WO2018107526A1 - 一种制备三羰基锝-99m中间体的方法 - Google Patents
一种制备三羰基锝-99m中间体的方法 Download PDFInfo
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- WO2018107526A1 WO2018107526A1 PCT/CN2016/112642 CN2016112642W WO2018107526A1 WO 2018107526 A1 WO2018107526 A1 WO 2018107526A1 CN 2016112642 W CN2016112642 W CN 2016112642W WO 2018107526 A1 WO2018107526 A1 WO 2018107526A1
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- Prior art keywords
- tricarbonyl
- manganese
- cyclopentadienyl
- ruthenium
- carbonyl
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- 238000000034 method Methods 0.000 title claims abstract description 39
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 title abstract 4
- 229940056501 technetium 99m Drugs 0.000 title abstract 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- QKOHYQVZNLEAJH-UHFFFAOYSA-N oxomethylidenemanganese Chemical compound O=C=[Mn] QKOHYQVZNLEAJH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 239000003638 chemical reducing agent Substances 0.000 claims description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- WRRRYSZBUYTWLY-UHFFFAOYSA-N [Mn]C1=CC=CC1 Chemical compound [Mn]C1=CC=CC1 WRRRYSZBUYTWLY-UHFFFAOYSA-N 0.000 claims description 26
- DEIHRWXJCZMTHF-UHFFFAOYSA-N [Mn].[CH]1C=CC=C1 Chemical compound [Mn].[CH]1C=CC=C1 DEIHRWXJCZMTHF-UHFFFAOYSA-N 0.000 claims description 23
- -1 dicarbonyl dodecyl manganese Chemical compound 0.000 claims description 22
- 239000012279 sodium borohydride Substances 0.000 claims description 22
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- ANHQLUBMNSSPBV-UHFFFAOYSA-N 4h-pyrido[3,2-b][1,4]oxazin-3-one Chemical group C1=CN=C2NC(=O)COC2=C1 ANHQLUBMNSSPBV-UHFFFAOYSA-N 0.000 claims description 14
- 239000011572 manganese Substances 0.000 claims description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- DYZMIPFPXGPVDW-UHFFFAOYSA-N [Mn].C1(=CC=CC1)C(=O)O Chemical compound [Mn].C1(=CC=CC1)C(=O)O DYZMIPFPXGPVDW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052748 manganese Inorganic materials 0.000 claims description 12
- 230000009471 action Effects 0.000 claims description 11
- QFEOTYVTTQCYAZ-UHFFFAOYSA-N dimanganese decacarbonyl Chemical group [Mn].[Mn].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] QFEOTYVTTQCYAZ-UHFFFAOYSA-N 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 239000001476 sodium potassium tartrate Substances 0.000 claims description 10
- 235000011006 sodium potassium tartrate Nutrition 0.000 claims description 10
- JBANFLSTOJPTFW-UHFFFAOYSA-N azane;boron Chemical compound [B].N JBANFLSTOJPTFW-UHFFFAOYSA-N 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 239000011521 glass Substances 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- QSHYGLAZPRJAEZ-UHFFFAOYSA-N 4-(chloromethyl)-2-(2-methylphenyl)-1,3-thiazole Chemical compound CC1=CC=CC=C1C1=NC(CCl)=CS1 QSHYGLAZPRJAEZ-UHFFFAOYSA-N 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 125000004989 dicarbonyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- KRHOUGAQUGCCJI-UHFFFAOYSA-N cyclopenta-1,3-diene-1-carboxylic acid Chemical compound OC(=O)C1=CC=CC1 KRHOUGAQUGCCJI-UHFFFAOYSA-N 0.000 claims 1
- 238000002372 labelling Methods 0.000 abstract description 11
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000000523 sample Substances 0.000 abstract description 3
- 229910052713 technetium Inorganic materials 0.000 abstract 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 abstract 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 33
- 229910052707 ruthenium Inorganic materials 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 230000014759 maintenance of location Effects 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 229930182555 Penicillin Natural products 0.000 description 7
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 7
- 229940049954 penicillin Drugs 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 230000002285 radioactive effect Effects 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 4
- 239000010453 quartz Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VFAHXTJRZRHGDN-UHFFFAOYSA-N [Ru].[C]=O Chemical group [Ru].[C]=O VFAHXTJRZRHGDN-UHFFFAOYSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229960002885 histidine Drugs 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000012217 radiopharmaceutical Substances 0.000 description 3
- 229940121896 radiopharmaceutical Drugs 0.000 description 3
- 230000002799 radiopharmaceutical effect Effects 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- RJYMRRJVDRJMJW-UHFFFAOYSA-L dibromomanganese Chemical compound Br[Mn]Br RJYMRRJVDRJMJW-UHFFFAOYSA-L 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- CEYVKTKJMLCDGD-UHFFFAOYSA-N 1-isocyano-1-methoxy-2-methylpropane Chemical compound COC([N+]#[C-])C(C)C CEYVKTKJMLCDGD-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OMVFGTABSHECNI-UHFFFAOYSA-N bis(oxomethylidene)manganese Chemical compound O=C=[Mn]=C=O OMVFGTABSHECNI-UHFFFAOYSA-N 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
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- 238000012631 diagnostic technique Methods 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 150000002697 manganese compounds Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PLFLRQISROSEIJ-UHFFFAOYSA-N methylborane Chemical compound CB PLFLRQISROSEIJ-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 238000012633 nuclear imaging Methods 0.000 description 1
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- 125000002524 organometallic group Chemical group 0.000 description 1
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- 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
- C07F17/00—Metallocenes
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G99/00—Subject matter not provided for in other groups of this subclass
-
- 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
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
-
- 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
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/87—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by chromatography data, e.g. HPLC, gas chromatography
Definitions
- the invention relates to a method for preparing a tricarbonyl ruthenium-99m intermediate, in particular to a method for preparing a tricarbonyl ruthenium-99m intermediate at normal pressure and room temperature.
