CN106631908B - 一种放射性碘标记方法 - Google Patents
一种放射性碘标记方法 Download PDFInfo
- Publication number
- CN106631908B CN106631908B CN201610820535.2A CN201610820535A CN106631908B CN 106631908 B CN106631908 B CN 106631908B CN 201610820535 A CN201610820535 A CN 201610820535A CN 106631908 B CN106631908 B CN 106631908B
- Authority
- CN
- China
- Prior art keywords
- compound
- added
- radioiodination
- reaction
- copper
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 claims abstract description 16
- PDWUPXJEEYOOTR-UHFFFAOYSA-N 2-[(3-iodophenyl)methyl]guanidine Chemical compound NC(=N)NCC1=CC=CC(I)=C1 PDWUPXJEEYOOTR-UHFFFAOYSA-N 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 68
- 239000010949 copper Substances 0.000 claims description 36
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 24
- 229910052802 copper Inorganic materials 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 11
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical group [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- 229940126214 compound 3 Drugs 0.000 claims description 9
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 7
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 3
- 229940126543 compound 14 Drugs 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 2
- 241000338742 Erebia meta Species 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- 229910001431 copper ion Inorganic materials 0.000 claims 1
- 229940112669 cuprous oxide Drugs 0.000 claims 1
- 239000002243 precursor Substances 0.000 abstract description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract description 10
- 238000002372 labelling Methods 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052740 iodine Inorganic materials 0.000 abstract description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 7
- 239000011630 iodine Substances 0.000 abstract description 6
- 239000005711 Benzoic acid Substances 0.000 abstract description 5
- 235000010233 benzoic acid Nutrition 0.000 abstract description 5
- 230000002285 radioactive effect Effects 0.000 abstract description 5
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 21
- 239000011734 sodium Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- HXITXNWTGFUOAU-UHFFFAOYSA-N dihydroxy-phenylborane Natural products OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 11
