CN109053781A - A kind of integrated boron carrying agent of tumour diagnosis and treatment - Google Patents
A kind of integrated boron carrying agent of tumour diagnosis and treatment Download PDFInfo
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- CN109053781A CN109053781A CN201810761625.8A CN201810761625A CN109053781A CN 109053781 A CN109053781 A CN 109053781A CN 201810761625 A CN201810761625 A CN 201810761625A CN 109053781 A CN109053781 A CN 109053781A
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- boron
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- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 229910052796 boron Inorganic materials 0.000 title claims abstract description 50
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 48
- 238000003745 diagnosis Methods 0.000 title claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 37
- 238000012879 PET imaging Methods 0.000 claims abstract description 8
- 239000000523 sample Substances 0.000 claims description 13
- 230000002285 radioactive effect Effects 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 10
- 206010018338 Glioma Diseases 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 208000032612 Glial tumor Diseases 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 150000002466 imines Chemical class 0.000 claims description 6
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 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
- 239000012216 imaging agent Substances 0.000 claims description 3
- 230000010354 integration Effects 0.000 claims description 3
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- KWXVDUACPKJCCN-UHFFFAOYSA-N 4-[(3,4-diethoxyphenyl)methylamino]benzenecarboximidamide Chemical compound C1=C(OCC)C(OCC)=CC=C1CNC1=CC=C(C(N)=N)C=C1 KWXVDUACPKJCCN-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- -1 F-18 ion Chemical class 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 238000002372 labelling Methods 0.000 claims 1
- 238000001228 spectrum Methods 0.000 claims 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 abstract description 8
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 abstract description 8
- 201000011510 cancer Diseases 0.000 abstract description 6
- 238000003384 imaging method Methods 0.000 abstract description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 abstract 3
- 229910015900 BF3 Inorganic materials 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 238000012636 positron electron tomography Methods 0.000 description 22
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 238000009826 distribution Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000003068 static effect Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 4
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 229960002725 isoflurane Drugs 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- JORMZLCKCZMVJM-UHFFFAOYSA-N 4'-(4-fluorophenyl)acetanilide Chemical compound C1=CC(NC(=O)C)=CC=C1C1=CC=C(F)C=C1 JORMZLCKCZMVJM-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 108010068561 Fructose-Bisphosphate Aldolase Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 231100000693 bioaccumulation Toxicity 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000013170 computed tomography imaging Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002354 inductively-coupled plasma atomic emission spectroscopy Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000003325 tomography Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- TXAHPQBGJGJQME-UHFFFAOYSA-N acetaldehyde;phenol Chemical compound CC=O.OC1=CC=CC=C1 TXAHPQBGJGJQME-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000001636 atomic emission spectroscopy Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- ZBCKWHYWPLHBOK-UHFFFAOYSA-N cyclohexylphosphane Chemical compound PC1CCCCC1 ZBCKWHYWPLHBOK-UHFFFAOYSA-N 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002221 fluorine Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 208000030173 low grade glioma Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000120 microwave digestion Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000012831 peritoneal equilibrium test Methods 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000012877 positron emission topography Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 150000003668 tyrosines Chemical class 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
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
- A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
-
- 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
- A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
- A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a kind of integrated boron of tumour diagnosis and treatment to carry agent, and it is the tyrosine boron trifluoride (FBY) obtained on the basis of tyrosine with boron trifluoride group replacement carboxyl that the boron, which carries agent,.FBY can be used for BNCT, treat malignant tumour；Through radioactivity18The FBY of F label can also be used in PET imaging diagnosis.18The imaging diagnosis and precisely treatment of cancer can be achieved at the same time in F-FBY.
Description
Technical field
The invention belongs to tumor diagnosis and therapy fields, and in particular to one kind is used for tumour PET imaging diagnosis and/or BNCT
The reagent precisely treated, the in particular to integrated boron of a kind of tumour diagnosis and treatment derived from tyrosine carry agent.
Background technique
Tumour is still a kind of common disease and frequently-occurring disease for seriously threatening the mankind for health now, is to cause dead main original
One of because.Molecular image technology combines molecular probe and Medical Imaging Technology, can be in vivo pathology, physiology course in cell
And molecular level carries out qualitative and quantitative study.(Positron Emission is imaged in positron emission computerized tomography
Tomography, PET) it is a kind of molecular image technology for relying on radioactive molecule probe.The basis of PET technology is positive electron
Bury in oblivion the detection of the pairs of photon issued.From 11C,18The positively charged son emitted in the isotope of the positron decays such as F,
Bury in oblivion quickly with widely distributed negatively charged sub- collision around, and converts the opposite energy of both direction for energy and be
The photon of 511keV.Two photons are detected simultaneously by by two opposite probes of instrument, show to have occurred on two probe lines
Once bury in oblivion.In this way, PET can the distribution to body radioactivity accurately positioned and quantified.Using computer weight
It builds, can be obtained three-dimensional human body PET image.Most widely used molecular probe is in PET imaging at present18F-FDG, pernicious
Diagnosing tumor, by stages, in terms of therapeutic evaluation and prognosis evaluation have apparent clinical value, the diagnostic accuracy compared with CT and MRI
It is higher, however under Partial tumors or specific tumors state18F-FDG PET/CT there are still relatively low diagnosis sensitivity and
However specificity can shake still without other imaging agents at present18F-FDG status (Huang Gang etc., Chinese nuclear medicine impurity,
The 3rd phase of volume 27, page 129).
Boron neutron capture therapy (Boron neutron capture therapy, BNCT) is a kind of binary targeting radiation
Accurate medical technology.The boron that can be first enriched in tumour cell to patient's application carries agent drug, then hankers sufferer
The irradiation of son or epithermal neutron.Its principle is that the boracic drug of strong targeting is imposed on to sufferer and is generated in cancer cell rich
Collection,10B is very high for the normal element that human body forms for the capture cross section of thermal neutron, using thermal neutron with10B is former
The capture reaction of son, the energy of the high-energyα-particle and Li particle that generate it acts only in about 10 μm of cancer cell, to cell
Structure cause irreversible damage, prevent it from repairing and apoptosis.Carrying out treating malignant tumor using the therapy can kill
Tumor tissues simultaneously, utmostly retain affected part normal surrounding tissue and function, to improve quality of life and life after patient's treatment
Deposit period.4- boric acid-L-phenylalanine (4-L-boronophenylalanine, BPA) is that the clinic of FDA approval is most common
Boron applied to BNCT carries agent drug.Although being successfully related to having synthesized a variety of boron carrying agent, comprehensive cancer target based on BPA
Property, the BNCT reagent with clinical value such as toxicity, therapeutic effect it is extremely rare.
PET imaging on the basis of combined treatment component, realize tumor imaging it is integrated with treatment be technology develop side
To.The fluoro- 4- boric acid of 2--L-phenylalanine (2-fluoro-4-L-boronophenylalanine, FBPA) is No. 2 positions on phenyl ring
The BPA that fluorine atom replaces.This fluorine atom can be radioactive18F, the molecule can be used as PET probe at this time, with simulation
The distribution situation of BPA in vivo.With [18F]-FBPA be probe PET image technology be applied to the treatment of BNCT now before examine
It is disconnected, help understand BPA the intracorporal DYNAMIC DISTRIBUTION information of sufferer (Ishiwata K, et al.Melanoma Research,
1992.PMID:1450671), however, FBPA and BPA have differences on molecular structure, the FBPA of probe dosage cannot be represented
The distribution situation of the BPA of therapeutic dose in vivo, FBPA-PET technology is simultaneously immature, therefore develops a kind of completely new can be realized
Diagnosis and treatment integration drug molecule is very urgent.
Summary of the invention
It is existing in the prior art to solve18F-FDG PET/CT imaging false positive and false negative misdiagnosis rate height, BNCT are controlled
Agent is ineffective, diagnosis and treatment integrated technique the is unstable problem for the treatment of, the present invention provide it is a kind of it is new for PET imaging diagnosis and
BNCT treats integrated boron and carries agent.
The discovery of inventor's early-stage study: (1) tyrosine is enriched in tumor by local, especially rich in glioma part
Collection；(2) derivative of tyrosine may have the same or similar drug metabolism and pharmacokinetics to be distributed with tyrosine, especially
It is derivative similar with tyrosine charge and molecular size；(3) compound for carrying BF3 can be in such a way that isotope exchanges
It introduces18F.On the basis of above-mentioned previous research, inventor proposes following technical scheme.
On the one hand, the present invention provides a kind of boron and carries agent, is compound shown in following (formula 1), its is pharmaceutically acceptable
Salt, solvate, isomers or derivative:
C thereinaFor α carbon, B is10B。
Boron of the present invention carries agent, which is characterized in that wherein at least one F is18F。
Second aspect, the present invention provide the boron and carry purposes of the agent in preparation tumour PET imaging agents.
Purposes of the present invention, it is characterised in that the tumour is brain tumor, preferably glioma.
The third aspect, the present invention provide the boron and carry purposes of the agent in preparation tumour diagnosis and treatment integration drug.
Purposes of the present invention, it is characterised in that the tumour is brain tumor, preferably glioma；The drug is
Radioactive probe.
Fourth aspect, the present invention provide a kind of pharmaceutical composition, it includes:
(1) boron of the present invention carries agent, and
(2) pharmaceutically acceptable carrier.
5th aspect, the present invention also provides the preparation methods that a kind of boron carries agent comprising following steps:
(1) aldehyde and R- t-butyl sulfonamide are dissolved in tetrahydrofuran, tetraisopropyl titanate is added and reacts to obtain relatively
The imines answered；
(2) the toluene solution mixing of the imines for preparing step 1 and connection pinacol borate, is added catalyst, room temperature stirs
It mixes；
(3) after diluting the reaction product of step 2, hydrochloric acid is added and potassium bifluoride reaction generates FBY, high performance liquid chromatography
Isolated boron carries agent.
Boron of the present invention carries the preparation method of agent, it is characterised in that further includes step (4) in radioactive isotope F-
Isotope exchange is carried out in solution existing for 18 ions, is obtained18The boron of F label carries agent.
Boron of the present invention carries the preparation method of agent, it is characterised in that: the catalyst in the step (2) is by three hexamethylenes
Base phosphine borofluoride 1.2%eq, copper sulphate 1.2%eq, benzylamine 5%eq are made.
Compared with prior art, technical solution of the present invention has the advantage that
(1) boron of the invention carries physical and chemical parameters and the biological functions such as agent molecule size, charge, with native tyrosine height
Spend similar, therefore it has metabolism identical with native tyrosine and distribution characteristics in vivo, can be enriched in tumor locus, special
It is not in Patients with gliomas, bioaccumulation efficiency is high.
(2) boron of the invention carrying agent preparation method is simple, high production efficiency, and can be efficient by isotopic
The label of rate18F is applied to PET image checking high resolution, is higher than to the early diagnosis accuracy rate of glioma known18F-
FDG。
(3) boron of the invention carries agent small toxicity, high in the bioaccumulation efficiency of tumor locus, meets BNCT institute in tumor by local
The boron content needed, PET with higher is diagnosed, BNCT treats integrated prospect.PET sensitivity is high, can measure in tissue
The concentration and probe concentration of fM (10-15mol) rank；PET can obtain the pharmacokinetics data that boron carries agent, it is easier to help doctor
Understand boron and carries agent drug in the DYNAMIC DISTRIBUTION process of entire patient；Furthermore PET can also carry out absolute quantitation；It is prior
It is that PET is a kind of diagnostic techniques of Noninvasive, reduces the pain of patient to the full extent.
Detailed description of the invention
By reading the following detailed description of the preferred embodiment, various other advantages and benefits are common for this field
Technical staff will become clear.The drawings are only for the purpose of illustrating a preferred embodiment, and is not considered as to the present invention
Limitation.And throughout the drawings, the same reference numbers will be used to refer to the same parts.In the accompanying drawings:
Fig. 1: FBY anion peak mass spectrogram.
Fig. 2:18The high performance liquid chromatography and radioactivity high-efficient liquid phase chromatogram of F-FBY
Fig. 3:18F-FBY is applied to the PET image of tumor-bearing mice.
Fig. 4: under different injection dosages18F-FBY is applied to the PET image of tumor-bearing mice.
Fig. 5: tumor-bearing mice18F-FBY injection dosage and tumor uptake rate curve.
Fig. 6: tumor-bearing mice18F-FBY intake and boron concentration curve.
Boron concentration curve in Fig. 7: FBY injection volume and histoorgan.
Fig. 8: the PET-CT image in Low Grade Gliomas patient:
A:18F-FBY
B:18F-FDG
Fig. 9:18PET-CT image of the F-FBY in middle-and-high-ranking other Patients with gliomas.
Specific embodiment
The illustrative embodiments of the disclosure are more fully described below with reference to accompanying drawings.Although showing this public affairs in attached drawing
The illustrative embodiments opened, it being understood, however, that may be realized in various forms the disclosure without the reality that should be illustrated here
The mode of applying is limited.It is to be able to thoroughly understand the disclosure on the contrary, providing these embodiments, and can be by this public affairs
The range opened is fully disclosed to those skilled in the art.
Embodiment according to the present invention proposes following embodiment
Embodiment 1,18The preparation of F-FBY
1, para hydroxybenzene acetaldehyde (1eq) and R- t-butyl sulfonamide (1.2eq) are dissolved in 100ml tetrahydrofuran, are added
Tetraisopropyl titanate (2eq), stirring at normal temperature is overnight, adds water quenching reaction, filtration drying, and rotary evaporation removes solvent rear pillar chromatography
Separation, obtains corresponding imines.
2, the toluene solution of the imines (1eq) and connection pinacol borate (2eq) that prepare step 1, is added in advance by three
Cyclohexyl phosphine borofluoride (1.2%eq), copper sulphate (1.2%eq), in catalyst made from benzylamine (5%eq), stirring at normal temperature
24h。
3, after ethyl acetate dilution being added in the reaction product of step 2,4M hydrochloric acid and 3M potassium bifluoride solution is added, and add
Entering dilution in acetonitrile is acetonitrile: 2h is stirred at room temperature in water=1:1 reaction system, and rotary evaporation removes solvent later, and it is molten that acetonitrile is added
Solution, high performance liquid chromatography separation obtain FBY.
4, Mass Spectrometric Identification is carried out to the FBY that step 3 synthesizes, molecular weight is about 204, is consistent with expection.As a result such as Fig. 1 institute
Show.
The synthetic technology route of FBY is as follows:
R and R ' can be H and be also possible to other substituent groups.
The F (fluorine) combined in FBY with B (boron) can be exchanged with the F ion dissociated in aqueous solution, in radioactive isotope F-
In solution existing for 18 (there is radioactive F isotope, the stable isotope usually used is F-19) ions, it can pass through
The radioactive label for having exchanged molecular pairs of isotope produces radioactive molecule probe.To radioactive molecule probe18F-FBY
It is analyzed with high performance liquid chromatography and radioactivity high performance liquid chromatography, shows to be successfully prepared18F-FBY, as a result such as Fig. 2 institute
Show.
Embodiment 2,18PET image of the F-FBY in tumor-bearing mice
About 3.7MBq's18F-FBY under isoflurane anesthesia by tail vein injection to tumor-bearing mice body, after injection
The static state that 10min is carried out when 60min collects PET image data.As a result as shown in figure 3, Fig. 3 shows18F-FBY is mainly by kidney
Dirty bladder is metabolized, and removes gall-bladder, kidney, the main metabolics extraorgan such as bladder, remaining normal tissue nothing is obvious to be absorbed, and swollen
The intake of tumor position is obvious.
Embodiment 3,18F-FBY is applied to PET image when tumor-bearing mice with various dose
Under isoflurane anesthesia, about 3.7MBq's18The F-FBY and FBY (0.2mg, 1mg, 5mg, 25mg) of various dose is mixed
By in tail vein injection to tumor-bearing mice body, the static state for carrying out 10min when 90min after injection collects PET after conjunction
Image data.As a result as shown in Figure 4.
When FBY carries agent applied to boron neutron capture therapy as boron, need dosage in 100mg/kg-1000mg/kg model
In enclosing, mouse is administered according to the dosage, the results showed that when carrying out radioactive label and PET imaging with this dosage, according to
It so can specifically be enriched in tumor locus to carry out tracer to tumor region, and radiated signal does not subtract significantly
It is weak.
Embodiment 4,18Distribution of the F-FBY in tumor-bearing mice Different Organs
About 3.7MBq's18F-FBY mixed with the FBY of 25mg after isoflurane anesthesia under by tail vein injection to tumor-bearing mice
In vivo, the static state for carrying out 10min when 90min after injection collects PET image data (Fig. 5).Fig. 5's the result shows that
FBY can be largely enriched in tumor locus, boron content needed for fully meeting BNCT, be can be used as potential boron and carried agent application
In BNCT.
Mouse is put to death immediately after the static state acquisition PET image data end of scan, and takes Different Organs (brain, muscle, tumour
Deng) boron concentration (Fig. 6) is measured with ICP-OES after micro-wave digestion.Fig. 6's the result shows that pass through ICP- under different FBY dosage
The each organ boron content and radiated signal of OES measurement have good corresponding relationship, show FBY and the drug agent of probe dosage
The FBY of amount is almost the same in vivo, the FBY of probe dosage can aids drug dosage completely FBY in patient's body
Distribution, to dynamically carry out quantitative detection to boron concentration.
Embodiment 5,18Boron atom number relationship in F-FBY injection dosage and tumour cell.
Under isoflurane anesthesia, the FBY (0.2mg, 1mg, 5mg, 25mg) of various dose is dissolved in water to be infused by tail vein
It is incident upon in tumor-bearing mice body, 90min puts to death mouse after injection, dense with ICP-OES measurement boron after taking tumor microwave to clear up
Degree.And assume that cell dia is 10 μm of estimation boron atom numbers, as a result as shown in fig. 7, tumour is thin when injecting the FBY of 25mg
Boron atom number intracellular fully meets the Treatment need of BNCT.
Embodiment 6,18PET-CT imaging results of the F-FBY in Patients with gliomas
About 370MBq's18F-FBY is injected intravenously with normal saline dilution to 2ml to patient's body, after injection
The static state that 15min is carried out when 90min collects PET image data.As a result as Figure 8-9.Fig. 8 A shows18F-FBY is suffering from
There is apparent high intake at place, is tumor region at cross；Fig. 8 B shows18Tumor locus and normal cerebral tissue cannot be distinguished in F-FDG.
Fig. 9 shows18F-FBY has the intake of apparent high contrast in affected part.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
In the technical scope disclosed by the present invention, any changes or substitutions that can be easily thought of by anyone skilled in the art,
It should be covered by the protection scope of the present invention.Therefore, protection scope of the present invention should be with the protection model of the claim
Subject to enclosing.
Claims (10)
- It is compound, its pharmaceutically acceptable salt, solvate, isomers shown in following (formula 1) 1. a kind of boron carries agent Or derivative:C thereinaFor α carbon, B is10B。
- 2. boron as described in claim 1 carries agent, which is characterized in that wherein at least one F is18F。
- 3. boron as claimed in claim 1 or 2 carries purposes of the agent in preparation treatment tumour PET imaging agents.
- 4. purposes as claimed in claim 3, it is characterised in that the tumour is brain tumor, preferably glioma.
- 5. boron as claimed in claim 1 or 2 carries purposes of the agent in preparation tumour diagnosis and treatment integration drug.
- 6. purposes as claimed in claim 5, it is characterised in that the tumour is brain tumor, preferably glioma；The medicine Object is radioactive probe.
- 7. a kind of pharmaceutical composition, it is characterised in that include:(1) boron of any of claims 1 or 2 carries agent, and(2) pharmaceutically acceptable carrier.
- 8. the preparation method that a kind of boron carries agent comprising following steps:(1) aldehyde and R- t-butyl sulfonamide are dissolved in tetrahydrofuran, addition tetraisopropyl titanate reacts to obtain corresponding Imines；(2) the toluene solution mixing of the imines for preparing step 1 and connection pinacol borate, is added catalyst, stirring at normal temperature；(3) after diluting the reaction product of step 2, hydrochloric acid is added and potassium bifluoride reaction generates boron and carries agent, high-efficient liquid phase color Spectrum separation.
- 9. method according to claim 8, it is characterised in that further include that step (4) exists in radioactive isotope F-18 ion Solution in carry out isotope exchange, obtain isotope labelling boron carry agent.
- 10. preparing the preparation method that boron carries agent as described in claim 8 or 9, it is characterised in that the catalysis in the step (2) Agent is made by tricyclohexyl phosphine borofluoride 1.2%eq, copper sulphate 1.2%eq, benzylamine 5%eq.
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