CN105524113A - 99mTcN nucleus-marked glucose dithiocarbamate complex containing triazole ring and preparation method and application of glucose dithiocarbamate complex - Google Patents
99mTcN nucleus-marked glucose dithiocarbamate complex containing triazole ring and preparation method and application of glucose dithiocarbamate complex Download PDFInfo
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- CN105524113A CN105524113A CN201610123746.0A CN201610123746A CN105524113A CN 105524113 A CN105524113 A CN 105524113A CN 201610123746 A CN201610123746 A CN 201610123746A CN 105524113 A CN105524113 A CN 105524113A
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- tagdtc
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- glucose
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- OSQPMEBEJDAVFQ-BTVCFUMJSA-N carbamodithioic acid (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound C(N)(S)=S.O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO OSQPMEBEJDAVFQ-BTVCFUMJSA-N 0.000 title abstract description 6
- 125000001425 triazolyl group Chemical group 0.000 title abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 36
- 239000003446 ligand Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000004821 distillation Methods 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- -1 butyl-propargyl acid amides Chemical group 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 102100033884 GPN-loop GTPase 3 Human genes 0.000 claims description 3
- 101001068964 Homo sapiens GPN-loop GTPase 3 Proteins 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 3
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 238000009206 nuclear medicine Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- 241000699670 Mus sp. Species 0.000 abstract description 8
- 238000003384 imaging method Methods 0.000 abstract description 6
- 210000003205 muscle Anatomy 0.000 abstract description 5
- 238000002603 single-photon emission computed tomography Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 2
- 239000012216 imaging agent Substances 0.000 abstract description 2
- 230000014759 maintenance of location Effects 0.000 abstract 1
- 239000013110 organic ligand Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 240000002853 Nelumbo nucifera Species 0.000 description 7
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 7
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 7
- 206010039491 Sarcoma Diseases 0.000 description 7
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000002474 experimental method Methods 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
- 239000000126 substance Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZCXUVYAZINUVJD-AHXZWLDOSA-N 2-deoxy-2-((18)F)fluoro-alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O ZCXUVYAZINUVJD-AHXZWLDOSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 239000004952 Polyamide Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000002303 glucose derivatives Chemical class 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229920002647 polyamide Polymers 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- XNCSCQSQSGDGES-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]propyl-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)C(C)CN(CC(O)=O)CC(O)=O XNCSCQSQSGDGES-UHFFFAOYSA-N 0.000 description 1
- SYWGIQGTUMHSRZ-YEPTVKRMSA-L 3-oxo-2-[2-[1-oxo-3-sulfido-1-[[(2r,4r)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]amino]propan-2-yl]azanidylethylazanidyl]-3-[[(2r,4s,5s)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]amino]propane-1-thiolate;technetium-99(4+) Chemical compound [99Tc+4].O[C@H]1C(O)C(CO)O[C@@H](O)C1NC(=O)C(C[S-])[N-]CC[N-]C(C[S-])C(=O)NC1[C@H](O)[C@H](O)C(CO)O[C@H]1O SYWGIQGTUMHSRZ-YEPTVKRMSA-L 0.000 description 1
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- 102000005548 Hexokinase Human genes 0.000 description 1
- 108700040460 Hexokinases Proteins 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical group NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 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 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000004659 dithiocarbamates Chemical class 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- 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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses 99mTcN(TAGDTC)2 complex and a preparation method and application thereof. The 99mTcN(TAGDTC)2 complex uses a 99mTcN nucleus as the central nucleus, the glucose dithiocarbamate containing a triazole ring is used as the organic ligand coordinated with the central nucleus, and the 99mTcN(TAGDTC)2 complex is prepared by synthesizing the ligand TAGDTC. The complex is high in radiochemical purity, good in stability, high in uptake and good in retention in the tumor parts of tumor-bearing mice, high in tumor/muscle ratio, good in SPECT tumor imaging effect and capable of being popularized and used as a novel tumor imaging agent.
Description
Art
The present invention relates to
99mthe radiopharmaceutical chemistry of Tc mark and clinical nuclear medicine technical field, relate to one specifically
99mtcN core mark contains glucose dithiocarbamate complexes and the preparation method and application of triazole ring.
