CN105963724A - {0><}0{>Radio-labeled tumor developing agent as well as preparation method and application thereof - Google Patents
{0><}0{>Radio-labeled tumor developing agent as well as preparation method and application thereof Download PDFInfo
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- CN105963724A CN105963724A CN201610307569.1A CN201610307569A CN105963724A CN 105963724 A CN105963724 A CN 105963724A CN 201610307569 A CN201610307569 A CN 201610307569A CN 105963724 A CN105963724 A CN 105963724A
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 238000002372 labelling Methods 0.000 claims abstract description 36
- 239000000126 substance Substances 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- 238000005406 washing Methods 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 7
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- 150000001450 anions Chemical class 0.000 claims description 5
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 5
- 239000004327 boric acid Substances 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 208000035126 Facies Diseases 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 229940125782 compound 2 Drugs 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
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- WFJZBOIOPMOUCB-UHFFFAOYSA-N pyridazine;hydrochloride Chemical compound Cl.C1=CC=NN=C1 WFJZBOIOPMOUCB-UHFFFAOYSA-N 0.000 claims description 3
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 3
- 229960005055 sodium ascorbate Drugs 0.000 claims description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 3
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 3
- CKMXBZGNNVIXHC-UHFFFAOYSA-L ammonium magnesium phosphate hexahydrate Chemical compound [NH4+].O.O.O.O.O.O.[Mg+2].[O-]P([O-])([O-])=O CKMXBZGNNVIXHC-UHFFFAOYSA-L 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- 229910052567 struvite Inorganic materials 0.000 claims description 2
- 238000002242 deionisation method Methods 0.000 claims 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims 1
- 239000007853 buffer solution Substances 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 abstract description 38
- 235000019152 folic acid Nutrition 0.000 abstract description 22
- 239000011724 folic acid Substances 0.000 abstract description 22
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 abstract description 16
- 229960000304 folic acid Drugs 0.000 abstract description 16
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 230000008685 targeting Effects 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 5
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 abstract description 3
- 235000008206 alpha-amino acids Nutrition 0.000 abstract 2
- 235000001014 amino acid Nutrition 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 210000003734 kidney Anatomy 0.000 description 7
- -1 methoxyl group Chemical group 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 238000012879 PET imaging Methods 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 229940064302 folacin Drugs 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 240000002853 Nelumbo nucifera Species 0.000 description 4
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 4
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- ZMHWUUMELDFBCZ-UHFFFAOYSA-N copper(1+);hydrate Chemical compound O.[Cu+] ZMHWUUMELDFBCZ-UHFFFAOYSA-N 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- MKWJZTFMDWSRIH-UHFFFAOYSA-N (4-fluoro-3-nitrophenyl)methanol Chemical compound OCC1=CC=C(F)C([N+]([O-])=O)=C1 MKWJZTFMDWSRIH-UHFFFAOYSA-N 0.000 description 1
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 239000002028 Biomass Substances 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- ZMQBBPRAZLACCW-UHFFFAOYSA-N acetic acid;dichloromethane Chemical compound ClCCl.CC(O)=O ZMQBBPRAZLACCW-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000005202 decontamination Methods 0.000 description 1
- 230000003588 decontaminative effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 108020005243 folate receptor Chemical class 0.000 description 1
- 102000006815 folate receptor Human genes 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000003141 isotope labeling method Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 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
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052756 noble gas Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 230000008672 reprogramming Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 239000005460 tetrahydrofolate Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000012991 uterine carcinoma Diseases 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
-
- 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
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
-
- 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
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
{0><}0{>The invention discloses a radio-labeled tumor developing agent as well as a preparation method and application thereof. <0}{0><}0{>The radio-labeled tumor developing agent structurally contains an alpha-amino acid derivate structure capable of labeling nuclide and a tumor-targeted folic acid molecule, wherein radionuclide is 18F, and the alpha-amino acid derivate structure and the folic acid molecule are connected in a specific chemical mode. <0}{0><}0{>The invention further relates to a preparation method of the compound and application of the compound serving as a tracing developing agent in PET development in a human body or an animal body. The radio-labeled tumor developing agent has the advantages of simplicity in preparation, low price and strong targeting property especially when serving as a tumor developing agent.
Description
Technical field
The invention belongs to Medical Imaging Technology field, be specifically related to one18The tumor developer of F labelling, its preparation method
And application.