- the method is to directly reduce [ 99m TcO 4 ] - in the aqueous phase with a boron hydride gas (such as NaBH 4 ) in the presence of carbon monoxide gas, and obtain a tricarbonyl ruthenium intermediate [ 99m Tc(H 2 O) 3 (CO) in one step. 3 ] + .
- a boron hydride gas such as NaBH 4
- CO tricarbonyl ruthenium intermediate
- the present invention provides a process for preparing a tricarbonyl ruthenium-99m intermediate comprising reacting a carbonyl manganese compound as a carbon monoxide donor with perrhenate and water to prepare a solution.
- the tricarbonyl ruthenium-99m intermediate is described.
- the method comprises mixing the carbonyl manganese compound, a reducing agent sodium borohydride, sodium potassium tartrate, sodium carbonate and a perrhenic acid aqueous solution, and reacting for 10 to 30 minutes under ultraviolet light irradiation. Obtaining the tricarbonyl ruthenium-99m intermediate; or
- the carbonyl manganese compound, the reducing agent ammonia borane, the concentrated phosphoric acid and the perrhenic acid aqueous solution are mixed, and then reacted under ultraviolet light for 10 to 30 minutes to obtain the tricarbonyl ruthenium-99m intermediate;
- a glass container is selected as the reaction container.
- cyclopentadienyl formaldehyde manganese tricarbonyl is reacted by dimethylformamide and formic acid to obtain 1-cyclopentadienyl manganese tricarbonyl-N,N-dimethylmethaneamine;
- the method comprises mixing the 1-cyclopentadienyl manganese tricarbonyl-N,N,N-trimethylborohydride with an aqueous solution of perrhenate, under ultraviolet light irradiation.
- the reaction is carried out for 10 to 30 minutes to prepare the tricarbonyl ruthenium-99m intermediate.
- the method for preparing the tricarbonyl ruthenium-99m intermediate according to an embodiment of the present invention can complete the preparation of the intermediate at normal pressure and room temperature, and has the advantages of simple operation, easy availability of raw materials and high labeling rate, and can be used for preparing various types of three.
- Figure 2 is a high performance liquid chromatogram of the intermediate [ 99m Tc(H 2 O) 3 (CO) 3 ] + in the comparative example;
- Figure 3 is a high performance liquid chromatogram of tricarbonyl ruthenium methoxyisobutyl isocyanide of Application Example 1 of the present invention
- Fig. 4 is a high performance liquid chromatogram of tricarbonyl quinone histidine of Application Example 2 of the present invention.
- 1-cyclopentadienyl manganese tricarbonyl-N,N,N-trimethylborohydride etc.
- the reaction needs to be carried out under ultraviolet light irradiation.
- ultraviolet light having a wavelength of 300 to 400 nm, for example, 365 nm may be used, and a glass bottle or a quartz bottle may be used as the reaction bottle.
- the solution obtained after the reaction was purified by a needle filter to remove a small amount of insoluble matter.
- the carbonyl manganese compound may be cyclopentadienyl manganese tricarbonyl, methyl cyclopentadienyl manganese tricarbonyl, cyclopentadienic acid manganese tricarbonyl, and the amount thereof may be 1 to 250 mg; the amount of the reducing agent may be 1 ⁇ 10mg; the amount of sodium potassium tartrate can be 1 ⁇ 40mg; the amount of sodium carbonate can be 1 ⁇ 10mg; the pH value of the final reaction after adjustment can be 10 ⁇ 12; the ultraviolet light irradiation can be selected by hand-held ultraviolet lamp.
