CN108239101A - It is used to prepare compound, the preparation method and applications of the compound specifically bound with amyloid beta - Google Patents
It is used to prepare compound, the preparation method and applications of the compound specifically bound with amyloid beta Download PDFInfo
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- CN108239101A CN108239101A CN201611207546.XA CN201611207546A CN108239101A CN 108239101 A CN108239101 A CN 108239101A CN 201611207546 A CN201611207546 A CN 201611207546A CN 108239101 A CN108239101 A CN 108239101A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- 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
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- 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
- A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
Abstract
One aspect of the present invention discloses a kind of compound, and the compound has such as structure structure shown in formula A, wherein substituent group R1Can be NO2May be NH2；On the other hand the compound is further disclosed to prepare and the application in the compound of amyloid beta specific binding.
Description
Technical field
The present invention relates to the application of a kind of novel compound, preparation method and the compound, the especially compounds to exist
It prepares and the application in the compound of amyloid beta specific binding.
Background technology
Alzheimer's disease (Alzheimer ' s disease, be usually abbreviated as AD) is the most common type in the elderly
Dementia, Histopathologic appearance are mainly senile plaque, neurofibrillary tangles and the Regional neural as caused by apoptosis
Cell death etc..
Some researches show that the abnormal deposition of amyloid beta (Amyloid β-protein, be usually abbreviated as A β) is A Er
One of Zi Haimo disease main pathogenesis.Amyloid beta is by egg of the amyloid precusor protein (APP) through β and gamma secretase
White hydrolysis and the polypeptide containing 39~43 amino acid generated commonly contain 40 (A β in human body1~40) or 42 (A
β1~42) a amino acid polypeptide, wherein A β1~42With stronger toxicity, it is easier to build up into amyloid beta deposition patch
Core, the amyloid beta deposition patch that amyloid beta is formed after depositing can cause neurotoxic effect.
Preparing a kind of compound that can be specifically bound with amyloid beta by chemical method helps further to grind
Study carefully the relationship of amyloid beta and AD pathogenesis, more likely using new technology (such as BNCT) to eliminate amyloid beta,
Alleviate or cure AD and provide a kind of new approaches.
Invention content
One aspect of the present invention provides a kind of compound, which has such as structure structure shown in formula A,
Structural formula A
Wherein, R1Can be-NO2May be-NH2,
Work as R1For-NO2When, the compound is 2- (4- nitrobenzenes) -6- dihydroxy boryl benzothiazoles；
Work as R1For-NH2When, the compound is 2- (4- aminobenzenes) -6- dihydroxy boryl benzothiazoles.
Structural formula A compounds represented 2- (4- nitrobenzenes) -6- dihydroxy boryl benzothiazoles and 2- (4- aminobenzenes) -6-
Boron element in dihydroxy boryl benzothiazole can be11B may be10B, it is preferred that structural formula A compounds represented
In boron element be10B。
10B is a kind of nucleic big to thermal neutron capture cross section, wherein the nucleic big to thermal neutron capture cross section is
Refer under the thermal neutron irradiation of identical energy, neutron capture section is more than or equal to the basic component of human body (C, H, O, N, P, S)
Neutron capture section 100 times and above nucleic, wherein forming human body group substantially under the thermal neutron irradiation of identical energy
Neutron capture section into the H in element is maximum, the thermal neutron capture cross section of H under conditions of thermal neutron energy is 0.025eV
For 0.2barn,10The thermal neutron capture cross section of B is 3800barn.
The nucleic big to thermal neutron capture cross section10B occurs to react as follows under the irradiation of neutron ray, radiant：
Reaction equation I
The known ground of those skilled in the art, it is above-mentioned10The mechanism of B element and neutron reaction is commonly used for neutron capture treatment
(BNCT) during.Therefore when the compound contains10During B nucleic, which can be applied to neutron capture therapeutic process
In or contained using this10The compound of B element further prepares other changes that can be applied in neutron capture therapeutic process
Close object.
Another aspect of the present invention is provided such as the preparation method of structural formula A compounds represented, wherein, 2- (4- nitros
Benzene) -6- dihydroxy boryl benzothiazoles are prepared by reacting as follows：
By 2- (4- nitrobenzenes) -6- bromo benzothiazoles and connection boric acid pinacol ester reaction generation 2- (4- nitrobenzenes) -6- boron
The step of sour pinacol ester benzothiazole；
2- (4- nitrobenzenes) -6- pinacol borates benzothiazoles are by oxidizing for 2- (4- nitrobenzenes) -6- dihydroxies
The step of base boryl benzothiazole.