Background technology
A-amino acid is the construction unit of protein, plays vital work in neurotransmitter and ATP energy convert
With.A-amino acid is also tumor cell existence and the necessary nutrient substance of propagation simultaneously, and most tumors all can be to amino
The high picked-up of acid, this can cause again the higher picked-up of high-level tumor and the transfer of tumor.Aminoacid is that the signal of tumor proliferation divides
Son, also functions to the effect of the reprogramming metabolism network biomass accumulation relevant to tumor.
It addition, folacin receptor high expressed in many tumor tissues, as ovarian cancer, renal carcinoma, uterus carcinoma, carcinoma of testis, the brain cancer,
Colon cancer, adenocarcinoma of lung etc..Folate molecule has the highest selectivity to these tumors.
CN103827057A discloses a kind of quilt18The novel compound of F labelling and corresponding warp18The compound of F labelling
, its their warp own19The analog of F fluorination and its they as reference standard purposes, prepare the side of this compounds
Method, the compositions comprising this compounds, comprise this compounds or the test kit of compositions and this compounds, compositions
Or test kit is for the purposes of the diagnosing image by pet Positron Emission Tomography imaging (PET).
CN101723850A discloses a class Novel radioactive18F labelling ArAA, breaks for tumor positron emission
Layer (PET) imaging research, it is characterised in that: one end has F substituted alkoxy benzoyl structure;The other end has a-amino acid
Structure, substituent R 1 is positioned in alpha site of carboxyl group, and R1 is phenyl, benzyl, 3-indole methyl, and R2 is methoxyl group, and n is 1-5.R1 is benzene
Base, benzyl, 3-indole methyl, R2 is methoxyl group, and n is 1-5.
CN101723847A discloses one18F labelling p-nitrophenyl benzoyl amino acid compound, is characterized in that: with
Time there is 2-18F-4-Nitrobenzol formyl and a-amino acid structure, and substituted base R is positioned in alpha site of carboxyl group, for hydrogen, methyl, second
Base, propyl group, isopropyl, butyl, isobutyl group, benzyl, 2-methylmercaptoethyl, carboxyethyl, carboxylic propyl group, phenyl, imidazolmethyl.Two ends
Structure is joined directly together by amido link.
CN102126985A discloses18F labelled precursor compound, further simultaneously discloses its preparation method, include successively with
Lower step: 1) synthesis of labelled precursor compound: by 3,4-dinitrobenzoic acid, amino alkynes, 1-(3-dimethylamino-propyl)-3-
Ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole are dissolved in dimethylformamide, stirring reaction;The product of reaction gained
Post-treated, obtain precursor compound;2) labelling of precursor compound.Above-mentioned18F labelled precursor compound can use click
The method labeled amino acid of chemistry, polypeptide compounds;Also PET imaging can be applied to as molecular image probe.
Bioconjugate Chem., 2008,19,2462 2470 disclose a kind of with18The folacin compound of F labelling,
It is characterized in that: use18F-P-toluenesulfonyl anion on ion nucleophilic displacement of fluorine labelled precursor, then utilizes click
The method labeled leaf acid compounds of chemistry, and it is applied to PET imaging.
But, in the above prior art, most little molecular imaging probes often comprise only a group with targeting,
Produce the delay of target organ for receptor or some physical factor, but non-target organ is probably due to have similar receptor or have
The high picked-up same to probe of similar physical property, thus cause target to non-target ratio value the highest.
Summary of the invention
It is an object of the invention to overcome aminoacid targeting not strong, and folic acid is in the problem of the high picked-up of kidney, simultaneously
Have the picked-up of amino acid whose tumor height and the folic acid advantage in the targeting picked-up of tumor concurrently, it is provided that a kind of folic acid and a-amino acid
Derivant coupling18The tumor developer of F labelling, its preparation method and application, and by PET imaging use it for tumor or its
The diagnosis of his disease or curative effect evaluation.