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(II) bromide Substances [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 230000009514 concussion Effects 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000002603 single-photon emission computed tomography Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- -1 radioiodine ion Chemical class 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 4
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 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 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- GHICCUXQJBDNRN-UHFFFAOYSA-N 4-iodobenzoic acid Chemical compound OC(=O)C1=CC=C(I)C=C1 GHICCUXQJBDNRN-UHFFFAOYSA-N 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical class C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003205 fragrance Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 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 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- 0 *1[N+]C2=C1C=N2 Chemical compound *1[N+]C2=C1C=N2 0.000 description 2
- 101000712600 Homo sapiens Thyroid hormone receptor beta Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 240000002853 Nelumbo nucifera Species 0.000 description 2
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 2
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 102100033451 Thyroid hormone receptor beta Human genes 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 230000000149 penetrating effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229910052701 rubidium Inorganic materials 0.000 description 2
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 208000019360 selective pituitary resistance to thyroid hormone Diseases 0.000 description 2
- 208000003126 selective pituitary thyroid hormone resistance Diseases 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- SIAVMDKGVRXFAX-UHFFFAOYSA-N 4-carboxyphenylboronic acid Chemical class OB(O)C1=CC=C(C(O)=O)C=C1 SIAVMDKGVRXFAX-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- CMVDGKXNMYEUOS-UHFFFAOYSA-N C=CCCS(CC(CC1)=CC=C1Br)(=O)=O Chemical compound C=CCCS(CC(CC1)=CC=C1Br)(=O)=O CMVDGKXNMYEUOS-UHFFFAOYSA-N 0.000 description 1
- VHKBUIRREASHIN-HIFPTAJRSA-N CCCNCCC[C@H](C)C1(C)[F](C)C1C Chemical compound CCCNCCC[C@H](C)C1(C)[F](C)C1C VHKBUIRREASHIN-HIFPTAJRSA-N 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- FECNWVGSNARTFE-UHFFFAOYSA-M [Cl+].[O-]I(=O)=O Chemical compound [Cl+].[O-]I(=O)=O FECNWVGSNARTFE-UHFFFAOYSA-M 0.000 description 1