Background technology
Current, cancer has become first of the disease cause of the death, and M & M is also soaring, causes grave danger to public health.In order to reduce the mortality ratio of malignant tumour and improve curative ratio, early diagnosis tool is carried out to it and is of great significance.Radionuclide tumor imaging can the molecular biology behavior of noninvasive detection tumour and physiopathologic change, accurately can detect the position of focus, specificity is high, nowadays nucleic Tumor imaging techniques has become a large class detection means of cancer diagnosis, particularly along with the use of SPECT-CT, PET-CT, radionuclide tumor imaging is one of advantage becoming nuclear medicine diagnostic.
In tumor imaging medicament,
18f-fluorodeoxyglucose (
18f-FDG) be clinical at present in most widely used tumor developer, its clinical value gains public acceptance.In human body
18f-FDG can enter tumour cell through glucose transporter, then through hexokinase effect be converted into 6-phosphoric acid-
18f-FDG, 6-phosphoric acid-
18f-FDG enters tumour cell can not metabolism further, 6-phosphoric acid simultaneously-
18f-FDG is electronegative freely can not pass through cytolemma, is finally trapped in tumour cell.But
18f-FDG is a kind of pet imaging agent, positron radionuclide [
18f] need to be produced by accelerator, expensive, limit its applying in clinical diagnosis to a certain extent.And
99mtc has excellent nulcear properties, and
99mo-
99msucceeding in developing of Tc producer makes
99mtc radiopharmaceuticals is easy to prepare, can medicine box, cheap and easy to get, reliable in quality, therefore
99mthe glucose tumor developer of Tc mark becomes radiopharmaceutic study hotspot.
Up to now,
99mtc labelled glucose derivative majority is still in the laboratory study stage, only has
99mtc-ethylenedicysteine-deoxyglucose (referred to as
99mtc-ECDG) enter II phase clinical investigation phase, but there is tumor uptake value and the shortcoming such as tumour/blood is on the low side, therefore the excellent property of development of new further
99mtc labelled glucose class tumor developer has important practical significance.
Click chemistry is a kind of modularization synthetic method of new development, conveniently be easy to get because it has raw material, easy reaction, reaction conditions is gentle, insensitive to oxygen G&W, good product selectivity, productive rate is high, and the advantage such as the easy purifying of product, aftertreatment are simple receives the very big concern of vast chemical research person.The particularly nitrine of Cu (I) catalysis and 1 of alkynes, the triazole ring that 3-Dipolar Cycloaddition generates has higher stability, good water-soluble and certain biological activity, reduce the fat-soluble of title complex when the tie as connection metal radionuclide and biomolecules, Click chemistry is used widely in recent years in radiopharmaceuticals synthesis.
Due to
99mthe chemical stability of TcN triple bond is good, and the bio distribution character of its corresponding title complex with [
99mtcO]
3+core or [
99mtcO
2]
+caryogamy compound has larger difference, thus
99mthe research of TcN caryogamy compound causes the extensive concern of people.Especially with SDH (succinyl two hydrazides, H
2nNHCOCH
2cH
2cONHNH
2) as N
3-ion donor, SnCl
2as reductive agent at room temperature successfully prepare [
99mtcN]
2+the method of intermediate makes a breakthrough, for novel [
99mtcN]
2+radiopharmaceutic research and development is had laid a good foundation.
Successfully preparing
99mtcN (DGDTC)
2(JunboZhang, JialeiRen, XiaoLin, XuebinWang.Synthesisandbiologicalevaluationofanovel on the basis of title complex
99mtcnitridoradiopharmaceuticalwithdeoxyglucosedithiocarbam ate, showingtumoruptake [J], Bioorganic & MedicinalChemistryLetters, 2009,19:2752 – 2754), in order to improve its tumor uptake value and tumour/muscle ratio deficiency on the low side, the present invention uses Click chemistry, by ingenious for glucose be converted into containing triazole ring glucose dithiocarbamate part (referred to as: TAGDTC), then utilize sulphur atom in dithiocarbamate part with
99mtcN caryogamy position is formed stable
99mtcN Seleroglucar dithiocarbamate complexes seeks novel tumor molecular probe, has important scientific meaning and application and development value.
