CN105963724B - A kind of radiolabeled tumor developer, preparation method and application - Google Patents
A kind of radiolabeled tumor developer, preparation method and application Download PDFInfo
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- CN105963724B CN105963724B CN201610307569.1A CN201610307569A CN105963724B CN 105963724 B CN105963724 B CN 105963724B CN 201610307569 A CN201610307569 A CN 201610307569A CN 105963724 B CN105963724 B CN 105963724B
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 239000012216 imaging agent Substances 0.000 claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 21
- 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
- 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
- 230000000694 effects Effects 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 238000010828 elution Methods 0.000 claims description 9
- 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
- 239000002904 solvent Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 238000010898 silica gel chromatography 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- 238000010790 dilution Methods 0.000 claims description 6
- 239000012895 dilution Substances 0.000 claims description 6
- 239000011261 inert gas 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
- 238000001816 cooling Methods 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- WFJZBOIOPMOUCB-UHFFFAOYSA-N pyridazine;hydrochloride Chemical compound Cl.C1=CC=NN=C1 WFJZBOIOPMOUCB-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- ZMHWUUMELDFBCZ-UHFFFAOYSA-N copper(1+);hydrate Chemical compound O.[Cu+] ZMHWUUMELDFBCZ-UHFFFAOYSA-N 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
- 239000012074 organic phase Substances 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- 238000001914 filtration Methods 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000002242 deionisation method Methods 0.000 claims 2
- 239000007853 buffer solution Substances 0.000 claims 1
- 238000005406 washing Methods 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 37
- 235000019152 folic acid Nutrition 0.000 abstract description 23
- 239000011724 folic acid Substances 0.000 abstract description 23
- 230000008685 targeting Effects 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 5
- 238000012879 PET imaging Methods 0.000 abstract description 4
- 150000001370 alpha-amino acid derivatives Chemical group 0.000 abstract description 3
- 229940014144 folate Drugs 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract 1
- 239000013626 chemical specie Substances 0.000 abstract 1
- 238000001948 isotopic labelling Methods 0.000 abstract 1
- 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 description 14
- 229960000304 folic acid Drugs 0.000 description 14
- -1 methoxyl group Chemical group 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 210000003734 kidney Anatomy 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
- 239000002243 precursor Substances 0.000 description 7
- 229940064302 folacin Drugs 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection 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
- 238000003384 imaging method Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000699660 Mus musculus Species 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
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group 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
- 235000013305 food Nutrition 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
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 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
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000003786 synthesis reaction 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 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
- 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
- 230000008859 change Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 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
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- 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
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 102000006815 folate receptor Human genes 0.000 description 1
- 108020005243 folate receptor Proteins 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
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 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
- 239000007788 liquid Substances 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000002953 preparative HPLC 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
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 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
- 206010046766 uterine cancer Diseases 0.000 description 1
- 238000005303 weighing Methods 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
Contain the invention discloses a kind of radiolabeled tumor developer, preparation method and application, in structure and can be used for the alpha-amino acid derivatives structure of isotope labeling and the folate molecule of cancer target, radionuclide is18F, the alpha-amino acid derivatives structure are connected with folate molecule with specific chemical species.The purposes of PET imaging is used for the invention further relates to the preparation method of the compound and its in human or animal's body as Trace imaging agent, is especially used as tumor developer, has the advantages that prepare simple, cheap and targeting strong.
Description
Technical field
The invention belongs to Medical Imaging Technology fields, and in particular to a kind of18Tumor developer, the preparation method of F label
And application.
Background technique
A-amino acid is the structural unit of protein, plays vital work in neurotransmitter and the conversion of ATP energy
With.Nutriment necessary to a-amino acid is also tumour cell existence and is proliferated simultaneously, most tumours all can be to amino
Sour high intake, this will lead to the transfer of high-level tumour higher intake and tumour again.Amino acid is the signal point of tumor proliferation
Son also functions to the effect for reprograming metabolism network biomass accumulation relevant to tumour.