- YBHSBVINPFFYRF-UHFFFAOYSA-N [I].C(C1=CC=CC=C1)NC(=N)N Chemical compound [I].C(C1=CC=CC=C1)NC(=N)N YBHSBVINPFFYRF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005619 boric acid group Chemical group 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[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 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 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
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- XOXYHGOIRWABTC-UHFFFAOYSA-N gentisin Chemical compound C1=C(O)C=C2C(=O)C3=C(O)C=C(OC)C=C3OC2=C1 XOXYHGOIRWABTC-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- PDWUPXJEEYOOTR-JRGAVVOBSA-N iobenguane (131I) Chemical compound NC(N)=NCC1=CC=CC([131I])=C1 PDWUPXJEEYOOTR-JRGAVVOBSA-N 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000003608 radiolysis reaction Methods 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/008—Peptides; Proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/13—Labelling of peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明公开了一种放射性碘标记方法,在反应溶剂中,于铜配位化合物存在下,使Ar‑B(OH)2与NanI反应获得Ar‑nI,实现放射性碘的标记。该方法特别适合于合成放射性碘标记的间碘苄胍及苯甲酸活化酯。本发明所涉及的标记方法具有标记条件温和,操作简单,标记前体价廉易得,对官能团有很好的容忍性及普适性,标记率、放射化学纯度及比活度均较高等优点。
Description
技术领域
本发明属于放射性元素标记技术领域,具体涉及一种放射性碘标记方法。
背景技术
放射性碘元素标记的药物可用于疾病治疗、体内无创诊断及治疗效果监测等,在临床及生命科学研究中有着重要的作用,因此,对化学小分子,多肽,单抗及蛋白进行放射性碘标记也显得尤为重要。
CN102712603A公开了一种放射性碘标记生物学靶向部分的方法,所述方法包括:(i)提供式(Ia)或(Ib)化合物;(ii)在点击环加成催化剂存在下将所述式(Ia)或(Ib)化合物与式(II)化合物反应,通过点击环加成分别得到式(IIIa)或(IIIb)缀合物,其中:I*为碘放射性同位素;L1为可存在或不存在的接头基团;BTM为所述生物学靶向部分。
CN101563305A公开了放射性标记的化合物的方法,涉及这类方法中可用的前体并涉及可由这类方法获得的放射性标记的化合物,涉及在尤其用于用放射性标记激动剂使神经受体成像的正电子发射断层成像术(PET)和单光子发射计算机断层成像术(SPECT)中可用的方法、前体和放射性标记的化合物。
CN101985045A公开了一种131I标记SAP的应用,该应用为131I标记SAP在制备诊断淀粉样变的试剂中的应用,采用131I标记的SAP进行完整的动物体内试验及临床前试验研究,建立了淀粉样变的小鼠模型,经病理证实后进行131I标记SAP显像,结果显示小鼠腹部有浓聚。
CN101985483A公开了一种放射性碘标PRTH、其制备方法及其应用,涉及一种肿瘤/癌症诊断、治疗试剂,其将纳米技术与分子核医学相结合,对PRTH进行碘化标记,利用其EPR效应,用于肿瘤/癌症的早期诊断与治疗。
WO2007/007021A1公开了一种稳定化放射性药物组合物,所述组合物包含:(i)用123I标记的合成化合物,当体内给药时,该化合物靶向哺乳动物体内的部位;(ii)包含龙胆酸或其盐的稳定剂,该龙胆酸或其盐具有将所述123I标记的合成化合物稳定防止辐解有效量的生物相容性阳离子;(iii)含水的生物相容性载体介质;其中在所述介质中,123I的放射性浓度为8-1000MBq/cm3,且所述生物相容性载体介质的pH为4.5-8.5;条件是当靶向哺乳动物体内部位的所述合成化合物为间碘苄基胍时,所述生物相容性载体介质的pH为5.0-8.5。