Summary of the invention
The object of this invention is to provide that a kind of radiochemical purity is high, good stability, be applied in tumor imaging field
99mthe glucose dithiocarbamate complexes containing triazole ring of TcN core mark, also provides its preparation method simultaneously.
In order to achieve the above object, the present invention by the following technical solutions: a kind of
99mtcN core mark containing triazole ring glucose dithiocarbamate complexes (
99mtcN (TAGDTC)
2), its structural formula is:
In this structural formula: with [
99mtcN]
2+core centered by core, in two TAGDTC ligand moleculars 4 sulphur atoms with
99mtc coordination obtains
99mtcN (TAGDTC)
2title complex.
99mtcN (TAGDTC)
2the preparation method of title complex is as follows:
A: the synthesis of part TAGDTC:
Its synthetic route is:
The first step: appropriate GPN3 and the tertiary butyl-propargyl acid amides are placed in 50mL two mouthfuls of flasks, adds tetrahydrofuran (THF) and dissolves, then add and be dissolved with cupric sulfate pentahydrate and ascorbic a small amount of aqueous solution, stirred at ambient temperature, and under condition of nitrogen gas, reaction is spent the night.After reaction terminates, underpressure distillation obtains faint yellow solid, adds a small amount of water dissolution, is extracted with ethyl acetate 3 times, merges organic phase and uses anhydrous MgSO
4dry.Underpressure distillation is except desolventizing, and silica column purification (petroleum ether-ethyl acetate) obtains light yellow solid.
Second step: be dissolved in methyl alcohol by appropriate the first step product, adds 1mol/LHCl and regulates pH ~ 2, reacting by heating 4h at 60 DEG C.Saturated NaHCO is added after reaction terminates
3solution is adjusted to neutrality, with dichloromethane extraction, is separated organic phase, and dry, filtration is rear except desolventizing.Residue is dissolved in 50mL methyl alcohol, adds appropriate KOH, stirred at ambient temperature 3h.Reaction terminates rear 1mol/LHCl and regulates pH to neutral, and underpressure distillation, except desolventizing, adds ethanol, filters, and collects filtrate, except desolventizing obtains crude product.This crude product is dissolved in suitable quantity of water, adds a certain amount of KOH, under ice-water bath condition, drip CS
2, continue to be placed in ice-water bath and react 1h.After reaction terminates, underpressure distillation is except desolventizing, and ethyl alcohol recrystallization obtains light yellow solid TAGDTC.
B:
99mtcN (TAGDTC)
2the preparation of title complex:
99mtcN (TAGDTC)
2preparation adopt ligand exchange reaction, reaction scheme is as follows:
99mTcO
4 -+SDH+SnCl
2·2H
2O+PDTA→[
99mTcN]
int 2+
[
99mTcN]
int 2++TAGDTC→
99mTcN(TAGDTC)
2
Concrete steps are: by proper amount of fresh
99mtcO
4 -leacheate joins containing succinyl two hydrazides (SDH), 1,2-trimethylenedinitrilo-tertraacetic acid, SnCl
22H
2in the SDH froze-dried kit of O, after shaking up, under room temperature, react 15min, obtain [
99mtcN]
2+intermediate.Then by 1mL concentration be the TAGDTC aqueous solution of 1g/L join above-mentioned preparation [
99mtcN]
2+in intermediate, in boiling water bath, react 20min after mixing namely obtain described
99mtcN (TAGDTC)
2title complex.
Above-mentioned chemical reagent used is all commercial goods, and wide material sources, easily obtain; SDH froze-dried kit is provided by Beijing Shihong Pharmaceutical Research Center.
Prepared by aforesaid method
99mtcN (TAGDTC)
2the radiochemical purity of title complex is greater than 90%, its vitro stability is good, and in tumor-bearing mice tumour, have the delay that high picked-up is become reconciled, tumour/muscle ratio is high, it is obvious dense poly-that SPECT video picture shows that tumor locus has, and can become a kind of novel tumor developer.