- a glass bottle or a quartz bottle can be used as the reaction bottle at a wavelength of 365 nm, and a quartz bottle can be used as a reaction bottle at a wavelength of 254 nm.
- the tricarbonyl ruthenium intermediate is prepared by using cyclopentadienic acid manganese tricarbonyl as a carbon monoxide donor and sodium borohydride as a reducing agent:
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- Chemical & Material Sciences (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种制备三羰基锝-99m中间体的方法,包括以羰基锰化合物作为一氧化碳供体,与高锝酸根及水反应,制得所述三羰基锝-99m中间体。本发明一实施方式的制备三羰基锝-99m中间体的方法,在常压、室温下即可完成该中间体的制备,操作简便、原料易得、标记率高,可以用于制备各类三羰基锝标记的探针。
Description
本发明涉及一种制备三羰基锝-99m中间体的方法,具体为一种在常压、室温下制备三羰基锝-99m中间体的方法。
分子影像(Molecular Imaging)可以通过无创的显像技术研究正常或病理状态下的分子过程。其中核医学的分子影像诊断技术,包括单光子发射断层显像(SPECT)和正电子发射断层显像(PET),已在临床上得到广泛应用。它具有高特异性和灵敏性,是分子影像领域的重要研究方向。
放射性核素锝-99m(99mTc)有着优异的核素性质、成本低、制备简便、辐射剂量负担小、价态丰富,是公认的优良的SPECT核素。在一价金属锝放射性药物中羰基锝核心([99mTc(CO)3]+)受到了科研工作者的大量关注。其中99mTc(I)处于d6低自旋,处于动力学惰性,三个面式排布的CO供电子官能团填充金属的三个配位位置,剩下的三个位置可和多种配体发生取代从而形成八面体结构。[99mTc(CO)3]+核具有尺寸小、结构稳定,抗氧化,易制备的优良特性。例如应用羰基锝核心制备的羰基锝甲氧基异丁基异腈([99mTc(CO)3(MIBI)3]+)具有优良的生物性能。
早期三羰基锝需在高温高压下多步反应合成,这些方法对于应用到临床的日常需求并不具备可行性。例如Alberto等人报道了一种在低压(约105Pa)条件下制备水溶性的有机金属络合物[99mTc(H2O)3(CO)3]+的方法。该络合物在水和空气中均比较稳定,且水配体很容易被其他的络合能力较强的配体所取代,这使得羰基络合物可作为放射性药物应用于核医学。该方法是在一氧化碳气体存在下,用硼氢化合物(如NaBH4)在水相直接还原[99mTcO4]-,一步法得到三羰基锝中间体[99mTc(H2O)3(CO)3]+。但由于制备过程使用到剧毒气体CO,他们又进一步作了改进,用固体K2[H3BCO2]做为一氧化碳供体和还原剂,替代气体CO和NaBH4,同样将Tc(Ⅶ)还原到Tc(I)得到三羰基锝中间体[99mTc(H2O)3(CO)3]+。两种方法均需要在加热条件下反应,合成条件如下反应式所示。
然而,以上两种方法均存在一些缺陷,如需要一氧化碳气体、K2[H3BCO2]制备方法复杂、需要加热条件下进行标记等,影响其在临床医院的推广和使用。寻找一种能够在常压室温水相条件下制备三羰基锝中间体[99mTc(H2O)3(CO)3]+的方法,是目前本技术领域需要解决的重要课题。
发明内容
为解决上述现有技术的至少一种缺陷,本发明提供了一种制备三羰基锝-99m中间体的方法,包括以羰基锰化合物作为一氧化碳供体,与高锝酸根及水反应,制得所述三羰基锝-99m中间体。
根据本发明一实施方式,所述羰基锰化合物选自十羰基二锰、五羰基卤化锰、环戊二烯三羰基锰、甲基环戊二烯三羰基锰、环戊二烯甲酸三羰基锰及1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵中的一种或多种。
根据本发明一实施方式,所述方法包括将所述高锝酸根在还原剂的作用下与所述羰基锰化合物及水反应,制得所述三羰基锝-99m中间体;其中,所述羰基锰化合物选自十羰基二锰和/或五羰基卤化锰。