One of the technical solution adopted for the present invention to solve the technical problems is:
A kind of18The tumor developer of F labelling, shown in the following formula I of its structural formula:
The two of the technical solution adopted for the present invention to solve the technical problems are:
A kind of above-mentioned18The preparation method of the tumor developer of F labelling, shown in the following reaction scheme of this preparation method:
Including:
1) in the first organic solvent, under purity titanium tetraethoxide catalysis, compound 1 and compound 2 according to mol ratio 1:1~
The ratio of 1.5, at room temperature reacts overnight;After adding saturated nacl aqueous solution cancellation, kieselguhr filters, and filtrate takes organic facies,
Washing is dried, and removes solvent, and the dichloromethane-ethyl acetate mixed liquor drip washing of crude product volume ratio 10~20:1 carries out silica gel
Column chromatography purification, obtains compound 3;
2) under inert gas shielding, in a second organic solvent, (1,3-dicyclohexyl-2-subunit) tertiary fourth oxygen copper (I) is urged
Under change, compound 3 and compound 4, according to mol ratio 1:1.5~the ratio of 2.5, react 20~48h at-5~5 DEG C;Remove molten
Agent, the dichloromethane-ethyl acetate mixed liquor drip washing of crude product volume ratio 10~20:1 carries out silica gel chromatography, obtains
Compound 5;
3) under inert gas shielding, in the 3rd organic solvent, under hydrogen chloride effect, the first of compound 5 and 5~15 equivalent
Alcohol at room temperature reacts 0.5~3h, generates compound 6;
4) in the 4th organic solvent, under hydrogen chloride effect, compound 6 and KHF2At room temperature reaction 15~25h, removes
Solvent, the dichloromethane-ethyl acetate mixed liquor drip washing of crude product volume ratio 10~20:1 carries out silica gel chromatography,
To compound 7-1;
5) in the mixed solution of pyridazine-hydrochloride buffer that pH value is 1~3 and DMF, 5~20mCi18F and compound
7-1 reacts 5~20min at 50~100 DEG C, generates compound 7-2, is compound shown in formula II;
6), in water, under the catalysis of copper sulfate and sodium ascorbate, compound 7-2 and compound 8 are 50~100 DEG C of reactions
5~20min, generate compound 9, be shown in formula I18The tumor developer of F labelling.
In one embodiment: described step 5) including:
A) will18F gets off with potassium carbonate, Kryptofix 2.2.2 mixed solution drip washing from anion trapping column;
B) compound 7-1 is dissolved in N,N-dimethylformamide that volume ratio is 1:0.8~1.2 and pH value is 1~3 to rattle away
In piperazine-hydrochloride buffer;
C) product of step a) with step b) is mixed, at 50~100 DEG C, react 5~30min, cooling, then add and go in right amount
After ionized water dilution, with boric acid and volume ratio 1:0.5~volume ratio 1:1.5 of the PBS-ethanol solution of 1.5~the mixed liquor of 2.5
Carry out C18 column purification as eluent, obtain compound 7-2.
In one embodiment: described first organic solvent, the second organic solvent, the 3rd organic solvent, the 4th organic solvent are
Oxolane, toluene, Isosorbide-5-Nitrae-dioxane, the one in DMF, and can be identical or different.
In one embodiment: described step 3) in, hydrogen chloride is the Isosorbide-5-Nitrae-dioxane solution of the hydrogen chloride of concentration 4M.
In one embodiment: described step 4) in, hydrogen cloride concentration is 4M.
The three of the technical solution adopted for the present invention to solve the technical problems are:
Above-mentioned18The application in preparation tumor or struvite relevant disease developer of the tumor developer of F labelling.
The four of the technical solution adopted for the present invention to solve the technical problems are:
One can be used for preparing above-mentioned18The compound of the tumor developer of F labelling, shown in the following formula II of its structural formula:
The five of the technical solution adopted for the present invention to solve the technical problems are:
The preparation method of compound shown in a kind of above-mentioned formula II, including:
A) will18F gets off with potassium carbonate, Kriptofix 2.2.2 mixed solution drip washing from anion trapping column;
B) compound 7-1 is dissolved in N,N-dimethylformamide and pH value is 1~in 3 pyridazines-hydrochloride buffer;
C) product of step a) with step b) is mixed, at 50~100 DEG C, react 5~30min, cooling, then add and go in right amount
After ionized water dilution, with boric acid and volume ratio 1:0.5~volume ratio 1:1.5 of the PBS-ethanol solution of 1.5~the mixed liquor of 2.5
Carry out C18 column purification as eluent, obtain compound 7-2.
The noble gas of indication of the present invention, such as nitrogen etc., for completely cutting off the air in experimental situation, it is to avoid produces reaction
Raw impact;The reaction carried out under inert gas shielding can be carried out in glove box.