由上述现有技术可以看出,目前常用的放射性碘标记方法主要是利用氧化剂将放射性碘离子氧化为碘单质或碘化氯之后与活化的苯环或者烯烃发生亲电取代反应进行标记,例如脱三丁基锡法及脱硼法。该类亲电取代标记法虽然有着广泛应用,但依然存在着一些较为严重的问题,首先,氯胺T是该类方法最常用的一种氧化剂,其强氧化性会使标记底物发生副反应,降低其活性,再次,该类标记方法标记过程中产生的碘单质极易挥发,为避免对操作人员及环境造成损害,对标记设施有着较高要求,增加了标记成本,除此之外,标记前体较难获得,例如三丁基锡活化的前体需要钯催化加热条件下反应三天,且产率也比较低,及放射化学产率较低,例如脱硼法,都是该类标记方法的不足之处。卤素交换法是另外一种较为常用的放射性碘标记方法,将放射性碘离子与苯环上的溴或碘原子直接发生卤素交换来进行标记,由于该反应为亲核取代反应,需要较高能量,因此,标记温度较高,一般接近200℃,再者,由于标记产物与标记前体的极性一样或较为接近,很难进行分离,因此导致所得药物比活度比较低。
综上所述,现有的放射性碘标记方法均存在着各种缺陷,这使得本领域亟需一种标记条件温和,高效,标记率及比活度高的新型放射性碘标记方法。
发明内容
本发明的目的在于克服现有技术的不足之处,提供了一种放射性碘标记方法,标记条件温和,操作简单且高效,特别适合用于间碘苄胍(MIBG)及苯甲酸活化酯(SIB)的放射性碘标记。
本发明解决其技术问题所采用的技术方案是:
一种放射性碘标记方法,包括:在反应溶剂中,于铜配位化合物存在下,使Ar-B(OH)2与NanI反应获得Ar-nI,实现放射性碘的标记。
所述铜配位化合物可来源于提供一价或二价铜离子的铜源化合物CuX以及铜的配体化合物,铜源化合物CuX和铜的配体化合物在反应体系中可形成所述铜配位化合物。
本发明的放射性碘标记方法可以用下面反应式表示,即,在铜介导下,放射性碘离子与待标记底物芳香族苯硼酸类化合物Ar-B(OH)2发生氧化偶联反应来进行放射性碘的标记,其反应式如下:
其中,Ar代表芳香基,例如为苯基,萘基及杂环芳香基如吡啶、呋喃、噻吩等。而且,Ar可以是取代或未被取代的芳香基,可以带一个或多个取代基,这些取代基相对于硼酸官能团-B(OH)2可以是邻位、间位或对位的位置,常见的取代基有烃基(优选烷基)、羟基、羧基、酯基、酰胺基和卤素等。与现有技术的方法相比,该方法对不同官能团具有很好的普适性。
其中,B为硼,-B(OH)2为硼酸官能团。
其中,n为放射性碘的质量数,nI选自123I、124I、125I、131I中的一种或至少两种的组合。NanI可以为NanI的水溶液或无水NanI。
其中,铜源化合物CuX为催化剂,可以是一价或者二价的铜盐或氧化物,例如氧化亚铜Cu2O,氯化亚铜CuCl,溴化亚铜CuBr,碘化亚铜CuI,氯化铜CuCl2,溴化铜CuBr2中的一种或至少两种的组合;该催化剂铜源化合物可用商品化试剂,无需特殊处理,其催化用量优选为待标记底物的5%及以上摩尔当量。当反应时间为1h时,一价铜源(Cu2O,CuCl,CuBr,CuI等)的催化效率优于二价铜源(CuCl2,CuBr2等)。因此,优选地,当反应时间为1h时,铜源选择Cu2O,CuCl,CuBr,CuI等或其任意组合。
其中,铜的配体化合物选自1,10-菲啰啉,二联吡啶,四甲基乙二胺,N,N’-二甲基乙二胺中的一种或至少两种的组合,优选1,10-菲啰啉。上述配体化合物用商品化试剂即可,无需特殊处理。
铜的配体化合物可适当过量于铜源化合物CuX,优选为所用铜源化合物CuX的两倍当量。
优选地,所述铜配位化合物可来源于铜源化合物CuX和铜的配体化合物的下述组合中的一种:Cu2O/1,10-菲啰啉,CuCl/1,10-菲啰啉,CuBr/1,10-菲啰啉,CuI/1,10-菲啰啉;特别优选为Cu2O/1,10-菲啰啉。
所述反应溶剂选自乙腈,甲醇,二氯甲烷,四氢呋喃,N,N’-二甲基甲酰胺,和水中的一种或至少两种的组合,优选为乙腈。上述反应溶剂采用商品化试剂即可,无需特殊处理。
本发明方法的反应时间及反应温度可以根据不同的标记底物略有不同,反应的结束以放射性碘离子检测消失为准。优选地,所用温度为25~80℃或直接在室温下反应,反应时间一般为0.5~4h,可以用震荡的方式促进反应进行;反应过程可加热,加热方式可用震荡模块或其它加热方式。
典型地,当芳香基Ar为苯基,所用催化体系为Cu2O/1,10-菲啰啉,溶剂为乙腈,所用放射性碘元素为131I时,本发明方法的反应式如下所示:
典型地,所述Ar-B(OH)2为下式所示的化合物3;
化合物3
化合物3可通过以下方法制得:将化合物1与化合物2以1~10:1~10的比例溶于甲醇中后加入三乙胺,在室温下进行反应,反应结束后经分离(优选过柱分离)即得到化合物3;
化合物1
化合物2
对化合物3进行放射性碘标记方法包括:将含有Cu2O和1,10-菲啰啉的乙腈溶液加入至含有化合物3的反应容器中,混合均匀,然后加入NanI反应,反应结束后加入三氟乙酸脱保护,得标记产物即下式所示化合物4,即放射性碘标记的间碘苄胍;
化合物4
上述间碘苄胍的放射性碘标记反应路线如下式所示(以Na131I为例):
典型地,所述Ar-B(OH)2为下式所示的化合物6;
化合物6
化合物6可通过以下方法制得:将化合物5与N,N’-二环己基碳二亚胺(DCC)及N-羟基琥珀酰亚胺(NHS)以1~10:1~10:1~10的比例溶于无水四氢呋喃中,室温反应过夜,分离(优选过柱分离)即得到化合物6;
化合物5
对化合物6进行放射性碘标记方法包括:将含有Cu2O和1,10-菲啰啉的乙腈溶液加入至含有化合物6的反应容器中,混合均匀,然后加入NanI反应,反应结束后加入三氟乙酸脱保护,得标记产物即下式所示化合物7,为放射性碘标记的苯甲酸活化酯类物质(nI-SIB);
化合物7
上述苯甲酸活化酯的放射性碘标记反应路线如下式所示(以Na131I为例):
典型地,所述Ar-B(OH)2为下式所示的化合物13;
化合物13