In addition, folacin receptor high expression in many tumor tissues, as oophoroma, kidney, uterine cancer, carcinoma of testis, the cancer of the brain,
Colon cancer, adenocarcinoma of lung etc..Folate molecule has very high selectivity to these tumours.
CN103827057A discloses a kind of quilt18The novel compound of F label and corresponding warp18The compound of F label
In itself, its their warp19The fluorinated analog of F and its they as reference standard purposes, prepare the side of such compound
Method, the composition comprising such compound, the kit comprising such compound or composition and such compound, composition
Or kit is used for the purposes of the diagnosing image by positron emission tomography Positron Emission Tomography imaging (PET).
CN101723850A discloses a kind of novel radioactive18F marks ArAA, disconnected for tumour 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 are located in alpha site of carboxyl group, and R1 is phenyl, benzyl, 3- indole methyl, and R2 is methoxyl group, n 1-5.R1 is benzene
Base, benzyl, 3- indole methyl, R2 are methoxyl group, n 1-5.
CN101723847A discloses one kind18F marks p-nitrophenyl benzoyl amino acid compound, it is characterized in that: together
When have 2-18F-4- nitrobenzene formyl and a-amino acid structure, and substituted base R is located in alpha site of carboxyl group, is hydrogen, methyl, second
Base, propyl, isopropyl, butyl, isobutyl group, benzyl, 2-methylmercaptoethyl, carboxyethyl, carboxylic propyl, phenyl, imidazolmethyl.Both ends
Structure is connected directly by amido bond.
CN102126985A is disclosed18F labelled precursor compound, further simultaneously discloses preparation method, successively include with
Lower step: the 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, are stirred to react;React resulting product
It is post-treated, obtain precursor compound;2) label of precursor compound.It is above-mentioned18F labelled precursor compound can use click
Method labeled amino acid, the polypeptide compounds of chemistry;Also it can be used as molecular image probe, be applied to PET and image.
Bioconjugate Chem., 2008,19,2462-2470 disclose it is a kind of with18The folacin compound of F label,
It is characterized in that: using18F-Then p-toluenesulfonyl anion on ion nucleophilic displacement of fluorine labelled precursor utilizes click
The method of chemistry marks folacin compound, and is applied to PET and is imaged.
However, in the above prior art, most small molecule Imaging probes often contain only a group with targeting,
The delay of target organ is generated for receptor or certain physical factors, but non-target organ may be because have similar receptor or have
The high intake same to probe of similar physical property, it is very high so as to cause target to non-target ratio value.
Summary of the invention
It is an object of the invention to overcome amino acid targeting not strong and folic acid is the high intake of kidney the problem of, simultaneously
The advantage that the intake of tumour height and folic acid for having both amino acid are absorbed in the targeting of tumour, provides a kind of folic acid and a-amino acid
Derivative coupling18F label tumor developer, preparation method and application, and by PET image be used for tumour or its
The diagnosis of his disease or curative effect evaluation.
The technical solution adopted by the present invention to solve the technical problems first is that:
It is a kind of18The tumor developer of F label, structural formula is as shown in following formula I:
The technical solution adopted by the present invention to solve the technical problems second is that:
It is a kind of above-mentioned18The preparation method of the tumor developer of F label, shown in the following reaction route of the preparation method:
Include:
1) in the first organic solvent, under purity titanium tetraethoxide catalysis, compound 1 and compound 2 according to molar ratio 1:1~
1.5 ratio, reaction is stayed overnight at room temperature;After addition saturated sodium chloride solution is quenched, diatomite filtering, filtrate takes organic phase,
Drying is washed, solvent is removed, crude product carries out silica gel with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio
Column chromatography purifying, 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 react 20~48h according to the ratio of molar ratio 1:1.5~2.5 at -5~5 DEG C;It removes molten
Agent, crude product carry out silica gel chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio, obtain
Compound 5;
3) under inert gas shielding, in third organic solvent, under hydrogen chloride effect, the first of the equivalent of compound 5 and 5~15
Alcohol reacts 0.5~3h at room temperature, generates compound 6;
4) in the 4th organic solvent, under hydrogen chloride effect, compound 6 and KHF215~25h is reacted at room temperature, is removed
Solvent, crude product carry out silica gel chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio, obtain
To compound 7-1;
5) in the mixed solution for the pyridazine-hydrochloride buffer and DMF for being 1~3 in pH value, 5~20mCi's18F and compound
7-1 reacts 5~20min at 50~100 DEG C, generates compound 7-2, as compound shown in formula II;
6) in water, under the catalysis of copper sulphate and sodium ascorbate, compound 7-2 and compound 8 are reacted at 50~100 DEG C
5~20min generates compound 9, as shown in formula I18The tumor developer of F label.