根据本发明一实施方式,所述方法包括将所述高锝酸根在还原剂的作用下,通过紫外光照射与所述羰基锰化合物及水反应,制得所述三羰基锝-99m中间体;其中,所述羰基锰化合物选自环戊二烯三羰基锰、甲基环戊二烯三羰基锰及环戊二烯甲酸三羰基锰中的一种或多种。
根据本发明一实施方式,所述还原剂为硼氢化钠或氨硼烷。
根据本发明一实施方式,所述方法包括将所述羰基锰化合物、还原剂硼氢化钠、酒石酸钾钠、碳酸钠及高锝酸根水溶液混合后,在紫外光照射下反应10~30分钟,制得所述三羰基锝-99m中间体;或者
将所述羰基锰化合物、还原剂氨硼烷、浓磷酸及高锝酸根水溶液混合后,在紫外光照射下反应10~30分钟,制得所述三羰基锝-99m中间体;
其中,所述羰基锰化合物选自环戊二烯三羰基锰、甲基环戊二烯三羰基锰、环戊二烯甲酸三羰基锰中的一种或多种。
根据本发明一实施方式,所述方法包括将所述高锝酸根在紫外光照射的作用下与1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵及水反应,制得所述三羰基锝-99m中间体。
根据本发明一实施方式,所述紫外光的波长为300~400nm时,选用玻璃容器作为反应容器。
根据本发明一实施方式,所述1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵的制备方法包括:
将环戊二烯三羰基锰在正丁基锂的作用下与二甲基甲酰胺反应,制得环戊二烯甲醛三羰基锰;
将所述环戊二烯甲醛三羰基锰在二甲基甲酰胺及甲酸的作用下,反应得到1-环戊二烯三羰基锰-N,N-二甲基甲烷胺;以及
将所述1-环戊二烯三羰基锰-N,N-二甲基甲烷胺在碘甲烷及硼氢化钠的作用下,反应得到所述1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵。
根据本发明一实施方式,所述方法包括将所述1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵与高锝酸根水溶液混合后,在紫外光照射下反应10~30分钟,制得所述三羰基锝-99m中间体。
本发明一实施方式的制备三羰基锝-99m中间体的方法,在常压、室温下即可完成该中间体的制备,操作简便、原料易得、标记率高,可以用于制备各类三羰基锝标记的探针。
图1为本发明实施例2的中间体[99mTc(H2O)3(CO)3]+的高效液相色谱图;
图2为对比例的中间体[99mTc(H2O)3(CO)3]+的高效液相色谱图;
图3为本发明应用例1的三羰基锝甲氧基异丁基异腈的高效液相色谱图;
图4为本发明应用例2的三羰基锝组氨酸的高效液相色谱图。
体现本发明特征与优点的典型实施方式将在以下的说明中详细叙述。应理解的是本发明能够在不同的实施方式上具有各种的变化,其皆不脱离本发明的范围,且其中的说明及
图示在本质上是当作说明之用,而非用以限制本发明。
本发明一实施方式的制备三羰基锝-99m中间体的方法,包括以羰基锰化合物作为一氧化碳供体,与高锝酸根及水反应,制得所述三羰基锝-99m中间体。其中,羰基锰化合物能够分解出CO,可作为一氧化碳供体,因此无需直接使用有毒的一氧化碳,且原料简单易得。
本发明一实施方式的制备三羰基锝-99m中间体的方法,工艺简化,在常压、室温下即可完成中间体的制备,从而避免了临床制备过程中,由于采用水浴或金属浴等加热方式,可能造成的反应容器破损、污染、放射性沾污等问题。
其中,羰基锰化合物可以为十羰基二锰Mn2(CO)10、环戊二烯类三羰基锰及五羰基卤化锰Mn(CO)5X,X可以为Cl、Br、I等,优选为Br;环戊二烯类三羰基锰的结构式可以为:
R可以为H、CH3、COOH或CH2N+Me3BH4
-。具体地,环戊二烯类三羰基锰可以为环戊二烯三羰基锰(R=H)、甲基环戊二烯三羰基锰(R=CH3)、环戊二烯甲酸三羰基锰(R=COOH)、1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵(R=CH2N+Me3BH4
-)等。
本发明一实施方式的制备三羰基锝-99m中间体的反应式如下,其中仅示出了主要反应物的结构式,省略了反应物水的结构。
上述反应根据一氧化碳供体的不同,具体反应条件也不相同。例如,其可在不外加还原剂的条件下进行,也可在加入还原剂的条件下进行;可在不外加紫外光照射的条件下进行,也可在紫外光照射的条件下进行。
具体地,例如,1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵可同时作为一氧化碳供体和还原剂,当以1-环戊二烯三羰基锰-N,N,N-三甲基硼为一氧化碳供体时,不需外加还原剂;而以十羰基二锰、五羰基溴化锰、环戊二烯三羰基锰(R=H)、甲基环戊二烯三羰基