2- (4- aminobenzenes) -6- dihydroxy boryl benzothiazoles are by 2- (4- nitrobenzenes) -6- dihydroxy boryl benzothiazoles
It is prepared, wherein, 2- (4- aminobenzenes) -6- dihydroxy boryl benzothiazoles are by 2- (4- nitrobenzenes) -6- dihydroxy boryls
Benzothiazole is prepared through reduction reaction.
Third aspect present invention is provided such as structural formula A compounds represented 2- (4- nitrobenzenes) -6- dihydroxy boryl benzene
And thiazole and 2- (4- aminobenzenes) -6- dihydroxy boryl benzothiazoles are in the chemical combination prepared and amyloid beta is specifically bound
Application in object, is such as not specifically noted in the present invention, and the compound of described and amyloid beta specific binding refers to
2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles.
Preferably, in the application and amyloid beta specific binding compound by structure shown in formula Aization
Object is closed to be prepared via a method which：
2- (4- the nitrobenzenes) -6- dihydroxy boryl benzothiazoles are reduced to the 2- (4- ammonia by reduction reaction
Base benzene) -6- dihydroxy boryl benzothiazoles；
2- (4- the aminobenzenes) -6- dihydroxy boryls benzothiazole, iodomethane and silver triflate are in high temperature item
Reaction generation 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles under part.
The present invention provides a kind of new compounds containing boron element and the compound to prepare and amyloid beta spy
Application in the compound that the opposite sex combines provides new technical support for research amyloid beta.The present invention only lists institute
It states compound preparing and the application in the compound of amyloid beta specific binding, however not excluded that structural formula A institutes in the present invention
Other purposes for the compound shown.
Description of the drawings
Fig. 1 is 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles1HNMR collection of illustrative plates；
Fig. 2 is the floor map of the neutron capture therapeutic device of accelerator neutron generator；
Fig. 3 is the floor map of the neutron capture therapeutic device in pile neutron source；
(1) figure and (2) figure in Fig. 4 are respectively112- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles of C flag
Stability collection of illustrative plates in 30min and 60min respectively；
A figures and B figures in Fig. 5 are injection respectively112- (4- methylaminos benzene) -6- dihydroxy boryl benzo thiophenes of C flag
The PET images of control mouse and SAMP8 model mouses after azoles 30min；
Fig. 6 is bovine serum albumin(BSA) and H3 10BO3Mixed solution respectively at collimator port different location through spoke
SDS-PAGE electrophoresis spectrum after radiation exposure；
Fig. 7 is 2- (4- nitrobenzenes) -6- dihydroxy boryl benzothiazoles and 2- (4- aminobenzenes) -6- dihydroxy boryl benzos
The general structure of thiazole.
Specific embodiment
Technical scheme of the present invention is described in further detail below by embodiment, to enable those skilled in the art
It can implement according to this with reference to specification word, it should be appreciated that the embodiment cited by the present invention is not intended to limit this hair
Bright advocated interest field.
One or more of the other ingredient is not precluded in such as " having ", "comprising" and " comprising " term used herein
The presence or addition of or combination.
If do not illustrated, " such as structural formula A compounds represented " refers to 2- (4- nitrobenzenes) -6- two in the present invention
Dihydroxyboryl benzothiazole and 2- (4- aminobenzenes) -6- dihydroxy boryl benzothiazoles.
Fast neutron of the present invention for can area be more than 40keV neutron, epithermal neutron energy area 0.5eV to 40keV it
Between, subzone is hankered less than 0.5keV.
The compound provided by the invention that can be specifically bound with amyloid beta is 2- (4- methylaminos benzene) -6- two
Dihydroxyboryl benzothiazole, the confirmation of structure is as shown in Figure 1.The compound can be combined with neutron capture therapeutic device
To deposit patch to eliminate amyloid beta.
As shown in Figure 2 or Figure 3：The neutron capture therapeutic device includes neutron source, beam-shaping body and collimator, wherein
Beam-shaping body includes reflector, slow body, thermal neutron absorber and radiation shield device, and wherein neutron source is included in accelerator
Component and pile neutron source.