In one embodiment: the step 5) includes:
A) will18F is eluted from anion trapping column with potassium carbonate, Kryptofix 2.2.2 mixed solution;
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) step a) is mixed with the product of step b), 5~30min is reacted at 50~100 DEG C, it is cooling, then plus go in right amount
After ionized water dilution, with the mixed liquor of volume ratio 1:1.5~2.5 of boric acid and the PBS- ethanol solution of volume ratio 1:0.5~1.5
C18 column purification is carried out as eluent, obtains compound 7-2.
In one embodiment: first organic solvent, the second organic solvent, third organic solvent, the 4th organic solvent are
Tetrahydrofuran, toluene, Isosorbide-5-Nitrae-dioxane, one of n,N-Dimethylformamide, and can be identical or different.
In one embodiment: in the step 3), hydrogen chloride is Isosorbide-5-Nitrae-dioxane solution of the hydrogen chloride of concentration 4M.
In one embodiment: in the step 4), hydrogen cloride concentration 4M.
The technical solution adopted by the present invention to solve the technical problems third is that:
It is above-mentioned18Application of the tumor developer of F label in preparation tumour or inflammatory related disease imaging agent.
The technical solution adopted by the present invention to solve the technical problems fourth is that:
One kind can be used for preparing above-mentioned18The compound of the tumor developer of F label, structural formula is as shown in following formula II:
The technical solution adopted by the present invention to solve the technical problems fifth is that:
A kind of preparation method of compound shown in above-mentioned formula II, comprising:
A) will18F is eluted from anion trapping column with potassium carbonate, Kriptofix 2.2.2 mixed solution;
B) compound 7-1 is dissolved in N,N-dimethylformamide and pH value is in 1~3 pyridazine-hydrochloride buffer;
C) step a) is mixed with the product of step b), 5~30min is reacted at 50~100 DEG C, it is cooling, then plus go in right amount
After ionized water dilution, with the mixed liquor of volume ratio 1:1.5~2.5 of boric acid and the PBS- ethanol solution of volume ratio 1:0.5~1.5
C18 column purification is carried out as eluent, obtains compound 7-2.
Signified inert gas of the invention, such as nitrogen etc. avoid producing reaction for completely cutting off the air in experimental situation
It is raw to influence;The reaction carried out under inert gas shielding can carry out in glove box.
The technical program compared with the background art, it has the following advantages:
1. the present invention overcomes amino acid targeting in the prior art is not strong and folic acid is the high intake of kidney the problem of,
It is prepared by the way that folic acid to be coupled with alpha-amino acid derivatives18The tumor developer of F label, effectively increases marker
Polarity and water solubility are conducive to improve folate-targeted and increase tumor uptake, so that the tumor developer has both amino acid
The advantage that the intake of tumour height and folic acid are absorbed in the targeting of tumour, and the two does not interfere with each other, targeting is strong, Neng Gouxian
It lands and improves target to non-target ratio value, be verified by experiments, can get 5 or more target to non-target ratio value, and tumor/muscle ratio in mouse
Up to 9.20, biological assessment effect is good, is conducive to clinical expansion.
2. in preparation method of the invention, being coupled, being made by reacting amino acid derivativges using click with folic acid
It must react efficiently, purifying is simple, is conducive to large-scale production.
3. in preparation method of the invention, isotope labeling method used has marked capacity strong, the label time is short, label
Yield is high, the simple feature of step, and without anhydrous label and HPLC purifying.
Detailed description of the invention
Fig. 1 is of the invention18The tumor developer of F label is in the intracorporal PET imaging (2h after administration) of lotus KB tumor mouse.
Fig. 2 is of the invention18In the intracorporal PET imaging of lotus KB tumor mouse, (folic acid inhibits control to the tumor developer of F label
Group, 2h after administration).
Specific embodiment
The contents of the present invention are illustrated below by embodiment:
Embodiment 1: labelled precursor, that is, compound 7-1 and compound 7-2 synthesis
1) it in 10ml tetrahydrofuran, is added compound 1 (0.99g, 0.01mol), compound 2 (1.45g,
0.012mol), purity titanium tetraethoxide (4.56g, 0.02mol) is added, is stirred to react at room temperature overnight;It is dilute that 10ml ethyl acetate is added
It after releasing, adding 10ml saturated sodium chloride solution and is quenched, stir 5min, diatomite is filtered to remove insoluble matter, and filtrate takes organic phase,
It is washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, removes solvent, the dichloromethane of crude product 10~20:1 of volume ratio
Alkane-ethyl acetate mixtures elution carries out silica gel chromatography, obtains compound 3,1.63g;
2) in glove box, compound 3 (0.2g, 1mmol) is added in 2ml toluene;Separately by compound 4 (0.51g,
It 2mmol) is dissolved in 2mL toluene, is added into 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, is added into the solution containing compound 3 and compound 4;At 0 DEG C
After reacting 48h, the dilution of 10ml ethyl acetate is added, removes solvent, methylene chloride-acetic acid of crude product 10~20:1 of volume ratio
The elution of ethyl ester mixed liquor carries out silica gel chromatography, obtains compound 5,0.11g;
3) under nitrogen protection, in Isosorbide-5-Nitrae-dioxane solution of 0.25ml 4M hydrogen chloride, be added compound 5 (0.33g,
1mmol), methanol 0.41ml is stirred to react 1h at room temperature, removes solvent, is washed with the n-hexane of volume ratio 2:1-ether mixed liquor
Solid is washed, compound 6,0.22g is obtained;
4) be added 80 μ L n,N-Dimethylformamide in the Eppendorf pipe of 1.5mL, be added compound 6 (65mg,
8.48 μm of ol), the KHF of 3M240 μ L, 4M hydrochloride aqueous solution of aqueous solution, 20 μ L, 20 μ L water, vortex concussion mix, at room temperature
Placing response 20h, is removed in vacuum solvent, and crude product is eluted with the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio
Silica gel chromatography is carried out, compound 7-1,3.5mg are obtained.
Embodiment 2:18The preparation of tumor developer, that is, compound 9 of F label
(1) prepare compound 7-2
A) will18F is from anion trapping column QMA with potassium carbonate, Kriptofix 2.2.2 (K2.2.2) (mass ratio 5:1)
Mixed solution elutes, and obtains the K of 5~20mCi18F aqueous solution;
B) the 7.5 μ L of pyridazine-hydrochloride buffer that pH is 2.5, n,N-Dimethylformamide are added in 1.5mL centrifuge tube
7.5 μ L, the compound 7-1,1mg prepared in embodiment 1;
C) K for obtaining step a)18F aqueous solution (5~20mCi, 10 μ L) is added into the solution of step b), is heated to 60
10min is reacted at DEG C, it is cooling, then plus the dilution of 2ml deionized water after, carry out C18Sep-Pak cartridge column chromatography, first with
2ml deionized water drenches decontamination, then uses the mixed liquor of 0.5ml boric acid and the PBS- ethanol solution of 1ml volume ratio 1:1 as elution
Agent elutes lower product, obtains compound 7-2;It is analyzed using HPLC, Radiochemical yield 60%, radiochemical purity is
98%;
(2) it in the above-mentioned solution containing 7-2, is added compound 8 (1g), sodium ascorbate 0.1mg, anhydrous cupric sulfate
0.1mg is heated to 80 DEG C of reaction 15min, then by reactant by preparative HPLC, mobile phase is acetonitrile/water, isolatedization
Object 9 is closed, as shown in formula I18The tumor developer of F label.
Embodiment 3:18The bio distribution of the tumor developer (compound 9) of F label
The nude mice for selecting 18~20g, in nude mice forelimb oxter, injection about cell quantity is 5 × 106KB cell liquid modeling.
Feeding is carried out in the food that the last week of experiment should use weary folic acid instead.Every mouse is prepared by tail vein injection embodiment 218Tumor developer, that is, compound 9 of F label, injection dosage is 10 μ Ci/100 μ L (physiological saline), upon administration at 1h and 2h
Extremely, the main organs such as blood and the heart, liver, lung, kidney are taken, weighs and counts.Inhibit injecting in control group in folic acid18F label swells
10min injects 100 μ g folic acid and is inhibited before tumor imaging agent, and puts to death mouse after 2h is administered, and equally takes main organs
Weighing counts.As a result see Table 1 for details and 2.
It can be seen in table 1 that intake of the compound 9 in the highly expressed mouse tumor of folacin receptor and kidney is all higher, body
Good folacin receptor affinity is showed.And apparent retention of activity is all not observed in other non-target organs, energy
Enough obtain higher target to non-target ratio value (tumor/muscle ratio up to 9.20) (table 2).Inhibit by the excessive unmarked folic acid of injection
Afterwards, tumour and kidney intake are all substantially reduced and (reduce 82.5% and 68.2% respectively), it was demonstrated that the intake of the compound and folic acid
Receptor-specific is highly relevant.
Table 118F marked tumor imaging agent, that is, compound 9 the intracorporal bio distribution result of lotus KB tumor nude mice (%ID/g,
Mean ± SD, n=5)
Table 218F marked tumor imaging agent, that is, compound 9 is in the intracorporal target of lotus KB tumor nude mice/non-target ratio
Embodiment 4:18The PET imaging of the tumor developer (compound 9) of F label
Tumor inoculation method is with embodiment 3, when tumour grows to 0.5~1cm of diameter, can carry out imaging experiment.It is all
Imaging mouse the experiment weary folic acid food of the last week feeding to avoid the tetrahydrofolate components contained in food caused by experimental result
It influences.Every mouse is prepared by tail vein injection embodiment 218Tumor developer, that is, compound 9 of F label, injection dosage
For 100 μ Ci/100 μ L (physiological saline).2h after injecting radioactively labelled substance is imaged.
From figure 1 it appears that intake of the compound 9 in tumour and kidney is all higher, embody good folic acid by
Body affinity.And apparent retention of activity is all not observed in other non-target organs, can obtain higher target with
The clear image of non-target ratio.After inhibiting, tumour and kidney intake are all substantially reduced (Fig. 2), it was demonstrated that the compound is taken the photograph
It takes highly relevant with folacin receptor specificity.As a result it is detailed in attached Fig. 1 and 2.
Above data shows that use is prepared by the present invention18F marked tumor imaging agent has mark rate height, synthesizing efficient etc.
Advantage.In the application, target to non-target ratio value is high, and biological assessment effect is good, is conducive to clinical expansion.
The above is only the preferred embodiment of the present invention, the range implemented of the present invention that therefore, it cannot be limited according to, i.e., according to
Equivalent changes and modifications made by the invention patent range and description, should still be within the scope of the present invention.
Claims (9)
1. a kind of18The tumor developer of F label, it is characterised in that: its structural formula is as shown in following formula I:
2. one kind can be used for preparing shown in claim 118The compound of the tumor developer of F label, it is characterised in that: it is tied
Structure formula is as shown in following formula II:
3. a kind of described in claim 118The preparation method of the tumor developer of F label, it is characterised in that: the preparation method is such as
Shown in lower reaction route:
Include:
1) in the first organic solvent, under purity titanium tetraethoxide catalysis, compound 1 and compound 2 are according to molar ratio 1:1~1.5
Ratio, reaction is stayed overnight at room temperature;After addition saturated sodium chloride solution is quenched, diatomite filtering, filtrate takes organic phase, and washing is dry
It is dry, solvent is removed, crude product carries out silica gel column chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio
Purifying, obtains compound 3;
2) under inert gas shielding, in a second organic solvent, under (1,3- dicyclohexyl -2- subunit) tertiary fourth oxygen copper (I) catalysis,
Compound 3 and compound 4 react 20~48h according to the ratio of molar ratio 1:1.5~2.5 at -5~5 DEG C;Solvent is removed, slightly
Product carries out silica gel chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1 of volume ratio, obtains chemical combination
Object 5;
3) under inert gas shielding, in third organic solvent, under hydrogen chloride effect, the methanol of the equivalent of compound 5 and 5~15 exists
0.5~3h is reacted at room temperature, generates compound 6;
4) in the 4th organic solvent, under hydrogen chloride effect, compound 6 and KHF215~25h is reacted at room temperature, removes solvent,
Crude product carries out silica gel chromatography with the elution of the dichloromethane-ethyl acetate mixed liquor of 10~20:1, obtains compound 7-
1;
5) in the mixed solution for the pyridazine-hydrochloride buffer and DMF for being 1~3 in pH value, 5~20mCi's18F and compound 7-1
5~20min is reacted at 50~100 DEG C, generates compound 7-2, as compound shown in formula II;
6) in water, under the catalysis of copper sulphate and sodium ascorbate, compound 7-2 and compound 8 react 5 at 50~100 DEG C~
20min generates compound 9, as shown in formula I18The tumor developer of F label.
4. according to claim 318The preparation method of the tumor developer of F label, it is characterised in that: the step 5) packet
It includes:
A) will18F is eluted from anion trapping column with potassium carbonate, Kriptofix 2.2.2 mixed solution;
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 pyridazine-salt
In acid buffer;
C) step a) is mixed with the product of step b), 5~30min is reacted at 50~100 DEG C, it is cooling, then plus deionization in right amount
Water dilution after, use the mixed liquor of volume ratio 1:1.5~2.5 of the PBS- ethanol solution of boric acid and volume ratio 1:0.5~1.5 as
Eluent carries out C18 column purification, obtains compound 7-2.
5. according to claim 318The preparation method of the tumor developer of F label, it is characterised in that: described first is organic
Solvent, the second organic solvent, third organic solvent, the 4th organic solvent are tetrahydrofuran, toluene, Isosorbide-5-Nitrae-dioxane, N, N-
One of dimethylformamide, and can be identical or different.
6. according to claim 318The preparation method of the tumor developer of F label, it is characterised in that: the step 3)
In, hydrogen chloride is Isosorbide-5-Nitrae-dioxane solution of the hydrogen chloride of concentration 4M.
7. according to claim 318The preparation method of the tumor developer of F label, it is characterised in that: the step 4)
In, hydrogen cloride concentration 4M.
8. a kind of preparation method of compound as claimed in claim 2, it is characterised in that: include:
A) will18F is eluted from anion trapping column with potassium carbonate, Kriptofix 2.2.2 mixed solution;
B) compound 7-1 is dissolved in N,N-dimethylformamide and pH value is in 1~3 pyridazine-hydrochloride buffer;
C) step a) is mixed with the product of step b), 5~30min is reacted at 50~100 DEG C, it is cooling, then plus deionization in right amount
Water dilution after, use the mixed liquor of volume ratio 1:1.5~2.5 of the PBS- ethanol solution of boric acid and volume ratio 1:0.5~1.5 as
Eluent carry out C18 column purification to get.
9. according to claim 118The tumor developer of F label is in preparation tumour or inflammatory related disease imaging agent
Application.
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