Will
99mtcN (TAGDTC)
2title complex with
99mtcN (DGDTC) is respectively being injected in lotus S180 sarcoma Mice Body after 2h, and its Biodistribution data compares, and the results are shown in Table 1.
Table 1
99mtcN (TAGDTC)
2with
99mtcN (DGDTC)
2in lotus S180 sarcoma Biodistribution in mice data (x ± s, %ID/g) after injection 2h
Above result shows,
99mtcN (TAGDTC)
2with
99mtcN (DGDTC)
2tumour/blood the ratio of title complex is more or less the same, but the former tumor uptake and tumour/muscle ratio are significantly increased than the latter,
99mtcN (TAGDTC)
2close tumour performance to obviously be better than
99mtcN (DGDTC)
2, have broad application prospects as a kind of Novel grape carbohydrate tumor developer.
Experiment shows,
99mtcN (TAGDTC)
2the performance of title complex is as follows:
1.
99mtcN (TAGDTC)
2the chromatography qualification of title complex
Thin-layer chromatography chromatogram (TLC) is identified: two kinds of systems of employing are respectively, and polyamide layer is as support, and acetonitrile is as developping agent; Polyamide layer is support, and physiological saline is developping agent.The tomographic results measured is in table 2.
The R of each component of table 2
fvalue
The radiochemical purity of the marker measured by above-mentioned chromatography is identified is greater than 90%.
2.
99mtcN (TAGDTC)
2the mensuration of the lipid of title complex
The phosphate buffered saline buffer (0.025mol/L) getting 0.98mLpH7.4, in 10mL centrifuge tube, adds 1.0mL n-Octanol and 0.02mL in centrifuge tube
99mtcN (TAGDTC)
2complex solution, cover stopper, fully shake up, centrifugal 5min (5000rpm), then from organic phase and aqueous phase, take out 0.1mL respectively, measure the radiocounting of two-phase and calculate logP value (radioactive activity of the radioactive activity/aqueous phase of P=organic phase).
99mtcN (TAGDTC)
2lipid logP=-0.97 ± 0.01, illustrate that it is a hydroaropic substance.
3.
99mtcN (TAGDTC)
2the Stability Determination of title complex
By what marked
99mtcN (TAGDTC)
2title complex respectively at room temperature and in 37 DEG C of mice serums, place different time (1,2,3,4,5,6 hour) measure its radiochemical purity afterwards, experimental result shows that this title complex is placed radiochemical purity after 6 hours at room temperature and in 37 DEG C of mice serums and is all greater than 90%, illustrates that its vitro stability is good.
4.
99mtcN (TAGDTC)
2the biodistribution experiments of title complex in lotus S180 sarcoma mouse model
From the tail vein injection 0.10mL complex solution (about 7.4 × 10 of the kunming mice (female, body weight is about 18-20g) of lotus S-180 sarcoma model
5bq), after injection respectively at 0.5h, 2h, 4h sacrificed by decapitation.Get related organization and the organs such as its heart, liver, lung, kidney, spleen, intestines, muscle, bone, blood, tumour, weigh after cleaning, and survey its radiocounting with technetium analyser, the tumor-bearing mice number of each phase is 5.Calculate every gram of percentage injected dose (%ID/g) of each tissue, the results are shown in Table 3.
Table 3
99mtcN (TAGDTC)
2the bio distribution (x ± s, %ID/g) of title complex in lotus S180 sarcoma mouse model
5.
99mtcN (TAGDTC)
2the SPECT video picture experiment of title complex in lotus S-180 sarcoma Mice Body
0.1mL is marked
99mtcN (TAGDTC)
2(about 1.85 × 10
7bq) kunming mice (female, body weight is about 18-20g) from tail vein injection to lotus S-180 sarcoma model, carries out SPECT video picture after 4h.SPECT image results shows
99mtcN (TAGDTC)
2title complex has obvious dense poly-at tumor locus, tumour and the non-target ratio of region of interest (ROI) reach 8.92, further demonstrate that
99mtcN (TAGDTC)
2title complex can as a kind of novel tumor developer of excellent property.