锰(R=CH3)、环戊二烯甲酸三羰基锰(R=COOH)等作为一氧化碳供体时,需外加还原剂。又如,十羰基二锰、五羰基溴化锰作为一氧化碳供体时,不需要外加紫外光照射,而以环戊二烯三羰基锰(R=H)、甲基环戊二烯三羰基锰(R=CH3)、环戊二烯甲酸三羰基锰(R=COOH)、1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵等作为一氧化碳供体时,需在紫外光照射的条件下进行反应。
于本发明一实施方式中,可通过将环戊二烯三羰基锰在正丁基锂的作用下与干冰(CO2)反应,制得环戊二烯甲酸三羰基锰。
于本发明一实施方式中,1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵可通过如下方法制得:
将环戊二烯三羰基锰在正丁基锂的作用下与二甲基甲酰胺(DMF)反应,制得环戊二烯甲醛三羰基锰;
将环戊二烯甲醛三羰基锰在DMF及甲酸的作用下,反应得到1-环戊二烯三羰基锰-N,N-二甲基甲烷胺;
将1-环戊二烯三羰基锰-N,N-二甲基甲烷胺在碘甲烷及硼氢化钠的作用下,反应得到1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵。
于本发明一实施方式中,高锝酸根可从医用99Mo-99mTc发生器中淋洗得到的高锝酸根99mTcO4
-淋洗液中获得。另外,由于淋洗液中高锝酸根的含量少,因此,所加入的羰基锰化合物是过量的,以使尽量多的高锝酸根参与反应。
本发明一实施方式的制备三羰基锝-99m中间体的方法中,紫外光是指波长为10~400nm的光。优选波长为250~400nm的紫外光,例如波长为254nm的紫外光;进一步优选300~400nm的紫外光,例如波长为365nm的紫外光,波长为254nm、365nm的紫外光均可通过手持式紫外灯获得。
于本发明一实施方式中,采用波长为254nm的紫外光,可选用石英瓶作为反应瓶。
于本发明另一实施方式中,采用波长为300~400nm,例如365nm的紫外光,可选用玻璃瓶或石英瓶作为反应瓶。
本发明一实施方式的制备三羰基锝-99m中间体的方法,采用普通玻璃反应瓶及手持式紫外灯即可完成中间体的制备,简化了放射性操作,有利于三羰基锝放射性药物的进一步的推广和应用。
本发明对所加入的还原剂的种类没有限定,例如可以为硼氢化钠(NaBH4)或氨硼烷(NH3BH3)等。
本发明一实施方式的制备三羰基锝-99m中间体的方法,以硼氢化钠作为还原剂,具体步骤包括:
将羰基锰化合物加入反应瓶中,并将还原剂硼氢化钠加入反应瓶中;
将酒石酸钾钠、碳酸钠作为调节pH的辅剂加入反应瓶中;
将从医用99Mo-99mTc发生器中淋洗获得的高锝酸根99mTcO4
-淋洗液加入反应瓶中;
将反应瓶密封后在紫外光照射条件下反应10~30分钟;
将反应后所得溶液通过针式滤器进行纯化,以除去少量不溶物。
上述步骤中,羰基锰化合物可以为环戊二烯三羰基锰、甲基环戊二烯三羰基锰、环戊二烯甲酸三羰基锰,其用量可以为1~250mg;还原剂的用量可以为1~10mg;酒石酸钾钠的用量可以为1~40mg;碳酸钠用量可以为1~10mg;调节后的最终反应时的pH值可以为10~12;紫外光照射条件可选用手持式紫外灯,波长为365nm时可选用玻璃瓶或石英瓶作为反应瓶,波长为254nm时可选用石英瓶作为反应瓶。
本发明另一实施方式的制备三羰基锝-99m中间体的方法,以氨硼烷作为还原剂,具体步骤包括:
将羰基锰化合物加入反应瓶中,并将还原剂氨硼烷加入反应瓶中;
将浓磷酸作为调节pH的辅剂加入反应瓶中;
将从医用99Mo-99mTc发生器中淋洗获得的高锝酸根99mTcO4
-淋洗液加入反应瓶中;
将反应瓶密封后在紫外光照射条件下反应10~30分钟;
将反应后所得溶液通过针式滤器进行纯化,以除去少量不溶物。
上述步骤中,羰基锰化合物可以为环戊二烯三羰基锰、甲基环戊二烯三羰基锰、环戊二烯甲酸三羰基锰,其用量可以为1~100mg;还原剂的用量可以为1~10mg;浓磷酸的用量可以为1~40μL;调节后的最终反应时的pH值可以为2~4。
本发明另一实施方式的制备三羰基锝-99m中间体的方法,以1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵作为一氧化碳供体,不外加还原剂,具体步骤包括:
将1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵加入反应瓶中;
将从医用99Mo-99mTc发生器中淋洗获得的高锝酸根99mTcO4