The technical program is compared with background technology, and it has the advantage that
1. instant invention overcomes aminoacid targeting in prior art not strong, and folic acid be in the problem of the high picked-up of kidney,
By folic acid is prepared with alpha-amino acid derivatives coupling18The tumor developer of F labelling, effectively increases label
Polarity and water solublity, be conducive to improving folate-targeted and increasing tumor uptake so that this tumor developer has concurrently amino acid whose
The advantage that the picked-up of tumor height and folic acid absorb in the targeting of tumor, and the two does not occurs interfering, targeting is strong, it is possible to aobvious
Write ground and improve target to non-target ratio value, be verified by experiments, mice can obtain the target to non-target ratio value of more than 5, and tumor/muscle ratio
Reaching 9.20, biological assessment is effective, beneficially clinical expansion.
2., in the preparation method of the present invention, carry out coupling by using click to react in amino acid derivativges and folic acid, make
Must react efficient, purification is simple, beneficially large-scale production.
3., in the preparation method of the present invention, it is strong that isotope labeling method used has marked capacity, and the labelling time is short, labelling
Productivity is high, the simple feature of step, and without anhydrous labelling and HPLC purification.
Accompanying drawing explanation
Fig. 1 is the present invention's18The tumor developer of F labelling PET imaging (2h after administration) in lotus KB tumor Mice Body.
Fig. 2 is the present invention's18PET imaging (the folic acid suppression comparison in lotus KB tumor Mice Body of the tumor developer of F labelling
Group, 2h after administration).
Detailed description of the invention
Present disclosure is illustrated below by embodiment:
Embodiment 1: labelled precursor i.e. compound 7-1 and the synthesis of compound 7-2
1) in 10ml oxolane, compound 1 (0.99g, 0.01mol) is added, compound 2 (1.45g,
0.012mol), adding purity titanium tetraethoxide (4.56g, 0.02mol), under room temperature, stirring reaction is overnight;Add 10ml ethyl acetate dilute
After releasing, adding 10ml saturated nacl aqueous solution cancellation, stir 5min, kieselguhr is filtered to remove insoluble matter, and filtrate takes organic facies,
Washing with saturated nacl aqueous solution, anhydrous sodium sulfate is dried, and removes solvent, the crude product dichloromethane of volume ratio 10~20:1
Alkane-ethyl acetate mixtures drip washing carries out silica gel chromatography, obtains compound 3,1.63g;
2) in glove box, 2ml toluene adds compound 3 (0.2g, 1mmol);Separately by compound 4 (0.51g,
2mmol) it is dissolved in 2mL toluene, adds to the solution containing compound 3;Again by (1,3-dicyclohexyl-2-subunit) tertiary fourth oxygen
Copper (I) (36.6mg, 0.1mmol) is dissolved in 2mL toluene, adds to the solution containing compound 3 and compound 4;At 0 DEG C
After reaction 48h, add 10ml diluted ethyl acetate, remove solvent, the crude product dichloromethane-acetic acid of volume ratio 10~20:1
Ethyl ester mixed liquor drip washing carries out silica gel chromatography, obtains compound 5,0.11g;
3) under nitrogen protection, in the Isosorbide-5-Nitrae-dioxane solution of 0.25ml 4M hydrogen chloride, add compound 5 (0.33g,
1mmol), methanol 0.41ml, under room temperature, stirring reaction 1h, removes solvent, washes with the normal hexane of volume ratio 2:1-ether mixed liquor
Wash solid, obtain compound 6,0.22g;
4) in the Eppendorf pipe of 1.5mL, add 80 μ L DMFs, add compound 6 (65mg,
8.48 μm ol), the KHF of 3M2Aqueous solution 40 μ L, 4M hydrochloride aqueous solution 20 μ L, 20 μ L water, eddy current concussion mixing, at room temperature
Placing response 20h, solvent removed in vacuo, the crude product dichloromethane-ethyl acetate mixed liquor drip washing of volume ratio 10~20:1
Carry out silica gel chromatography, obtain compound 7-1,3.5mg.