Embodiment:
Below by embodiment in detail the present invention is described in detail:
A kind of
99mtcN core mark containing triazole ring glucose dithiocarbamate complexes (
99mtcN (TAGDTC)
2), its structural formula is:
In this structural formula: with [
99mtcN]
2+core centered by core, in two TAGDTC ligand moleculars 4 sulphur atoms with
99mtc coordination obtains
99mtcN (TAGDTC)
2title complex.
99mtcN (TAGDTC)
2the preparation method of title complex is as follows:
A. the synthesis of part TAGDTC:
The first step: by GPN3 (5mmol, 2.16g) with the tertiary butyl-propargyl acid amides (5mmol, 0.78g) be placed in 50mL two mouthfuls of flasks, add 50mL tetrahydrofuran (THF) to dissolve, add again and be dissolved with 90mg cupric sulfate pentahydrate and the ascorbic a small amount of aqueous solution of 180mg, stirred at ambient temperature, under condition of nitrogen gas, reaction is spent the night.After reaction terminates, underpressure distillation obtains faint yellow solid, adds 20mL water dissolution, with ethyl acetate (3 × 10mL) extraction, merges organic phase and uses anhydrous MgSO
4dry.Underpressure distillation is except desolventizing, and silica column purification (petroleum ether-ethyl acetate) obtains light yellow solid.
1H-NMR(400MHz,CDCl
3):δ(ppm)7.57(s,1H),5.19-5.24(t,1H),5.06-5.11(t,1H),4.98-5.03(m,1H),4.43-4.46(t,2H),4.38-4.39(d,4H),4.09-4.12(t,2H),3.84-3.88(m,1H),3.71-3.74(m,1H),3.47-3.53(m,1H),2.22-2.29(m,2H),2.01-2.08(m,12H),1.44(s,9H).
13CNMR(400MHz,CDCl
3):δ(ppm)170.34,170.15,169.70,169.01,168.96,155.43,145.09,121.83,100.19,79.12,72.18,71.32,70.71,67.77,65.38,61.26,60.38,46.64,35.48,28.83,27.86,20.33,20.24,20.09.MS(ESI):587.4(MH
+)。
Second step: be dissolved in 50mL methyl alcohol by appropriate the first step product, adds 1mol/LHCl and regulates pH ~ 2, reacting by heating 4h at 60 DEG C.Saturated NaHCO is added after reaction terminates
3solution is adjusted to neutrality, with dichloromethane extraction, is separated organic phase, and dry, filtration is rear except desolventizing.Residue is dissolved in 50mL methyl alcohol, adds KOH (8mmol, 0.45g), stirred at ambient temperature 3h.Reaction terminates rear 1mol/LHCl and regulates pH to neutral, and underpressure distillation, except desolventizing, adds ethanol, filters, and collects filtrate, except desolventizing obtains crude product.This crude product is dissolved in 30mL water, adds 113mgKOH, under ice-water bath condition, drip 0.2mLCS
2, continue to be placed in ice-water bath and react 1h.After reaction terminates, underpressure distillation is except desolventizing, and ethyl alcohol recrystallization obtains light yellow solid TAGDTC.IR(KBr)/cm
-1:3449(νOH),1036(νC＝S).
1H-NMR(400MHz,CDCl
3):δ(ppm)7.84-7.91(m,1H),4.34-4.47(m,4H),3.81-3.91(d,2H),3.63-3.67(m,2H),3.19-3.52(m,8H).
13C-NMR(400MHz,CDCl
3):δ(ppm)215.143,184.044,147.030,126.623,62.973,60.808,49.850,45.122,34.398,26.363,25.963.MS(ESI):393.1(M-K
-)。
B.
99mtcN (TAGDTC)
2the preparation of title complex
Fresh by 37 ~ 370MBq
99mtcO
4 -leacheate 0.5 ~ 1mL joins in SDH froze-dried kit, after shaking up, reacts 15min under room temperature, obtain [
99mtcN]
2+intermediate.Then by 1mL concentration be the TAGDTC aqueous solution of 1g/L join above-mentioned preparation [
99mtcN]
2+in intermediate, in boiling water bath, react 20min after mixing namely obtain described
99mtcN (TAGDTC)
2title complex.