-淋洗液加入步骤反应瓶中;
将反应瓶密封后在紫外光照射条件下反应10~30分钟;
将反应后所得溶液通过针式滤器进行纯化,以除去少量不溶物。
上述步骤中,1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵的用量可以为0.1~
20mg。
本发明一实施方式的制备三羰基锝-99m中间体的方法,以羰基锰化合物为一氧化碳供体,外加还原剂或不加还原剂,在紫外光照射或无需紫外照射的条件下,常压、室温、水相条件下制得三羰基锝中间体[99mTc(H2O)3(CO)3]+。
本发明一实施方式的制备三羰基锝-99m中间体的方法,操作简便、原料易得、标记率高,可以用于制备各类三羰基锝标记的探针。
下面,结合具体实施例对本发明的制备三羰基锝-99m中间体的方法做进一步说明。其中,所使用的试剂均可通过市售获得。所涉及的薄层层析条件为:聚酰胺薄膜,展开剂为乙腈或生理盐水;放射性高效液相色谱(radio-HPLC)条件为:高效液相色谱仪HITACHI(D-2000);Kromaisl C18柱250×4.6mm,5μm A相为水(0.1%TFA),B相为甲醇(0.1%TFA);淋洗梯度为:0-3min:5%B相;3-3.1min:5%~25%B相;3.1-9min:25%B相;9-9.1min:25%~34%B相;9.1-20min:34%~100%B相;20-25min:100%B相;25-25.1min:100%~5%B相;25.1-30min:5%B相。流速1mL·min-1。
实施例1
以环戊二烯三羰基锰作为一氧化碳供体,以硼氢化钠为还原剂,制备三羰基锝中间体:
称取环戊二烯三羰基锰200mg、硼氢化钠10mg、酒石酸钾钠20mg、碳酸钠4mg加入石英玻璃瓶中。并向其中加入新鲜99mTcO4
-洗脱液1mL(37MBq),充分振荡,密封后置于手持式紫外灯下(254nm),室温下反应20min。反应结束后用0.1mol/L盐酸调节pH至6~7,溶液通过针式滤器即得到三羰基锝中间体[99mTc(H2O)3(CO)3]+。测得HPLC保留时间为9.2min,标记率96%。
实施例2
以甲基环戊二烯三羰基锰作为一氧化碳供体,以硼氢化钠为还原剂,制备三羰基锝中间体:
称取甲基环戊二烯三羰基锰20mg、硼氢化钠5.5mg、酒石酸钾钠20mg、碳酸钠4mg加入青霉素瓶中。并向其中加入新鲜99mTcO4
-洗脱液1mL(37MBq),充分振荡,密封后置于手持式紫外灯下(365nm),室温下反应20min。反应结束后用0.1mol/L盐酸调节pH至6~7,溶液通过针式滤器即得到三羰基锝中间体[99mTc(H2O)3(CO)3]+。测得HPLC保留时间为
9.5min,标记率98%,所得谱图参见图1。
实施例3
环戊二烯甲酸三羰基锰的制备
称取环戊二烯三羰基锰1g溶于10mL无水四氢呋喃中,在-45度氩气保护下,滴加入3.37mL正丁基锂溶液(1.6mol/L己烷溶液)。滴加完毕后加入过量的干冰(CO2),室温下搅拌2h。反应结束后旋干溶剂,加入水和乙酸乙酯充分振荡。水相加入盐酸,产生沉淀。将沉淀过滤收集干燥后,得到黄色粉末0.76g,产率62.5%。得到环戊二烯甲酸三羰基锰。
三羰基锝中间体[99mTc(H2O)3(CO)3]+的制备
以环戊二烯甲酸三羰基锰作为一氧化碳供体,以硼氢化钠为还原剂,制备三羰基锝中间体:
称取环戊二烯甲酸三羰基锰100mg、硼氢化钠6mg、酒石酸钾钠20mg、碳酸钠4mg加入青霉素瓶中。加入新鲜99mTcO4
-洗脱液1mL(37MBq),充分振荡,密封后置于手持式紫外灯下(365nm),室温下反应20min。反应结束后用0.1mol/L盐酸调节pH至6~7,溶液通过针式滤器即得到三羰基锝中间体[99mTc(H2O)3(CO)3]+。测得HPLC保留时间为8.9min,标记率98%。
实施例4
以甲基环戊二烯三羰基锰作为一氧化碳供体,以氨硼烷为还原剂,制备三羰基锝中间体:
称取甲基环戊二烯三羰基锰50mg,氨硼烷5mg加入青霉素瓶中。加入浓磷酸10μL,加入新鲜99mTcO4
-洗脱液1mL(37MBq),充分振荡,密封后置于手持式紫外灯下(365nm),室温下反应20min。反应结束后用0.1mol/L氢氧化钠调节pH至6~7,溶液通过针式滤器即得到三羰基锝中间体[99mTc(H2O)3(CO)3]+。测得HPLC保留时间为9.3min,标记率95%。
实施例5
1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵的制备