Embodiment 2:18The tumor developer of the F labelling i.e. preparation of compound 9
(1) compound 7-2 is prepared
A) will18F from anion trapping column QMA with potassium carbonate, Kriptofix 2.2.2 (K2.2.2) (mass ratio 5:1)
Mixed solution drip washing is got off, and obtains the K of 5~20mCi18F aqueous solution;
B) in 1.5mL centrifuge tube, pyridazine-hydrochloride buffer 7.5 μ L that pH is 2.5, DMF are added
7.5 μ L, the compound 7-1,1mg of preparation in embodiment 1;
C) K that step a) is obtained18F aqueous solution (5~20mCi, 10 μ L) adds to the solution of step b), is heated to 60
React 10min, cooling at DEG C, then after adding the dilution of 2ml deionized water, carry out C18Sep-Pak cartridge column chromatography, first with
2ml deionized water drenches decontamination, then with the mixed liquor of 0.5ml boric acid and the PBS-ethanol solution of 1ml volume ratio 1:1 as drip washing
Product under agent drip washing, obtains compound 7-2;Using HPLC to analyze, Radiochemical yield is 60%, and radiochemical purity is
98%;
(2) in the above-mentioned solution containing 7-2, compound 8 (1g), sodium ascorbate 0.1mg, anhydrous cupric sulfate are added
0.1mg, is heated to 80 DEG C of reaction 15min, then by reactant by preparation HPLC, flowing is acetonitrile/water mutually, isolated
Compound 9, is shown in formula I18The tumor developer of F labelling.
Embodiment 3:18The bio distribution of the tumor developer (compound 9) of F labelling
Selecting the nude mice of 18~20g, injecting about cell quantity in nude mice forelimb oxter is 5 × 106KB Cell sap modeling.
The food that should use weary folic acid the last week instead in experiment carries out feeding.Every mice is by tail vein injection embodiment 2 preparation18The tumor developer of F labelling i.e. compound 9, injection dosage is 10 μ Ci/100 μ L (normal saline), upon administration at 1h and 2h
Extremely, take the main organs such as blood and the heart, liver, lung, kidney, weigh and count.In folic acid suppression matched group, in injection18Swelling of F labelling
Before tumor developer, 10min injects 100 μ g folic acid and suppresses, and by sacrifice after being administered 2h, takes main organs equally
Weigh counting.The results detailed in Table 1 and 2.
It can be seen in table 1 that compound 9 is the highest with the picked-up in kidney at the mouse tumor of folacin receptor high expressed, body
Show good folacin receptor affinity.And in other non-target organ, the most do not observe obvious retention of activity, energy
The target to non-target ratio value (tumor/muscle ratio reaches 9.20) (table 2) that enough acquisitions are higher.Through injecting the suppression of excessive unmarked folic acid
After, tumor and kidney picked-up the most substantially reduce (reducing 82.5% and 68.2% respectively), it was demonstrated that the picked-up of this compound and folic acid
Receptor-specific height correlation.
Table 118The F marked tumor developer i.e. compound 9 bio distribution result in lotus KB tumor nude mouse (%ID/g,
Mean ± SD, n=5)
Table 218The F marked tumor developer i.e. compound 9 target/non-target ratio in lotus KB tumor nude mouse
Embodiment 4:18The PET imaging of the tumor developer (compound 9) of F labelling
Tumor inoculation method is with embodiment 3, when tumor grows to diameter 0.5~1cm, can carry out imaging experiment.All
Imaging mice one week feeding weary folic acid food on pretreatment is to avoid the tetrahydrofolate components contained in food to cause experimental result
Impact.Every mice is by tail vein injection embodiment 2 preparation18The tumor developer of F labelling i.e. compound 9, injects dosage
It is 100 μ Ci/100 μ L (normal saline).2h after injection radioactive marker carries out imaging.
From figure 1 it appears that compound 9 is the highest with the picked-up in kidney in tumor, embodies good folic acid and be subject to
Body affinity.And in other non-target organ, the most do not observe obvious retention of activity, it is possible to obtain higher target with
The picture rich in detail of non-target ratio.After suppression, tumor and kidney picked-up the most substantially reduce (Fig. 2), it was demonstrated that taking the photograph of this compound
Take and folacin receptor specificity height correlation.The results detailed in attached Fig. 1 and 2.
Data above shows, uses the present invention to prepare18It is high that F marked tumor developer has mark rate, synthesizing efficient etc.
Advantage.In the application, target to non-target ratio value is high, and biological assessment is effective, beneficially clinical expansion.
The above, only present pre-ferred embodiments, therefore the scope that the present invention implements can not be limited according to this, i.e. depend on
The equivalence change that the scope of the claims of the present invention and description are made with modify, all should still belong in the range of the present invention contains.
