP5048655B2/ja not_active Expired - Fee Related
- 2007-04-26 CA CA002657312A patent/CA2657312A1/en not_active Abandoned
- 2007-04-26 CN CNA2007800231536A patent/CN101472923A/zh active Pending
- 2007-04-26 NZ NZ572741A patent/NZ572741A/en not_active IP Right Cessation
- 2007-04-26 WO PCT/JP2007/059048 patent/WO2007125988A1/ja active Application Filing
- 2007-04-26 DE DE602007011601T patent/DE602007011601D1/de active Active
- 2007-04-26 KR KR1020087026312A patent/KR20080112343A/ko not_active Application Discontinuation
- 2007-04-26 AT AT07742483T patent/ATE493410T1/de not_active IP Right Cessation
- 2007-04-26 AU AU2007244313A patent/AU2007244313B2/en not_active Ceased
- 2007-04-26 US US12/226,561 patent/US8022207B2/en not_active Expired - Fee Related
-
2008
- 2008-10-23 IL IL194889A patent/IL194889A0/en unknown
- 2008-11-20 NO NO20084897A patent/NO20084897L/no not_active Application Discontinuation
-
2011
- 2011-04-28 US US13/096,159 patent/US20110201808A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2009057575A1 (ja) * | 2007-10-30 | 2011-03-10 | 日本メジフィジックス株式会社 | 新規アミロイド親和性化合物の使用及び製造方法 |
Also Published As
Publication number | Publication date |
---|---|
EP2022792B1 (en) | 2010-12-29 |
EP2022792A1 (en) | 2009-02-11 |
US20100249407A1 (en) | 2010-09-30 |
NZ572741A (en) | 2010-07-30 |
NO20084897L (no) | 2009-01-15 |
DE602007011601D1 (de) | 2011-02-10 |
WO2007125988A1 (ja) | 2007-11-08 |
AU2007244313A1 (en) | 2007-11-08 |
US8022207B2 (en) | 2011-09-20 |
ES2355079T3 (es) | 2011-03-22 |
AU2007244313B2 (en) | 2011-09-08 |
RU2008147002A (ru) | 2010-06-10 |
IL194889A0 (en) | 2011-08-01 |
EP2022792A8 (en) | 2009-04-29 |
KR20080112343A (ko) | 2008-12-24 |
JPWO2007125988A1 (ja) | 2009-09-10 |
TW200803903A (en) | 2008-01-16 |
CA2657312A1 (en) | 2007-11-08 |
ATE493410T1 (de) | 2011-01-15 |
US20110201808A1 (en) | 2011-08-18 |
CN101472923A (zh) | 2009-07-01 |
EP2022792A4 (en) | 2009-11-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5238496B2 (ja) | 新規アミロイド親和性化合物 | |
JP5313158B2 (ja) | 新規アミロイド親和性化合物 | |
JP5048655B2 (ja) | 新規アミロイド親和性化合物 | |
JP5180838B2 (ja) | 新規アミロイド親和性化合物 | |
WO2007148755A1 (ja) | 新規アミロイド親和性化合物 | |
JPWO2009054496A1 (ja) | 新規アミロイド親和性化合物 | |
JPWO2009057578A1 (ja) | 新規アミロイド親和性化合物の使用及び製造方法 | |
US20100267952A1 (en) | Use of novel compound having affinity for amyloid, and process for production of the same | |
JPWO2008059714A1 (ja) | 新規アミロイド親和性化合物 | |
JPWO2009057575A1 (ja) | 新規アミロイド親和性化合物の使用及び製造方法 | |
JP5247442B2 (ja) | 新規アミロイド親和性化合物 | |
JP2009120590A (ja) | 新規アミロイド親和性化合物 | |
JP2009120591A (ja) | 新規アミロイド親和性化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20100315 |
|
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: 20120703 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20120719 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20150727 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
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 |