称取环戊二烯三羰基锰5g溶于60mL无水四氢呋喃中,在-78度氩气保护下,滴加入19.1mL正丁基锂溶液(1.6mol/L己烷溶液)。滴加完毕后加入4.84mL DMF,室温下搅拌2h。反应结束后加入200mL 3N盐酸,再加入200mL水。用己烷萃取,有机相用水洗涤后用无水硫酸钠干燥,旋干得到棕色固体5.37g,产率94.5%。得到环戊二烯甲醛三羰基锰。
将所得环戊二烯甲醛三羰基锰1.5g加入1.75mLDMF中,加入1mL甲酸,避光加热至150~160℃反应3h。反应结束后冷却至室温,加入30mL 3N HCl,用己烷萃取。水相用6N NaOH碱化,然后用乙酸乙酯萃取。有机相用水洗涤后干燥,旋干,得到棕红色油状物0.73g,产率43.4%。得到1-环戊二烯三羰基锰-N,N-二甲基甲烷胺。
称取1-环戊二烯三羰基锰-N,N-二甲基甲烷胺0.73g,溶于2mL丙酮中,在零度氩气保护下,滴加0.8mL碘甲烷。在零度条件下继续搅拌半小时。旋干溶剂后,加入15mL乙腈,将浅黄色固体全部溶解。在室温氩气保护下加入0.266g硼氢化钠,搅拌反应6h。过滤除去少量不溶物,旋干溶剂后,加入二氯甲烷,过滤得到黄色固体0.7g,产率86%。得到-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵。
三羰基锝中间体[99mTc(H2O)3(CO)3]+的制备
以1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵作为一氧化碳供体,同时作为还原剂,制备三羰基锝中间体:
称取1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵5mg加入青霉素瓶中。加入新鲜99mTcO4
-洗脱液1mL(37MBq),充分振荡,密封后置于手持式紫外灯下(365nm),室温下反应20min。反应结束后用0.1mol/L盐酸调节pH至6~7,溶液通过针式滤器即得到三羰基锝中间体[99mTc(H2O)3(CO)3]+。测得HPLC保留时间为9.1min,标记率96%。
实施例6
以十羰基二锰作为一氧化碳供体,以硼氢化钠为还原剂,制备三羰基锝中间体:
称取十羰基二锰5mg、硼氢化钠5.5mg、酒石酸钾钠20mg、碳酸钠4mg加入青霉素瓶中。并向其中加入新鲜99mTcO4
-洗脱液1mL(37MBq),充分振荡,密封后,室温下反应20min。反应结束后用0.1mol/L盐酸调节pH至6~7,溶液通过针式滤器即得到三羰基
锝中间体[99mTc(H2O)3(CO)3]+。测得HPLC保留时间为8.8min,标记率51%。
实施例7
以五羰基溴化锰作为一氧化碳供体,以硼氢化钠为还原剂,制备三羰基锝中间体:
称取五羰基溴化锰5mg、硼氢化钠5.5mg、酒石酸钾钠20mg、碳酸钠4mg加入青霉素瓶中。并向其中加入新鲜99mTcO4
-洗脱液1mL(37MBq),充分振荡,密封后,室温下反应20min。反应结束后用0.1mol/L盐酸调节pH至6~7,溶液通过针式滤器即得到三羰基锝中间体[99mTc(H2O)3(CO)3]+。测得HPLC保留时间为8.9min,标记率98%。
对比例
对比例的三羰基锝中间体[99mTc(H2O)3(CO)3]+通过背景技术部分描述的湿法,即一氧化碳气体存在下,用NaBH4在水相直接还原[99mTcO4]-制得。称取硼氢化钠5.5mg、酒石酸钾钠20mg、碳酸钠4mg加入青霉素瓶中,密封并向瓶中通入CO气体10min。向其中加入新鲜99mTcO4
-洗脱液1mL(37MBq),充分振荡,100度水浴下反应20min。反应结束后用0.1mol/L盐酸调节pH至6~7,溶液通过针式滤器即得到三羰基锝中间体[99mTc(H2O)3(CO)3]+。测得HPLC保留时间为9.1min,标记率98%,所得谱图参见图2。
上述实施例所得三羰基锝中间体均通过薄层层析及放射性高效液相色谱鉴定,其放射化学纯度均大于95%(除采用十羰基二锰作为一氧化碳供体时,实施例6),且在室温下放置4小时后放化纯度无变化,有较好的稳定性。
以下,将本发明实施例所得的三羰基锝中间体[99mTc(H2O)3(CO)3]+用于制备各类三羰基锝标记物。
应用例1
三羰基锝甲氧基异丁基异腈99mTc(CO)3(MIBI)3的制备
将实施例2所得的三羰基锝中间体[99mTc(H2O)3(CO)3]+,调节pH值约6~7。将甲氧基异丁基异腈(MIBI)约10mg溶于0.5mL乙醇中,加入三羰基锝中间体,密封后加热至70℃反应20分钟,制得三羰基锝甲氧基异丁基异腈,通过薄层层析及放射性高效液相色谱鉴定,其放射化学纯度大于98%,在HPLC的保留时间为19.3min,所得谱图参见图3。
应用例2