During amyloid beta deposition patch is eliminated using neutron capture therapeutic device, need under normal conditions
The fast neutron come from the mixed radiation field of neutron source is adjusted to super in the beam-shaping body of neutron capture therapeutic device
Thermal neutron and the content for reducing other harm rays in mixed radiation field, although the chemical combination with amyloid beta specific binding
Nucleic on object is the nucleic big to thermal neutron capture cross section, it is contemplated that standard of the neutron beam from neutron capture therapeutic device
During straight device to the compound that can be specifically bound with amyloid beta, the energy of neutron beam can be with the two distance
Increase energy have a degree of attenuation, and neutron beam reaches and the chemical combination of amyloid beta specific binding
Other substances are often had during object and in various degree slow are carried out to the energy of neutron, therefore in order to ensure arrival and β
The energy and neutron intensity of the compound neutron of amyloid protein specific binding, needing under normal conditions will be in beam-shaping body
Fast neutron slowly for epithermal neutron, improve the content from the epithermal neutron in the neutron beam that collimator comes out.
The neutron capture therapeutic device that it is accelerator that neutron source as shown in Figure 2, which is, wherein accelerator 10a add proton
Speed is expanded the cross-sectional area of proton beam P by expand device 20, the proton beam P is made to get on target T and generates neutron,
Reaction principle is：The charged particles such as proton, deuteron accelerate to the energy for being enough to overcome target atom core Coulomb repulsion via accelerator,
Nuclear reaction occurs with metallic target T and generates daughter nucleus and neutron, wherein common metal targets are usually lithium and beryllium.It is produced by this method
Raw is mixed radiation field, when being irradiated using the neutron capture therapeutic device, needs to reduce other types as far as possible
Radiation, and the slow body 32a in beam-shaping body 30a has the function of the adjustment mixed radiation field energy, reflector
31a reflects the mixed radiation field spread to other directions, and to reduce the loss of neutron, beam-shaping body 30a can be with
Including thermal neutron absorber 33a, the relatively low thermal neutron of energy can be absorbed, one layer is set outside the beam-shaping body 30a
Radiation shield device 34a damages neighbouring people to avoid ray leakage.The rear portion of beam-shaping body 30a is equipped with standard
Straight device 40a, the beam after beam-shaping body 30a adjustment are converged again by collimator 40a.
As shown in Figure 3 be neutron capture therapeutic device that neutron source is reactor, wherein pile neutron source 10b leads to
The neutron beam N of generation is transferred to beam-shaping body 30b, pile neutron source 10b as accelerator 10a neutron sources by piping
What is generated is all mixed radiation field, and the higher fast neutron of the energy in the mixed radiation field passes through slow in beam-shaping body 30b
Fast body 32b is slowly the neutron that can destroy amyloid beta structure, and the ray spread to other directions is anti-by reflector 31b
It is emitted back towards in slow body 32b, to improve the utilization rate of ray；Thermal neutron absorber 33b in beam-shaping body can absorb mixing
The relatively low thermal neutron of energy in radiation field is so that epithermal neutron content higher in neutron beam N, and the neutron beam N is by accurate
The convergence of straight device 40b, to improve the precision that neutron exposure is.
The technical solution further illustrated the present invention below by embodiment.
Boron element in compound of the present invention is10It can contain radioactive element in B and the compound11C。
If do not done specified otherwise, the boron element in the compound of boracic of the present invention is10B。
<Embodiment 1>With the preparation method of the compound of amyloid beta specific binding
Compound 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles with amyloid beta specific binding can
It is prepared by reacting as follows：
2- (4- nitrobenzenes) -6- bromo benzothiazoles of 1g are dissolved in the ethyl alcohol of 10mL, add 5.39g's
SnCl2.2H2O, the reaction system stir 1h under conditions of 100 DEG C and obtain 2- (4- aminobenzenes) -6- bromo benzothiazoles；
1H NMR:400MHz DMSO
δ 8.29 (s, 1H), 7.80-7.82 (d, J=8.8Hz, 1H), 7.74-7.76 (d, J=8.8Hz, 2H), 7.58-
7.60 (m, 1H), 6.65-6.67 (d, J=8.4Hz, 2H), 5.95 (s, 2H).
16.4mmol formaldehyde is added in into 2- (4- aminobenzenes) -6- bromo benzothiazoles of 1g, then adds in 10mL's thereto
The sodium methoxide composition reaction solution of the methanol of tetrahydrofuran (THF) and 20mL, again property addition 0.886g, the reaction solution is 65
12h is stirred to react under conditions of DEG C, reaction solution is then cooled to 25 DEG C, adds in the sodium borohydride (NaBH of 620.41mg4), then
Reaction temperature is risen to 65 DEG C, 1h is stirred to react and obtains 2- (4- methylaminos benzene) -6- bromo benzothiazoles；
1H NMR:400MHz CDCl3
δ 7.97 (s, 1H), 7.89-7.91 (d, J=8.8Hz, 2H), 7.81-7.83 (d, J=8.8Hz, 1H), 7.52-
7.54 (m, 1H), 6.64-6.66 (d, J=8.8Hz, 2H), 2.93 (s, 3H).