化合物13可通过以下方法制得:将化合物8加入到含有亚硫酸钠及碳酸氢钠的水溶液中,反应结束后用乙酸乙酯进行萃取,之后旋蒸除去溶剂,将所得产物与4-溴-1-丁烯于N,N’-二甲基甲酰胺中反应,50℃反应过夜后经乙酸乙酯及饱和食盐水萃取后过柱分离得化合物9;将化合物9与碳酸氢钠以1~10:1~10的比例溶于水和乙腈的混合溶液中,之后缓慢加入过硫酸氢钾,反应结束后旋蒸除去溶剂,过柱分离得化合物10;将正丁基锂的己烷溶液滴加至化合物10的四氢呋喃溶液中,反应结束后用饱和氯化铵溶液终止反应,取有机层旋蒸除去溶剂,过柱分离,将所得化合物溶于二氯甲烷中,之后加入三乙胺及甲磺酰氯,反应结束后过柱分离得化合物11;将正丁基锂的己烷溶液滴加入化合物11的四氢呋喃溶液中,反应结束后加入氯化铵的饱和溶液终止反应,取有机层旋蒸除去溶剂后过柱分离得化合物12;将正丁基锂的己烷溶液滴加入化合物12的四氢呋喃溶液中,之后滴加入硼酸三异丙酯,反应结束后加入氯化铵的饱和溶液终止反应,取有机层,旋蒸除去溶剂后过柱分离即得化合物13。
化合物8
化合物9
化合物10
化合物11
化合物12
对化合物13进行放射性碘标记方法包括:将含有Cu2O和1,10-菲啰啉的乙腈溶液加入至含有化合物13的反应容器中,混合均匀,然后加入NanI反应,反应结束后加入三氟乙酸脱保护,得标记产物即下式所示化合物14;
化合物14
此外,本发明还提供了一种放射性碘标记的化合物,即下式所示的化合物15,其由多肽cRGDyK与上述化合物7nI-SIB反应制得:
化合物15。
本技术方案与背景技术相比,它具有如下优点:
(1)本发明的方法标记条件温和,不需要强氧化剂产生碘单质,对操作人员及环境的危害小,同时也避免降低标记底物活性,例如,与使用强氧化剂的放射性碘标记方法,本发明方法的标记底物活性降低可以被最大程度地得到减轻或避免;
(2)本发明方法所用的标记前体苯硼酸类化合物稳定,无毒,可以价廉易得,也可以简单地合成;
(3)本发明方法标记率高,标记率可以达到99%以上;
(4)用本发明方法标记所得产物与标记前体的极性有较大差别,可进行分离,提高标记产物的比活度;
(5)本发明方法所用催化剂铜源及配体较稳定,易保存,方便进行药盒化标记。
附图说明
下面结合附图和实施例对本发明作进一步说明。
图1为实施例1~5制备的131I标记苯硼酸的代表性HPLC分析图。
图2为实施例6制备的化合物131I-MIBG及其标准品127I-MIBG的HPLC分析图。
图3为实施例7制备的化合物131I-SIB及其标准品的HPLC分析图。
图4为实施例8制备的化合物125I-c(RGDyK)及其标准品的HPLC分析图。
图5为实施例8制备的化合物125I-c(RGDyK)在荷神经胶质瘤U87MG小鼠的SPECT显像图。
具体实施方式
下面通过实施例具体说明本发明的内容:
实施例1
不同铜源作为催化剂对苯硼酸进行放射性碘元素131I的标记:
将苯硼酸(2μmol)加入至1.5mL离心管中,之后加入含有CuX(0.1μmol)及1,10-菲啰啉(0.2μmol)的乙腈(或N,N’-二甲基甲酰胺)溶液(50μL),使其充分混合后,加入Na131I的水溶液(18.5-20MBq,5μL),室温条件下震荡反应,标记产物结构如下所示:
标记结果如下表所示:
Entry | Catalyst | Solvent | Time[h] | RCY[%][a] |
1 | Cu2O | CH3CN | 1 | >98 |
2 | CuI | CH3CN | 1 | >98 |
3 | CuCl | CH3CN | 1 | >98 |
4 | CuCl2 | CH3CN | 1 | 12.1 |
5 | CuBr2 | CH3CN | 1 | 4.8 |
6 | CuCl2 | CH3CN | 20 | >98 |
7 | CuBr2 | CH3CN | 20 | >98 |
8 | CuBr2 | DMF | 1 | <1 |
9 | CuBr2 | DMF | 20 | 57.4 |
[a]通过装备有放射性检测探头的高效液相色谱仪进行放射化学产率的检测。
实施例2
不同配体条件下对苯硼酸进行放射性碘元素131I的标记:
将苯硼酸(2μmol)加入至1.5mL离心管中,之后加入含有Cu2O(0.1μmol)及不同配体(0.2μmol)的乙腈溶液(50μL),使其充分混合后,加入Na131I的水溶液(18.5-20MBq,5μL),室温条件下震荡反应1h,标记结果如下表所示:
Entry | Ligand | RCY[%][a] |
1 | L1 | >98 |
2 | L2 | 37 |
3 | L3 | 26 |
4 | L4 | 5 |
5 | L5 | 4 |
[a]通过装备有放射性检测探头的高效液相色谱仪进行放射化学产率的检测。
实施例3
不同溶剂条件下对苯硼酸进行放射性碘元素131I的标记:
将苯硼酸(2μmol)加入至1.5mL离心管中,之后加入含有Cu2O(0.1μmol)及1,10-菲啰啉(0.2μmol)的溶液(50μL),使其充分混合后,加入Na131I的水溶液(18.5-20MBq,5μL),室温条件下震荡反应1h,标记结果如下表所示:
Entry | Solvent | RCY[%][a] |
1 | CH3CN | >98 |
2 | CH3OH | >98 |
3 | CH2Cl2 | 97 |
4 | THF | 98 |
5 | DMF | <1 |
6 | DMSO | <1 |
[a]通过装备有放射性检测探头的高效液相色谱仪进行放射化学产率的检测。
实施例4
不同催化剂浓度条件下对苯硼酸进行放射性碘元素131I的标记:
将苯硼酸(2μmol)加入至1.5mL离心管中,之后加入含有不同浓度的Cu2O及1,10-菲啰啉的乙腈溶液(50μL),使其充分混合后,加入Na131I的水溶液(18.5-20MBq,5μL),室温条件下震荡反应1h,标记结果如下表所示:
Entry | Cu2O concentration[%] | RCY[%][a] |
1 | 5 | >98 |
2 | 1 | 79 |
3 | 0.1 | 20 |
[a]通过装备有放射性检测探头的高效液相色谱仪进行放射化学产率的检测。
实施例5
对苯硼酸进行放射性碘元素131I的标记,于不同时间对其放射化学产率进行监测:
将苯硼酸(2μmol)加入至1.5mL离心管中,之后加入含有Cu2O(0.1μmol)及1,10-菲啰啉(0.2μmol)的乙腈溶液(50μL),使其充分混合后,加入Na131I的水溶液(18.5-20MBq,5μL),室温条件下震荡反应,分别于反应10min、30min、60min时对其标记产率进行监测,结果如下表所示:
Entry | Time[min] | RCY[%][a] |
1 | 60 | >98 |
2 | 30 | 77 |
3 | 10 | 37 |
[a]通过装备有放射性检测探头的高效液相色谱仪进行放射化学产率的检测。
实施例6
对间碘苄胍进行放射性碘元素131I标记,标记前体的合成及标记路线如下所示:
·化合物3的合成:
将93.0mg化合物1及61.7mg化合物2加入至反应瓶中,加入1mL甲醇,之后加入100μL三乙胺,氮气保护下室温搅拌反应过夜,旋蒸除去溶剂,通过制备硅胶板进行纯化,得产物化合物3。其核磁数据如下:1H NMR(600MHz,CD3SOCD3):δ8.62(s,1H),7.69-7.30(m,4H),4.52(d,J=5.08Hz,2H),3.04(dd,J1=15.74Hz,J2=7.27Hz,2H),1.47(s,9H),1.38(s,9H),1.16(t,J=7.34Hz,1H);13C NMR(150MHz,CD3SOCD3):δ163.59,155.85,152.54,137.42,133.43(d,J=9.83Hz),131.24,130.39(d,J=11.27Hz),128.68(d,J=211.37Hz),128.56(d,J=12.66Hz),83.47,78.74,45.84,28.44,28.09.质谱鉴定数据:m/z(EI)394.2([M+H]+,C18H29BN3O6,计算值为394.2)。
·131I标记的间碘苄胍的制备:
将化合物3(2μmol)加入至1.5mL离心管中,之后加入含有Cu2O(0.4μmol)及1,10-菲啰啉(0.8μmol)的乙腈溶液(50μL),使其充分混合后,加入Na131I的水溶液(18.5-20MBq,5μL),室温条件下震荡反应1h后,通过HPLC分离纯化,使标记产物与标记前体分离,之后通过三氟乙酸(TFA)脱Boc(叔丁氧羰基)后得高比活度标记产物131I-MIBG。
·标准品127I-Boc-MIBG的制备,结构式如下所示:
将18.9mg NaI加入到500μL含有20.0mg化合物3,7.3mg Cu2O,20.0mg 1,10-菲啰啉的乙腈溶液中,室温搅拌反应4h后通过制备硅胶板进行纯化,得标准品127I-Boc-MIBG。质谱鉴定数据:m/z(EI)476.1([M+H]+,C18H27IN3O4,计算值为476.1)。
·标准品127I-MIBG的制备,结构式如下所示:
将50μL CH2Cl2及50μL TFA加入至1mg 127I-Boc-MIBG中,反应2h后氮气吹干除去溶剂,之后通过HPLC分离纯化得产物127I-MIBG。质谱鉴定数据:m/z(EI)275.9([M+H]+,C8H11IN3,计算值为275.9)。
实施例7
对苯甲酸活化酯进行放射性碘元素131I的标记,标记前体的合成及标记路线如下所示:
·标记前体PB-NHS的制备:
将165.9mg化合物5与268.0mg N,N’-二环己基碳二亚胺(DCC)及149.6mg N-羟基琥珀酰亚胺(NHS)溶于无水四氢呋喃中,室温反应过夜后,过滤除去二环己基脲(DCU),旋蒸除去溶剂,过柱分离得化合物6。其核磁数据如下:1H NMR(600MHz,CD3SOCD3):δ8.45(s,2H),8.06-8.01(m,4H),2.90(s,4H);13C NMR(150MHz,CD3SOCD3):δ170.81,162.42,135.26,129.20,126.00,26.02.质谱鉴定数据:m/z(EI)264.1([M+H]+,C11H10BNO6,计算值为264.0)。
·131I标记的苯甲酸活化酯131I-SIB的制备:
将Na131I的水溶液(5μL)加入到1.5mL离心管中,之后加入适量无水乙腈,利用氮吹仪进行吹干,重复三次,将4-羧基苯硼酸活化酯(PB-NHS,2μmol)与含有Cu2O(0.4μmol)及1,10-菲啰啉(0.8μmol)的乙腈溶液(50μL)充分混合后加入到含有无水Na131I的离心管中,之后室温条件下震荡反应30min,得标记产物131I-SIB。
·标准品对碘苯甲酸活化酯的制备,结构式如下所示:
将248.0mg 4-碘苯甲酸与268.0mg N,N’-二环己基碳二亚胺(DCC)及149.6mg N-羟基琥珀酰亚胺(NHS)溶于无水四氢呋喃中,室温反应过夜后,过滤除去DCU,旋蒸除去溶剂,过柱分离得产物对碘苯甲酸活化酯。其核磁数据如下:1H NMR(600MHz,CDCl3):δ7.90-7.82(m,4H),2.91(s,4H);13C NMR(150MHz,CDCl3):δ169.08,161.61,138.33,131.67,124.57,103.40,25.67.