三羰基锝组氨酸99mTc(CO)3His的制备
将实施例5所得的三羰基锝中间体[99mTc(H2O)3(CO)3]+,调节pH值约6~7。将L-组氨酸约5mg溶于0.5mL水中,加入三羰基锝中间体,密封后加热70度反应20分钟。通过薄层层析及放射性高效液相色谱鉴定,其放射化学纯度大于98%,在HPLC的保留时间为12.4min,所得谱图参见图4。
除非特别限定,本发明所用术语均为本领域技术人员通常理解的含义。
本发明所描述的实施方式仅出于示例性目的,并非用以限制本发明的保护范围,本领域技术人员可在本发明的范围内作出各种其他替换、改变和改进,因而,本发明不限于上述实施方式,而仅由权利要求限定。
Claims (10)
- 一种制备三羰基锝-99m中间体的方法,包括以羰基锰化合物作为一氧化碳供体,与高锝酸根及水反应,制得所述三羰基锝-99m中间体。
- 根据权利要求1所述的方法,其中所述羰基锰化合物选自十羰基二锰、五羰基卤化锰、环戊二烯三羰基锰、甲基环戊二烯三羰基锰、环戊二烯甲酸三羰基锰及1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵中的一种或多种。
- 根据权利要求2所述的方法,包括将所述高锝酸根在还原剂的作用下与所述羰基锰化合物及水反应,制得所述三羰基锝-99m中间体;其中,所述羰基锰化合物选自十羰基二锰和/或五羰基卤化锰。
- 根据权利要求2所述的方法,包括将所述高锝酸根在还原剂的作用下,通过紫外光照射与所述羰基锰化合物及水反应,制得所述三羰基锝-99m中间体;其中,所述羰基锰化合物选自环戊二烯三羰基锰、甲基环戊二烯三羰基锰及环戊二烯甲酸三羰基锰中的一种或多种。
- 根据权利要求3或4所述的方法,其中所述还原剂为硼氢化钠或氨硼烷。
- 根据权利要求5所述的方法,包括将所述羰基锰化合物、还原剂硼氢化钠、酒石酸钾钠、碳酸钠及高锝酸根水溶液混合后,在紫外光照射下反应10~30分钟,制得所述三羰基锝-99m中间体;或者将所述羰基锰化合物、还原剂氨硼烷、浓磷酸及高锝酸根水溶液混合后,在紫外光照射下反应10~30分钟,制得所述三羰基锝-99m中间体;其中,所述羰基锰化合物选自环戊二烯三羰基锰、甲基环戊二烯三羰基锰、环戊二烯甲酸三羰基锰中的一种或多种。
- 根据权利要求2所述的方法,包括将所述高锝酸根在紫外光照射的作用下与1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵及水反应,制得所述三羰基锝-99m中间体。
- 根据权利要求4或7所述的方法,其中所述紫外光的波长为300~400nm时,选用玻璃容器作为反应容器。
- 根据权利要求7所述的方法,其中所述1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵的制备方法包括:将环戊二烯三羰基锰在正丁基锂的作用下与二甲基甲酰胺反应,制得环戊二烯甲醛三羰基锰;将所述环戊二烯甲醛三羰基锰在二甲基甲酰胺及甲酸的作用下,反应得到1-环戊二 烯三羰基锰-N,N-二甲基甲烷胺;以及将所述1-环戊二烯三羰基锰-N,N-二甲基甲烷胺在碘甲烷及硼氢化钠的作用下,反应得到所述1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵。
- 根据权利要求7所述的方法,包括将所述1-环戊二烯三羰基锰-N,N,N-三甲基硼氢化甲铵与高锝酸根水溶液混合后,在紫外光照射下反应10~30分钟,制得所述三羰基锝-99m中间体。
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---|
ALBERTO R ET AL.: "A Novel Organometallic Aqua Complex of Technetium for the Labeling of Biomolecules: Synthesis of [99mTc (OH2) 3 (CO) 3]+ from [99mTc04]-in Aqueous Solution and Its Reaction with a Bifunctional Ligand", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 120, no. 31, 24 July 1998 (1998-07-24), pages 7987 - 7988, XP002380957, ISSN: 0002-7863 * |
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