Claims (9)
1. one kind18The tumor developer of F labelling, it is characterised in that: shown in the following formula I of its structural formula:
2. one kind can be used for preparing shown in claim 118The compound of the tumor developer of F labelling, it is characterised in that: its knot
Shown in the following formula II of structure formula:
3. described in a claim 118The preparation method of the tumor developer of F labelling, it is characterised in that: this preparation method is such as
Shown in lower reaction scheme:
Including:
1) in the first organic solvent, under purity titanium tetraethoxide catalysis, compound 1 and compound 2 are according to mol ratio 1:1~1.5
Ratio, at room temperature reacts overnight;After adding saturated nacl aqueous solution cancellation, kieselguhr filters, and filtrate takes organic facies, and washing is dry
Dry, remove solvent, the dichloromethane-ethyl acetate mixed liquor drip washing of crude product volume ratio 10~20:1 carries out silica gel column chromatography
Purification, obtains compound 3;
2) under inert gas shielding, in a second organic solvent, under the catalysis of (1,3-dicyclohexyl-2-subunit) tertiary fourth oxygen copper (I),
Compound 3 and compound 4, according to mol ratio 1:1.5~the ratio of 2.5, react 20~48h at-5~5 DEG C;Remove solvent, slightly
The dichloromethane-ethyl acetate mixed liquor drip washing of product volume ratio 10~20:1 carries out silica gel chromatography, obtains chemical combination
Thing 5;
3), under inert gas shielding, in the 3rd organic solvent, under hydrogen chloride effect, the methanol of compound 5 and 5~15 equivalent exists
React 0.5~3h under room temperature, generate compound 6;
4) in the 4th organic solvent, under hydrogen chloride effect, compound 6 and KHF2At room temperature reaction 15~25h, removes solvent,
Crude product carries out silica gel chromatography with the dichloromethane-ethyl acetate mixed liquor drip washing of 10~20:1, obtains compound 7-
1;
5) in the mixed solution of pyridazine-hydrochloride buffer that pH value is 1~3 and DMF, 5~20mCi18F and compound 7-1
At 50~100 DEG C, react 5~20min, generate compound 7-2, be compound shown in formula II;
6) in water, under the catalysis of copper sulfate and sodium ascorbate, compound 7-2 and compound 8 50~100 DEG C of reactions 5~
20min, generates compound 9, is shown in formula I18The tumor developer of F labelling.
The most according to claim 318The preparation method of the tumor developer of F labelling, it is characterised in that: described step 5) bag
Include:
A) will18F gets off with potassium carbonate, Kriptofix 2.2.2 mixed solution drip washing from anion trapping column;
B) compound 7-1 is dissolved in N,N-dimethylformamide that volume ratio is 1:0.8~1.2 and pH value is 1~3 pyridazines-salt
In acid buffer;
C) product of step a) with step b) is mixed, react 5~30min at 50~100 DEG C, cool down, then add appropriate deionization
After water dilution, with boric acid and volume ratio 1:0.5~volume ratio 1:1.5 of the PBS-ethanol solution of 1.5~the mixed liquor conduct of 2.5
Eluent carries out C18 column purification, obtains compound 7-2.
The most according to claim 318The preparation method of the tumor developer of F labelling, it is characterised in that: described first organic
Solvent, the second organic solvent, the 3rd organic solvent, the 4th organic solvent are oxolane, toluene, Isosorbide-5-Nitrae-dioxane, N, N-
One in dimethylformamide, and can be identical or different.
The most according to claim 318The preparation method of the tumor developer of F labelling, it is characterised in that: described step 3)
In, hydrogen chloride is the Isosorbide-5-Nitrae-dioxane solution of the hydrogen chloride of concentration 4M.
The most according to claim 318The preparation method of the tumor developer of F labelling, it is characterised in that: described step 4)
In, hydrogen cloride concentration is 4M.
8. the preparation method of the compound described in a claim 2, it is characterised in that: including:
A) will18F gets off with potassium carbonate, Kriptofix 2.2.2 mixed solution drip washing from anion trapping column;
B) compound 7-1 is dissolved in N,N-dimethylformamide and pH value is 1~in 3 pyridazines-hydrochloride buffer;
C) product of step a) with step b) is mixed, react 5~30min at 50~100 DEG C, cool down, then add appropriate deionization
After water dilution, with boric acid and volume ratio 1:0.5~volume ratio 1:1.5 of the PBS-ethanol solution of 1.5~the mixed liquor conduct of 2.5
Eluent carries out C18 column purification, to obtain final product.
The most according to claim 118The tumor developer of F labelling is in preparation tumor or struvite relevant disease developer
Application.
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