By 2- (4- methylaminos benzene) -6- bromo benzothiazoles, the connection boric acid pinacol ester of 95.46mg and 92.23mg of 100mg
Potassium acetate form reaction system, into reaction system add in 4mL THF and 2mL dimethyl sulfoxide (DMSO) (DMSO), filled at 20 DEG C
The dichloro two (triphenyl phosphorus) that 26.39mg is added under conditions of nitrogen closes palladium (Pd (PPh3)2Cl2), it is stirred to react under the conditions of 90 DEG C
12h obtains 2- (4- methylaminos benzene) -6- pinacol borate benzothiazoles, and the wherein boron in connection boric acid pinacol ester is10B；
20mLTHF and 10mL water is added in 2- (4- methylaminos benzene) -6- pinacol borates benzothiazole of 300mg, then
Add in 875.93mg sodium metaperiodates (NaIO4) reaction system is formed, which is stirred to react 12h under the conditions of 25 DEG C
Obtain 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles.The compound1HNMR scanning spectras are as shown in Figure 1.
1H NMR:400MHz MeOH
δ 8.27 (s, 1H), 7.83-7.85 (m, 4H), 6.66-6.68 (d, J=7.6Hz, 2H), 2.85 (s, 3H).
Wherein, 2- (4- nitrobenzenes) -6- bromo benzothiazoles can be prepared by following steps：
The bromo- benzothiazoles of 2- amino -6- of 5g are added in the potassium hydroxide solution of a concentration of 10M of 25mL, add 5mL
The mixed solution that ethylene glycol is formed is stirred to react 2h in 125 DEG C, obtains 2- amino -5- bromothiophenols；
1H NMR:400MHz DMSO
δ7.21-7.26(m,1H),6.99(s,1H),6.81-6.72(m,1H),6.39(s,1H),5.72(s,2H)。
The paranitrobenzaldehyde of 1.48g is added in the 2- amino -5- bromothiophenols of 2g, the DMSO for adding 40mL is formed instead
Solution is answered, the reaction solution is stirred to react 0.5h in 180 DEG C, obtains 2- (4- nitrobenzenes) -6- bromo benzothiazoles；
1H NMR:400MHz DMSO
δ 8.54 (s, 1H), 8.34-8.41 (m, 4H), 8.07-8.09 (d, J=8.8Hz, 1H), 7.74-7.77 (m, 1H).
The specific reaction process of described 2- (4- methylaminos the benzene) -6- dihydroxy boryl benzothiazoles is synthesized in the present embodiment
(boron element in the reaction equation is as shown in reaction equation II10B)：
Reaction equation II
<Embodiment 2>With the preparation method of the compound of amyloid beta specific binding
In the present embodiment the synthetic method of 2- (4- nitrobenzenes) -6- bromo benzothiazoles and<Embodiment 1>Shown synthesis side
Method is identical.
Into 2- (4- nitrobenzenes) -6- bromo benzothiazoles of 100mg add in 90.91mg connection boric acid pinacol ester and
The potassium acetate of 87.84mg adds the DMSO of the THF and 2mL of 4mL, and the dichloro two of 25mg is added under conditions of 20 DEG C of nitrogen charging
(triphenyl phosphorus) closes palladium, and reaction system is stirred to react 15h under the conditions of 95 DEG C and obtains 2- (4- nitrobenzenes) -6- pinacol borates
Boron in benzothiazole, wherein connection boric acid pinacol ester is10B；
1H NMR:400MHz CDCl3
δ 8.44 (s, 1H), 8.35-8.37 (d, J=8.8Hz, 2H), 8.28-8.30 (d, J=8.8Hz, 2H), 8.11-
8.13 (d, J=8Hz, 1H), 7.96-7.98 (d, J=8Hz, 1H), 1.40 (s, 12H).