实施例8
利用125I-SIB标记多肽cRGDyK并进行单光子发射计算机断层扫描(SPECT)显像,标记路线如下所示:
·化合物9注射液的制备
称取1mg c(RGDyK)溶于50μL无水DMF中,加入5μL三乙胺,之后加入125I-SIB的无水乙腈溶液,反应1h后,HPLC分离得标记产物,旋蒸除去溶剂,溶于磷酸缓冲溶液PBS,无菌过滤后得化合物9的注射液。
·SPECT显像
取0.1mL制备好的放射化学纯度大于95%的化合物9的注射液(约18.5MBq),尾静脉注射于荷U87MG瘤裸鼠(体重约为20g),于注射后30min,1h,2h,4h后进行SPECT显像。显像结果见附图5,由显像结果可见化合物9在肿瘤部位有明显的富集,由此证明利用该标记方法所得125I-SIB成功应用于多肽的放射性碘元素标记。
以上所述,仅为本发明较佳实施例而已,故不能依此限定本发明实施的范围,即依本发明专利范围及说明书内容所作的等效变化与修饰,皆应仍属本发明涵盖的范围内。
Claims (6)
1.一种放射性碘标记方法,其特征在于:在反应溶剂中,于一价铜配位化合物存在下,使Ar-B(OH)2与NanI反应获得Ar-nI,实现放射性碘的标记;所述铜配位化合物来源于可提供一价铜离子的铜源化合物CuX以及铜的配体化合物;所述铜源化合物CuX选自氧化亚铜Cu2O,氯化亚铜CuCl,溴化亚铜CuBr,碘化亚铜CuI中的一种;所述铜的配体化合物选自1,10-菲啰啉;所述反应溶剂选自乙腈,甲醇,二氯甲烷,四氢呋喃中的一种或至少两种的组合。
2.根据权利要求1所述的放射性碘标记方法,其特征在于:所述nI选自123I、124I、125I、131I中的一种或至少两种的组合。
3.根据权利要求1所述的放射性碘标记方法,其特征在于:所述铜的配体化合物过量于铜源化合物CuX。
4.根据权利要求1所述的放射性碘标记方法,其特征在于:所述Ar-B(OH)2为下式所示的化合物3;所述放射性碘标记方法包括:将含有Cu2O和1,10-菲啰啉的乙腈溶液加入至含有化合物3的反应容器中,混合均匀,然后加入NanI反应,反应结束后加入三氟乙酸脱保护,得标记产物即下式所示化合物4,即放射性碘标记的间碘苄胍;
5.根据权利要求1所述的放射性碘标记方法,其特征在于:所述Ar-B(OH)2为下式所示的化合物6;所述放射性碘标记方法包括:将含有Cu2O和1,10-菲啰啉的乙腈溶液加入至含有化合物6的反应容器中,混合均匀,然后加入NanI反应,得标记产物即下式所示化合物7;
6.根据权利要求1所述的放射性碘标记方法,其特征在于:所述Ar-B(OH)2为下式所示的化合物13;所述放射性碘标记方法包括:将含有Cu2O和1,10-菲啰啉的乙腈溶液加入至含有化合物13的反应容器中,混合均匀,然后加入NanI反应,得标记产物即下式所示化合物14;
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610820535.2A CN106631908B (zh) | 2016-09-13 | 2016-09-13 | 一种放射性碘标记方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610820535.2A CN106631908B (zh) | 2016-09-13 | 2016-09-13 | 一种放射性碘标记方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106631908A CN106631908A (zh) | 2017-05-10 |
CN106631908B true CN106631908B (zh) | 2018-10-19 |
Family
ID=58853017
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610820535.2A Active CN106631908B (zh) | 2016-09-13 | 2016-09-13 | 一种放射性碘标记方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106631908B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108434468B (zh) * | 2018-06-08 | 2020-12-18 | 厦门大学 | 一种放射性碘标记的蛋白结合配体及其应用 |
CN112209966A (zh) * | 2020-10-15 | 2021-01-12 | 北京师范大学 | 放射性碘标记的三苯基膦类衍生物、其制备方法及应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008150439A1 (en) * | 2007-06-01 | 2008-12-11 | Cellectar, Inc. | Compositions of phospholipid ether boronic acids and esters and methods for their synthesis and use |
CN102911256A (zh) * | 2012-11-02 | 2013-02-06 | 厦门大学 | 一种放射性标记的多肽配合物及其制备方法和应用 |
WO2014132919A1 (ja) * | 2013-02-28 | 2014-09-04 | 国立大学法人京都大学 | 診断用組成物 |
-
2016
- 2016-09-13 CN CN201610820535.2A patent/CN106631908B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008150439A1 (en) * | 2007-06-01 | 2008-12-11 | Cellectar, Inc. | Compositions of phospholipid ether boronic acids and esters and methods for their synthesis and use |