Claims (3)
1. one kind
99mtcN (TAGDTC)
2title complex, its structural formula is as follows:
In this structural formula: with [
99mtcN]
2+core centered by core, in two TAGDTC ligand moleculars 4 sulphur atoms with
99mtc coordination obtains
99mtcN (TAGDTC)
2title complex.
2. as claimed in claim 1
99mtcN (TAGDTC)
2the preparation method of title complex, its processing step is as follows:
A: the synthesis of part TAGDTC:
The first step: appropriate GPN3 and the tertiary butyl-propargyl acid amides are placed in 50mL two mouthfuls of flasks, add tetrahydrofuran (THF) to dissolve, add again and be dissolved with cupric sulfate pentahydrate and ascorbic a small amount of aqueous solution, stirred at ambient temperature, under condition of nitrogen gas, reaction is spent the night, after reaction terminates, underpressure distillation obtains faint yellow solid, add a small amount of water dissolution, be extracted with ethyl acetate 3 times, merge organic phase and use anhydrous MgSO
4drying, underpressure distillation is except desolventizing, and silica column purification obtains light yellow solid;
Second step: be dissolved in methyl alcohol by appropriate the first step product, adds 1mol/LHCl and regulates pH ~ 2, reacting by heating 4h at 60 DEG C; Saturated NaHCO is added after reaction terminates
3solution is adjusted to neutrality, with dichloromethane extraction, is separated organic phase, and dry, filtration is rear except desolventizing; Residue is dissolved in 50mL methyl alcohol, adds appropriate KOH, stirred at ambient temperature 3h; Reaction terminates rear 1mol/LHCl and regulates pH to neutral, and underpressure distillation, except desolventizing, adds ethanol, filters, and collects filtrate, except desolventizing obtains crude product; This crude product is dissolved in suitable quantity of water, adds a certain amount of KOH, under ice-water bath condition, drip CS
2, continue to be placed in ice-water bath and react 1h, after reaction terminates, underpressure distillation is except desolventizing, and ethyl alcohol recrystallization obtains light yellow solid TAGDTC;
B:
99mtcN (TAGDTC)
2the preparation of title complex:
By proper amount of fresh
99mtcO
4 -leacheate joins containing succinyl two hydrazides, 1,2-trimethylenedinitrilo-tertraacetic acid, SnCl
22H
2in the SDH froze-dried kit of O, after shaking up, under room temperature, react 15min, obtain [
99mtcN]
2+intermediate, then by 1mL concentration be the TAGDTC aqueous solution of 1g/L join above-mentioned preparation [
99mtcN]
2+in intermediate, in boiling water bath, react 20min after mixing namely obtain described
99mtcN (TAGDTC)
2title complex.
3. described as claimed in claim 1
99mtcN (TAGDTC)
2title complex prepares the application in tumor developer in nuclear medicine image field.
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| CN101423535A (en) * | 2008-12-12 | 2009-05-06 | 北京师范大学 | <99m>TcN(DGDTC)2 complexes as well as preparation method and use thereof |
| CN102977174A (en) * | 2012-12-19 | 2013-03-20 | 北京师范大学 | 99mTc(CO)3 nuclear-labeled macrocyclic polyamine triazole ring glucose-based complex as well as preparation and application of complex |
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| CN106008636B (en) * | 2016-06-23 | 2018-03-09 | 北京师范大学 | Tc 99m labelled glucose dithiocarbamate complexes and preparation method and application |
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Address after: 100875 School of chemistry, Beijing Normal University, 19 Xinjie street, Haidian District, Beijing Patentee after: BEIJING NORMAL University Patentee after: Beijing Shihong Pharmaceutical Co., Ltd Address before: 100875 School of chemistry, Beijing Normal University, 19 Xinjie street, Haidian District, Beijing Patentee before: BEIJING NORMAL University Patentee before: Beijing Shihong drug development center |