The THF and 10mL of 30mL is added in into 2- (4- nitrobenzenes) -6- pinacol borate benzothiazoles of 539.7mg
Water adds the sodium metaperiodate of 1.51g, which reacts 23h under the conditions of 25 DEG C and obtain 2- (4- nitrobenzenes) -6- two
Dihydroxyboryl benzothiazole；
1H NMR:400MHz DMSO
δ 8.56 (s, 1H), 8.36-8.42 (m, 4H), 8.29 (m, 2H), 8.10-8.12 (d, J=8.4Hz, 1H), 8.00
(m,1H)。
200mg catalyst Pd/C are added in into 100mL methanol, add 2- (4- nitrobenzenes) -6- dihydroxy boron of 180mg
Base benzothiazole forms reaction system, and the reaction system vacuum outgas and is reacted under hydrogen environment under the conditions of 25 DEG C
10min generates 2- (4- aminobenzenes) -6- dihydroxy boryl benzothiazoles；
1H NMR:400MHz MeOH
δ 8.29 (s, 1H), 7.80-7.84 (m, 4H), 6.74-6.76 (d, J=8.8Hz, 2H).
After carrying iodomethane by being heated to 200 DEG C of silver triflate pipe using nitrogen, then it is passed into dissolving
Reaction solution is formed in the anhydrous propanone for there are 2- (4- aminobenzenes) -6- dihydroxy boryl benzothiazoles, by reaction solution in 80 DEG C of reactions
After 5min plus water quenches, and obtains 2- (4 methylamino benzene) -6- dihydroxy boryl benzothiazoles.
C wherein in iodomethane can be with radioactive11C, the 2- synthesized by it (4- methylaminos benzene) -6- dihydroxy
Boryl benzothiazole equally has radioactive element11C, therefore should have radioactive compound that can combine to chase after with PET
Track amyloid beta is deposited on the position of brain and the diagnosis of AD.
1H NMR:400MHz MeOH
δ 8.27 (s, 1H), 7.83-7.85 (m, 4H), 6.66-6.68 (d, J=7.6Hz, 2H), 2.85 (s, 3H).
(B in the reaction equation is the reaction process of the present embodiment as shown in reaction equation III10B)：
Reaction equation III
<Embodiment 3>112- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles of C flag are preparing amyloid beta
Application in PET developers
By experimental method well known to those skilled in the art, by<Embodiment 2>Middle synthesis by112- (the 4- methylamines of C flag
Base benzene) the HPLC purifying of -6- dihydroxy boryl benzothiazoles Jing Guo preparative, its radio-chemical purity is after purification
The retention time of 98.15%, HPLC are -6 dihydroxy boryl benzothiazole of 5.43min and standard items 2- (4- methylaminos benzene)
Retention time it is consistent, it may be determined that purified product be required radioactive compound.
It is detected using HPLC11The stabilization of 2- (4- methylaminos the benzene) -6- dihydroxy boryls benzothiazole of C flag in vitro
Property, time are selected as 30min and 60min, and (1) figure in attached drawing 4 is stability 30min radioactivity collection of illustrative plates, and (2) figure is stability
The radio-chemical purity of 60min radioactivity collection of illustrative plates, 30min and 60min are 100%, therefore, described11The radioactivity of C flag
The radio-chemical purity of compound meets requirement of experiment.
<Embodiment 4>112- (4- methylaminos the benzene) -6- dihydroxy boryl benzothiazoles and amyloid beta of C flag are special
Property combine experiment
SAMP8 (senescence accelerated mouse prone 8) mouse is current most common research AD
The animal model of (alzheimer's disease), for brain there are much starch sample proteinosis patch, the present embodiment uses SAMP8 small
Mouse is as model mouse, and for routine experimentation mouse as control mouse, model mouse and control mouse were 10 monthly ages, were noted respectively to both mouse
Penetrate containing112- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles of C flag, then 2- is studied by Micro-PET scannings
Whether (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles and amyloid beta have the property of specific binding.
The model mouse and control mouse that weight is 31.5 ± 0.3g are chosen respectively, inject 31.0 ± 0.6 μ Ci's to it respectively11C
2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles of label, and with the Micro-PET of Siemens model INVEON into
Row scanning, wherein scanning energy window is 350-650KeV.
The known ground of those skilled in the art, causes the main cause of disease of alzheimer's disease to deposit patch for amyloid beta
The cerebral cortex and hippocampus of brain are accumulated in, the present embodiment is scanned by Micro-PET and utilizes PMOD softwares to model mouse
It is compared with control mouse brain, analysis determines that SAMP8 model mouses and the cerebral cortex for compareing mouse and hippocampus are put to having
The absorption of 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles of penetrating property, to illustrate that can the compound to beta-amyloyd egg
White deposition patch can be specifically bound, and concrete outcome is as shown in Table 1 and Table 2：
Table 1, model mouse and control mouse cerebral cortex are to radioactivity 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles
Intake
As can be seen from Table 1：After injection of the radiopharmaceutical the 35th minute when, model mouse with compare mouse cerebral cortex intake
The ratio of amount is up to 2.7, higher than the boron concentration proportion (2.5) of the target and non-target of the treatment of effective boron neutron capture, this result
Explainable radioactivity 2- (4- methylaminos benzene) -6- dihydroxy boryls benzothiazole effectively can deposit spot knot with amyloid beta
It closes, and accumulates in affected area.The patient using boron neutron capture treatment alzheimer's disease can more be expected, affected area is subjected to
A large amount of dose of radiation achievees the purpose that treatment, and reduces the radiation injury of normal cerebral tissue.
The hippocampus of table 2, model mouse and control mouse is to radioactivity 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles
Intake
From table 2 it can be seen that 25 and 35 minutes after radiopharmaceutical injection, model mouse and the hippocampus ratio for compareing mouse
It is all 3.2, the boron concentration proportion (2.5) of the target and non-target of the high effective boron neutron capture treatment of what, this result can also prove
Radioactivity 2- (4- methylaminos benzene) -6- dihydroxy boryls benzothiazole can be combined effectively with amyloid beta deposition patch, and
Accumulate in affected area.
Morbidity mouse of the SAMP8 model mouses for the alzheimer's disease of accelerated ageing, in the disease of cerebral cortex and hippocampus
A large amount of amyloid beta deposition patch has all been built up at stove position, passes through model mouse in Tables 1 and 2 and the experiment number of control mouse
According to the cerebral cortex and hippocampus that can be seen that SAMP8 model mouses compared to normal control mouse to 2- (4- methylaminos benzene) -6-
Dihydroxy boryl benzothiazole has stronger absorbability, therefore illustrates 2- (4- methylaminos benzene) -6- dihydroxy boryl benzene
And thiazole and amyloid beta have specificity, can more treat to treat alzheimer's disease in the future using boron neutron capture,
Another advanced therapeutic modality is provided for alzheimer's disease patient.
According to the analysis result of table 2, radioactivity 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles are injected in mouse
Afterwards 25 to 35 minutes, radiopharmaceutical with the ratio for compareing mouse was all 3.2, therefore take centre in the hippocampus of model mouse brain
The radioactive 2- of further comparison (4- methylaminos benzene) -6- dihydroxy boryl benzo thiophenes of the Micro-PET striographs of value 30min
The situation that azoles is gathered in brain.
Fig. 5 is that PET when injecting radioactive 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazole 30min is swept
It retouches and through the processed image of AMIDE softwares, image when wherein A figures are control mouse injection of radioactive substances 30min, in A figures
(1) figure is control mouse coronal section scan-image, and (2) figure is section scanning figure of (1) figure along Y-axis, and (3) figure is (1) figure along X
Axial brain section scanning figure；Image when B figures are SAMP8 model mouse injection of radioactive substances 30min, similarly, in B figures
(1) figure is model mouse coronal section scan-image, and (2) figure is section scanning figure of (1) figure along Y-axis, and (3) figure is (1) figure along X
Axial brain section scanning figure.
(3) in (3) and B figures wherein in A figures can reflect brain radiopharmaceutical absorbing state, by this two width image
Comparison is as can be seen that the brain accumulation that the brain of the SAMP8 model mouses in B figures (3) schemes the control mouse in (3) relative to A has greatly
The radiopharmaceutical of amount, and there are known models mouse brain a large amount of amyloid betas to deposit patch, and 2- (4- first thus can be explained
Amido benzene) -6- dihydroxy boryl benzothiazoles to amyloid beta deposition patch have specificity, and future 2- (4- methylaminos
Benzene) -6- dihydroxy boryls benzothiazole available for boron neutron capture treat.
<Embodiment 5>It simulates 2- (4 methylamino benzene) -6- dihydroxy boryl benzothiazoles and is preparing elimination amyloid beta
Drug middle application experiment
The present embodiment boric acid (H3 10BO3) replace 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles, wherein
Boric acid (H3 10BO3) in boron element be10B simulates amyloid beta, by boric acid and ox blood with bovine serum albumin(BSA) (BSA)
The mixed solution that pure albumen is formed is placed in neutron capture therapeutic device and generates in neutron beam environment, passes through PAGE gel
Electrophoretic analysis neutron is to the effect of bovine serum albumin(BSA) and in H3 10BO3Under the conditions of existing, neutron is to bovine serum albumin(BSA)
Effect.
First, effect of the neutron to bovine serum albumin(BSA)
With the BSA solution that ultra-pure water configuration concentration is 0.01% (w/w), the solution of configuration is preserved under the conditions of 4 DEG C and reality
Test operation, 1mLBSA solution taken to be placed on the center line of the collimator port of neutron capture therapeutic device, wherein the solution away from
For 2cm with a distance from collimator port, setting neutron capture therapeutic device so that neutron intensity at collimator port for 2.4 ×
1011A/s, the BSA solution irradiate 2h in the Neutron Environment；It is another that 1mLBSA solution is taken to be shone as comparison liquid without neutron
It penetrates.
With coomassie brilliant blue staining and PAGE gel electricity will be done respectively with the BSA solution and comparison liquid of neutron exposure 2h
Swimming, is respectively quantified the color of protein band in the electrophoresis pattern of above-mentioned sample liquid and comparison liquid with Image J softwares,
Numerical value is used for representing the relative amount of protein, and the wherein BSA contents in defining contrast liquid are 1, are tested in above-mentioned neutron exposure
Under the conditions of, the content of the BSA after neutron exposure 2h is 0.8, and content probably has 20% reduction, it can be seen that, include
The radiation of neutron beam can influence the content of protein.
2nd, in H3 10BO3Under the conditions of existing, effect of the neutron to bovine serum albumin(BSA)
BSA and H is configured with ultra-pure water3 10BO3Solution, wherein, in the solution, a concentration of 0.01% (w/ of BSA
W), H3 10BO3A concentration of 0.18M；The solution of configuration is preserved at 4 DEG C and experimental implementation, takes 8 parts respectively from the solution
(number is respectively A, B, C, D, E, F, G, H), the solution of every part of 1mL is irradiated with neutron capture therapeutic device, respectively by 8 parts
Solution is placed on the center line of neutron capture therapeutic device collimator port, and distance of the solution A apart from collimator port is 2cm,
Solution B is 4cm apart from the outlet of collimator, and solution C is 6cm apart from the outlet of collimator, and so on.At collimator port
Beam in addition to including neutron ray, further include gamma ray and other radiation, destruction played to protein in reality and is made
Mainly neutron ray, the present embodiment describe the intensity of the beam with the neutron intensity in beam, wherein, this implementation
The neutron neutron intensity that uses of example is 2.4 × 1011A/s, 8 parts of solution irradiate 2h in the Neutron Environment；Separately from the BSA and
H3 10BO31mL is taken in solution, and as comparison liquid, the comparison liquid is without neutron exposure.
8 parts of solution that comparison liquid and the irradiation with radiation radiated through neutron capture therapeutic device are crossed are used into coomassie respectively
Brilliant blue dyes and does PAGE gel electrophoresis, and Fig. 6 show comparison liquid and the SDS-PAGE electrophoresis spectrum of 8 parts of solution.
The first two protein band is the BSA in comparison liquid in Fig. 6, remaining is respectively after the irradiation with radiation
BSA, 8 parts of solution are placed on collimator port center line, due to containing H in the solution on the center line3 10BO3,
And10B element has thermal neutron larger capture cross section, therefore from the neutron in the radiation that collimator port comes out by containing
H3 10BO3Solution after, neutron dose significantly declines, the solution more remote from collimator port, the radiation that BSA is received
Dosage is fewer.
From fig. 6, it can be seen that 8 solution through neutron exposure, compared to control sample, the color of protein band has
Different degrees of shoals, also, nearer from collimator port, and the color of the protein band in solution is more shallow, illustrates that albumen contains
Amount is reduced more, and nearer from collimator port, and the neutron irradiation dosage that solution is subject to is bigger, is further illustrated, neutron agent
The size of amount influences the content of BSA in solution, and neutron dose is stronger, and the content of BSA is got in the solution after the neutron exposure
It is few.
With Image J softwares respectively by the color of the BSA protein bands in comparison liquid and the corresponding electrophoresis pattern of 8 parts of solution
Being quantified, numerical value is used for representing the relative amount of albumen, wherein, the BSA contents in defining contrast liquid are 1, in above-mentioned
Under son irradiation experiment condition, the content of the BSA after neutron exposure 2h is as shown in table 3.
As can be seen from Table 3, BSA contents have different degrees of reduction in the solution through neutron exposure, apart from collimator
The solution of outlet 2cm is 2.4 × 10 through neutron intensity11After the neutron exposure 2h of a/s, BSA contents only surplus 5.3% illustrate
H3 10BO3Under the conditions of existing, neutron can significantly destroy BSA structures, reduce the content of BSA；And allow in experimental error
In the range of, 8 solution are more remote with distance of the solution apart from collimator port, and BSA contents are integrally in reduced trend, into one
Step illustrates content of the size to influence BSA of neutron dose.
Table 3, in H3 10BO3Under existence condition, effect of the neutron to bovine serum albumin(BSA)
| Solution numbers | BSA contents (%) |
| Comparison liquid | 100 |
| A | 5.3 |
| B | 2.6 |
| C | 18.9 |
| D | 14.0 |
| E | 22.9 |
| F | 35.1 |
| G | 49.6 |
| H | 60.7 |
Compound 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles and H provided by the invention3 10BO3Equally carry
The nucleic for having thermal neutron capture cross section big10B, and the compound can be specifically bound with amyloid beta, by the chemical combination
Object is placed in the environment containing amyloid beta, and the compound can form higher concentration around amyloid beta,
The region of the compound accumulation is irradiated with the neutron beam that neutron capture therapeutic device emits again, the energy of release can destroy
The structure of protein.
The present invention will be described for specific embodiment listed above, it should be pointed out that above example is served only for hair
It is bright to be described further, protection scope of the present invention is not represented, other people are according to the present invention to prompt that makes nonessential to repair
Change and adjust, still fall within protection scope of the present invention.
Claims (6)
1. a kind of compound, which is characterized in that the compound has such as structure structure shown in formula A,
Wherein, R1For-NO2Or-NH2,
Work as R1For-NO2When, the compound is 2- (4- nitrobenzenes) -6- dihydroxy boryl benzothiazoles；
Work as R1For-NH2When, the compound is 2- (4- aminobenzenes) -6- dihydroxy boryl benzothiazoles.
2. compound as described in claim 1, which is characterized in that the boron element in the compound is10B。
3. the preparation method of compound as described in claim 1, which is characterized in that 2- (4- the nitrobenzenes) -6- dihydroxy
Boryl benzothiazole is prepared via a method which：
By 2- (4- nitrobenzenes) -6- bromo benzothiazoles and connection boric acid pinacol ester reaction generation 2- (4- nitrobenzenes) -6- boric acid frequency
The step of any alcohol ester benzothiazole；
2- (4- nitrobenzenes) -6- pinacol borates benzothiazoles are by oxidizing for 2- (4- nitrobenzenes) -6- dihydroxy boron
The step of base benzothiazole.
4. the preparation method of compound as described in claim 1, which is characterized in that 2- (4- the aminobenzenes) -6- dihydroxy
Boryl benzothiazole is prepared by 2- (4- nitrobenzenes) -6- dihydroxy boryl benzothiazoles through reduction reaction.
5. compound as claimed in claim 1 or 2 is being prepared and answering in the compound of amyloid beta specific binding
With, which is characterized in that the compound of described and amyloid beta specific binding is 2- (4- methylaminos benzene) -6- dihydroxy boron
Base benzothiazole.
6. application as claimed in claim 5, which is characterized in that the compound of described and amyloid beta specific binding by
Structural formula A compounds represented are prepared via a method which：
2- (4- the nitrobenzenes) -6- dihydroxy boryl benzothiazoles are reduced to the 2- (4- amino by reduction reaction
Benzene) -6- dihydroxy boryl benzothiazoles；
2- (4- the aminobenzenes) -6- dihydroxy boryls benzothiazole, iodomethane and silver triflate are under the high temperature conditions
Reaction generation 2- (4- methylaminos benzene) -6- dihydroxy boryl benzothiazoles.
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|---|---|---|---|---|
| CN1112946C (en) * | 1994-06-27 | 2003-07-02 | 中子治疗有限公司 | Boron neutron capture enhancement of fast neutron therapy |
| WO2014003336A1 (en) * | 2012-06-27 | 2014-01-03 | 덕산하이메탈(주) | Compound, electro-organic device using same, and electronic device thereof |
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2016
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1112946C (en) * | 1994-06-27 | 2003-07-02 | 中子治疗有限公司 | Boron neutron capture enhancement of fast neutron therapy |
| WO2014003336A1 (en) * | 2012-06-27 | 2014-01-03 | 덕산하이메탈(주) | Compound, electro-organic device using same, and electronic device thereof |
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| Title |
|---|
| CHESTER A.MATHIS等: ""Synthesis and Evaluation of 11C-Labeled 6-Substituted 2-Arylbenzothiazoles as Amyloid Imaging Agents"", 《J.MED.CHEM.》 * |
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