CN102911256A (zh) * | 2012-11-02 | 2013-02-06 | 厦门大学 | 一种放射性标记的多肽配合物及其制备方法和应用 |
WO2014132919A1 (ja) * | 2013-02-28 | 2014-09-04 | 国立大学法人京都大学 | 診断用組成物 |
Non-Patent Citations (4)
Title |
---|
A new route to iodine-labeled N-isopropyliodoamphetamine via organoboranes;George W.Kabalka等;《Tetrahedron Letters》;19861231;第27卷(第33期);3843-3844页 * |
Copper-catalyzed halogenation of arylboronic acids;Guangyou Zhang等;《Tetrahedron Letters》;20110420;第52卷(第16期);1993-1995页 * |
MicroPET and Autoradiographic Imaging of Breast Cancer αv-Integrin Expression Using 18F- and 64Cu-Labeled RGD Peptide;Xiaoyuan Chen等;《Bioconjugate Chem.》;20021230;第15卷(第1期);41-49页 * |
Radioisotopic labelling by surface catalysis. III. Radioiodinations of organic molecules on silica gel surfaces;Thomas E. Boothe等;《Journal of Labelled Compounds and Radiopharmaceuticals》;19851231;第22卷(第11期);1109-1122页 * |
Also Published As
Publication number | Publication date |
---|---|
CN106631908A (zh) | 2017-05-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109336909B (zh) | 具有聚集诱导发光性质的近红外二区荧光化合物及制备方法、纳米粒胶束及其应用 | |
JP5341136B2 (ja) | 腫瘍画像化のためのアミノ酸アナログ | |
CN111467510B (zh) | 一种特异性靶向放射性核素标记物及其制备方法和应用 | |
JPS6069090A (ja) | テクネチウム−99mのアルキレンアミンオキシムとの錯体 | |
JP2009504849A (ja) | 放射標識されたトレーサの製造方法およびその前駆体 | |
WO2008023780A1 (fr) | Procédé de méthylation rapide, coffret pour préparer un traceur pet et procédé de fabrication d'un traceur pet | |
CN106631908B (zh) | 一种放射性碘标记方法 | |
JP2006510705A (ja) | ベンゾチアゾール類の固相フッ素化 | |
RU2523411C2 (ru) | Меченые молекулярные визуализирующие агенты, способы получения и способы применения | |
CN107522673B (zh) | 用于生物正交反应的1,2,4,5-四嗪化合物及其制备方法与应用 | |
CN114573558B (zh) | 一种水溶性甲基苄醚衍生物、正电子核素探针、核素标记物及制备方法和应用 | |
CN101723849B (zh) | 18f标记氨基酸类衍生物、其制备方法及其制备报告肿瘤的正电子发射断层显像分子探针中的应用 | |
CN104830316A (zh) | 一种用于核素标记的靶向探针及其制备方法和应用 | |
CN102126985A (zh) | 18f标记前体化合物及其制备方法和应用 | |
CN117700479A (zh) | 靶向前列腺特异性膜抗原抑制剂、放射性标记物及其制备方法和应用 | |
CN105963724A (zh) | 一种放射性标记的肿瘤显像剂、其制备方法和应用 | |
CN113583066B (zh) | 一种甘露糖衍生物及其应用 | |
WO1994028943A1 (en) | Analogs of cytochalasin b as radiopharmaceuticals for nuclear imaging of trans-membrane glucose transport | |
CN114031652B (zh) | 一种含环己烷的葡萄糖衍生物及其应用 | |
CN113150032B (zh) | 一种锝-99m标记含异腈的叶酸衍生物及其制备方法和应用 | |
CN107088228A (zh) | 基于色氨酸及其衍生物的新型影像诊疗试剂的开发与应用 | |
CN115286693A (zh) | 针对癌胚抗原相关细胞黏附分子ceacam6的肿瘤靶向肽及其应用 | |
CN108586524B (zh) | 氟代氧化膦类化合物及其在正电子发射显像中的应用 | |
US10968245B2 (en) | Method for preparing tricarbonyl technetium-99m intermediate | |
JP6037330B2 (ja) | 11c−標識チアミン及びその誘導体、11c−標識フルスルチアミン、チアミン前駆体、並びにpet用プローブ及びそれらを用いたイメージング方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |