WO2017114316A1 - 用于消除β淀粉样蛋白的中子捕获治疗系统 - Google Patents

用于消除β淀粉样蛋白的中子捕获治疗系统 Download PDF

Info

Publication number
WO2017114316A1
WO2017114316A1 PCT/CN2016/111811 CN2016111811W WO2017114316A1 WO 2017114316 A1 WO2017114316 A1 WO 2017114316A1 CN 2016111811 W CN2016111811 W CN 2016111811W WO 2017114316 A1 WO2017114316 A1 WO 2017114316A1
Authority
WO
WIPO (PCT)
Prior art keywords
neutron
compound
neutron capture
amyloid beta
formula
Prior art date
Application number
PCT/CN2016/111811
Other languages
English (en)
French (fr)
Inventor
刘渊豪
何静
陈瑞芬
Original Assignee
南京中硼联康医疗科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京中硼联康医疗科技有限公司 filed Critical 南京中硼联康医疗科技有限公司
Priority to EP16881105.7A priority Critical patent/EP3384960B1/en
Priority to RU2018127690A priority patent/RU2721284C2/ru
Priority to JP2018529662A priority patent/JP6709284B2/ja
Publication of WO2017114316A1 publication Critical patent/WO2017114316A1/zh
Priority to US16/010,818 priority patent/US10709783B2/en

Links

Images

Classifications

    • 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
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1077—Beam delivery systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
    • A61N2005/1019—Sources therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
    • A61N2005/1019—Sources therefor
    • A61N2005/1021—Radioactive fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1085—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy characterised by the type of particles applied to the patient
    • A61N2005/109—Neutrons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092—Details
    • A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device

Definitions

  • the present invention relates to a neutron capture therapy system, and more particularly to a neutron capture therapy system capable of eliminating beta amyloid.
  • AD Alzheimer's disease
  • Histopathological manifestations are mainly senile plaques, neurofibrillary tangles, and regional nerve cells caused by apoptosis. Death, etc.
  • amyloid ⁇ -protein (abbreviated as A ⁇ ) is one of the main pathogenesis of Alzheimer's disease.
  • Amyloid ⁇ is a polypeptide containing 39 to 43 amino acids produced by proteolysis of ⁇ - and ⁇ -secretase by amyloid precursor protein (APP). It is common in humans to contain 40 (A ⁇ 1-40 ) or 42 (A ⁇ 1 ⁇ 42 ) amino acid polypeptides, wherein A ⁇ 1 ⁇ 42 is more toxic, more easily accumulates into the core of ⁇ amyloid deposition plaque, and ⁇ amyloid deposition formed after ⁇ amyloid deposition Plaques can cause neurotoxic effects. Under normal physiological conditions, amyloid beta can be detected in both blood and cerebrospinal fluid, which indicates that beta amyloid itself does not cause Alzheimer's disease, and deposition of amyloid beta is caused by Al One of the causes of Zheimer's disease.
  • Amyloid beta protein can be degraded by various peptidases, such as insulin degrading enzyme (IDE) and neutral endopeptidase (NEP), both of which are zinc-dependent endoproteases, studies have shown that in IDE Under the condition of NEP, ⁇ amyloid protein is significantly reduced. However, under the condition of IDE and NEP deletion, how to destroy the structure of ⁇ amyloid and reduce the accumulation of amyloid ⁇ become the pathogenesis of Alzheimer's disease. Even one of the means to treat Alzheimer's disease, there is currently no way to effectively destroy the structure of amyloid beta.
  • IDE insulin degrading enzyme
  • NEP neutral endopeptidase
  • one aspect of the invention provides a neutron capture therapeutic system for eliminating beta amyloid, comprising: a neutron capture therapeutic device and a neutralizing device a compound that specifically binds to amyloid beta,
  • the compound comprises a nuclides having a large cross section for thermal neutron capture
  • the neutron beam generated by the neutron capture treatment device acts on the nucleus on the compound to destroy the energy The structure of the powdery protein, thereby achieving the purpose of eliminating these pathogenic proteins.
  • the beam generated by the neutron capture treatment device is a mixed beam comprising neutron rays, gamma rays, and other radiation, but is used in the process of using the beam to eliminate ⁇ amyloid.
  • the main thing is the neutron beam in the mixed beam.
  • Nuclides with large cross section for thermal neutron capture include, but are not limited to, 10 B, 155 Gd or 157 Gd.
  • the nuclide which has a large cross section for thermal neutron capture means that under the thermal neutron irradiation of the same energy, the neutron capture cross section is greater than or equal to the basic constituent elements of the human body (C, H, O, N, P, S).
  • the neutron captures nuclei 100 times or more of the cross section, wherein the neutron capture cross section of H which constitutes the basic constituent elements of the human body under the thermal neutron irradiation of the same energy is the largest, and the thermal neutron energy is 0.025 eV.
  • the thermal neutron capture cross section is 0.2 barn, the thermal neutron capture cross section of 10 B is 3800 barn, the thermal neutron capture cross section of 155 Gd is 60700 barn, and the thermal neutron capture cross section of 157 Gd is 254000 barn, both larger than the same energy.
  • the thermal neutron capture cross section of the H element under thermal neutron irradiation is 100 times.
  • the nucleus having a large thermal neutron capture cross section can undergo a nuclear reaction with thermal neutron action, releasing at least one lethal radiation having a short range and substantially destroying only the beta starch specifically bound to the compound.
  • the structure of the protein, without destroying other normal tissues, has little harm to normal tissues.
  • the nuclide having a large thermal neutron capture cross section is 10 B, 155 Gd or 157 Gd.
  • the radionuclide 10 B with a large thermal neutron capture cross section undergoes the following reaction under the irradiation of neutron rays, and the radiant energy:
  • the boron-containing ( 10 B) compound has a high capture cross section for thermal neutrons, and 4 He and 7 Li heavy loads are generated by 10 B(n, ⁇ ) 7 Li neutron capture and nuclear splitting reaction.
  • the average energy of the two charged particles is about 2.33 MeV, which has high linear transfer (LET) and short range characteristics.
  • the linear energy transfer and range of the ⁇ particles are 150 keV/ ⁇ m and 8 ⁇ m, respectively.
  • the 7 Li heavy particles are 175 keV/ ⁇ m, 5 ⁇ m.
  • the total range of the two particles is about one cell size. Therefore, the radiation damage caused by the organism can be limited to the cell level, when the boron-containing compound is specific to amyloid ⁇ . In the case of sexual combination, with the appropriate neutron source, the purpose of locally destroying the structure of amyloid beta protein can be achieved without causing too much damage to normal tissues.
  • the neutron capture therapy device comprises a neutron source, a beam shaping body and a collimator.
  • the neutron source is used to generate a neutron beam.
  • the beam shaping body is located at the rear of the neutron source and adjusts the fast neutrons in the neutron beam generated by the neutron source with a broader energy spectrum to super-thermal neutrons or thermal neutrons, generally
  • the fast neutron is defined as a neutron with an energy region greater than 40 keV
  • the superheated neutron energy region is between 0.5 eV and 40 keV
  • the thermal neutron energy region is less than 0.5 keV.
  • the collimator is located at the rear of the beam shaping body for converging the epithermal neutrons or thermal neutrons to make the treatment more targeted, and adopting a proper caliber collimation for different sizes of amyloid beta deposition plaques. Device.
  • the neutron source comprises an accelerator neutron source or a reactor neutron source.
  • the accelerator neutron source bombards an appropriate target nucleus (such as a lithium target or a ruthenium target) by accelerating charged particles (such as a proton beam), and generates neutrons through a nuclear reaction, and the most common nuclear reactions are (d, n), (p) , n) and ( ⁇ , n), etc.
  • an appropriate target nucleus such as a lithium target or a ruthenium target
  • accelerating charged particles such as a proton beam
  • the reactor neutron source generates a large number of neutrons by using a nuclear fission reactor.
  • a neutron source is the strongest thermal neutron source. Opening a hole in the wall of the reactor, the neutron can be extracted, and the resulting neutron energy is obtained. It is continuously distributed, very close to the Maxwell distribution, and certain measures are taken to obtain neutron beams of various energies.
  • the beam shaping body comprises a reflector and a retarding body, wherein the reflector surrounds the retarding body for directing The neutrons diffused outside the beam shaping are reflected back into the slowing body, which is used to slow the fast neutrons into epithermal neutrons or thermal neutrons.
  • the reflector is made of at least one of Pb or Ni;
  • the material of the retarder may be one of Al 2 O 3 , BaF 2 , CaF 2 , CF 2 , PbF 2 , PbF 4 and D 2 O Or a combination of several kinds, or may be composed of a lithium-containing substance added to the material of the slow-moving body, such as LiF or Li 2 CO 3 containing 6 Li.
  • the beam shaping body further comprises a thermal neutron absorber and a radiation shield, etc., wherein the thermal neutron absorber is made of 6 Li, and the radiation shield comprises a photon shield made of Pb and made of PE. Sub-shield.
  • the thermal neutron absorber is adjacent to the retarding body for absorbing thermal neutrons to avoid excessive doses with shallow normal tissue during treatment;
  • radiation shielding includes photon shielding made of Pb and neutron shielding made of PE Used to shield leaking neutrons or photons to reduce the normal tissue dose in the non-irradiated area, wherein the photon shield can be integrated with the reflector, and the neutron shield can be placed in the beam shaping body adjacent the beam exit.
  • the compound capable of specifically binding to amyloid ⁇ has a mechanism of formula I:
  • the compound of formula I is 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole, wherein B in the B(OH) 2 - group in the compound is 10 B; The abundance of 10 B nuclides in nature is 19.2%.
  • the 2-(4-methylaminophenyl)-6-dihydroxyboryl benzoate The boron element in B(OH) 2 - in the thiazole may be 10 B or 11 B, and the content of the compound containing 10 B element may be determined according to actual needs.
  • the methyl group of methyl 2-amino group in 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole is 12 C or 11 C, with 11 C of 2-(4-methylaminophenyl)-6-
  • dihydroxyborylbenzothiazole can also be used to determine the amyloid beta protein in the brain and used as an imaging agent for PET.
  • the compound of formula I acts as an intermediate in the neutron capture therapeutic system for the elimination of amyloid beta
  • the 10 B on the compound of formula I in the neutron capture therapeutic system is capable of capturing
  • the neutron captures the neutrons emitted by the therapeutic device and undergoes a nuclear reaction to generate energy that disrupts the structure of the beta amyloid protein that specifically binds to the compound of structural formula I, thereby reducing the beta amyloid content. Since the compound of structural formula I specifically binds to amyloid ⁇ , and 10 B on the compound is capable of capturing thermal neutrons, the neutron capture therapeutic system is efficient and target for elimination of amyloid beta Directional.
  • the compound of the formula I shown is prepared from the compound of the formula II:
  • the method of preparing a compound of formula I from a compound of formula II includes:
  • 2-(4-Methylaminophenyl)-6-boronic acid pinacol ester is oxidized by an oxidizing agent to the compound 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole of the formula I
  • the step wherein the oxidizing agent may preferably be sodium metaperiodate or other oxidizing agent similar to oxidizing and sodium metaperiodate.
  • the compound of formula I shown can also be prepared from the compound of formula II by the following reaction:
  • 2-(4-Aminophenyl)-6-dihydroxyborylbenzothiazole, methyl iodide and silver trifluoromethanesulfonate are reacted under high temperature to form the compound 2-(4-methylamino) of the formula I
  • 10 B of the compound of the formula I is derived from the reactant boranoic acid pinacol ester used. 10 B, as described above, the content of 10 B can be adjusted as needed.
  • C in methyl iodide may be 12 C or 11 C, and when C in methyl iodide is 11 C, the 2-(4-methylaminophenyl)-6-dihydroxyborylbenzo Thiazole is a compound labeled with radioactive element 11 C.
  • the 2-(4-methylaminophenyl)-6-dihydroxyborylbenzo Thiazole is a compound labeled with radioactive element 11 C.
  • it can also be used to prepare PET imaging agents for further localization of beta amyloid. In the position of the brain.
  • the compound capable of specifically binding to amyloid ⁇ protein in the present invention is not limited to the compound represented by Structural Formula I, and other compounds having a large neutron capture cross section and capable of specifically binding to amyloid ⁇ are present in Within the scope of protection of the present invention.
  • AV-45 is also capable of specifically binding to amyloid beta, and certain elements or functional groups of the compound are substituted by a group containing 10 B without changing its specificity to amyloid beta.
  • the nature of the binding, and its incident neutron beam irradiation can also destroy the structure of amyloid beta.
  • An aspect of the present invention provides a neutron capture therapeutic system for eliminating beta amyloid using a neutron capture therapeutic device, the system having the beneficial effect of specifically and efficiently eliminating beta amyloid; another aspect of the present invention Beta amyloid, which is also involved in the pathogenesis of Alzheimer's disease, also provides a compound that specifically binds to amyloid beta.
  • FIG. 1 is a schematic plan view of a neutron capture treatment system for an accelerator neutron source
  • FIG. 2 is a schematic plan view of a neutron capture treatment system for a reactor neutron source
  • Figure 3 is a 1 H NMR spectrum of a compound (2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole) which specifically binds to amyloid ⁇ ;
  • Figure A and Figure B are PET images of control mice and SAMP8 model mice after injection of 11 C-labeled 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole for 30 min;
  • Fig. 5 is an SDS-PAGE electrophoresis pattern of a mixed solution of BSA and H 3 10 BO 3 after being irradiated with radiation at different positions from the exit of the collimator, respectively.
  • the fast neutrons described herein are neutrons with an energy region greater than 40 keV, the superheated neutron energy region is between 0.5 eV and 40 keV, and the thermal neutron energy region is less than 0.5 keV.
  • Embodiments of the present invention provide a neutron capture therapeutic system for the purpose of targeted elimination of beta amyloid or reduction of beta amyloid content, the system comprising a neutron capture therapeutic device and capable of interacting with said beta starch A compound that specifically binds to a protein, which contains a nucleus with a large cross section for thermal neutron capture.
  • the commonly used nuclides are 10 B, 155 Gd, and 157 Gd.
  • the thermal neutrons of the neutron capture treatment device cause a nuclear reaction when the nuclide with a large cross section is captured by the thermal neutron, and the released energy destroys the structure of the amyloid beta.
  • the neutron capture treatment apparatus includes a neutron source, a beam shaping body, and a collimator, wherein the beam shaping body includes a reflector, a retarding body, a thermal neutron absorber, and a radiation.
  • the neutron source comprises an accelerator neutron source and a reactor neutron source.
  • the neutron capture therapeutic system In the practical application of the neutron capture therapeutic system to eliminate beta amyloid, it is usually necessary to adjust the fast neutrons in the mixed radiation field from the neutron source to super in the beam shaping of the neutron capture treatment device.
  • Thermal neutrons and reduce the content of other harmful rays in the mixed radiation field although the nuclide on the compound that specifically binds to amyloid beta is a nuclide with a large cross section for thermal neutron capture, but considering the neutron beam from During the process of capturing the collimator of the therapeutic device to a compound that specifically binds to amyloid beta, the energy of the neutron beam will be attenuated to some extent as the distance between the two increases, and the neutron shot During the process of reaching a compound that specifically binds to amyloid beta, there are often other substances that slow the energy of the neutrons to varying degrees, so in order to ensure the arrival of the compound neutrons that specifically bind to amyloid beta Energy and neutron intensity, usually need to slow the
  • the neutron capture therapy device in the neutron capture therapy system is an neutron capture therapy device of the accelerator neutron source, wherein the accelerator 10a accelerates the protons, and the cross-sectional area of the proton beam P is enlarged by the beam expander 20.
  • the proton beam P is struck on the target T and generates neutrons.
  • the reaction principle is that charged particles such as protons and helium nuclei are accelerated by the accelerator to an energy sufficient to overcome the Coulomb repulsion of the target atom, and a nuclear reaction occurs with the metal target T.
  • the daughter core and neutrons, among which the commonly used metal targets are usually lithium and ruthenium.
  • What is produced by this method is a mixed radiation field, and when the amyloid-producing device 53 is used, it is necessary to reduce other kinds of rays as much as possible, and the retarding body 32a in the beam shaping body 30a has an adjustment.
  • the action of the mixed radiation field energy the reflector 31a reflects back the mixed radiation field diffused in other directions to reduce the loss of the neutron, and the beam shaping body 30a may further include a thermal neutron absorber 33a capable of absorbing energy.
  • a radiation shielding device 34a is disposed outside the beam shaping body 30a to prevent radiation leakage from causing harm to nearby people.
  • a collimator 40a is attached to the rear portion of the beam shaping body 30a, and the beam adjusted by the beam shaping body 30a is concentrated by the collimator 40a to more accurately illuminate the core having a large cross section for thermal neutron capture.
  • Compound 52 which is capable of specifically binding to amyloid-like protein 53, is more fully utilized in the epithermal neutron beam.
  • the neutron capture therapy device in the neutron capture therapy system is a neutron capture therapy device of the reactor neutron source, wherein the reactor neutron source 10b transfers the generated neutron beam N to the beam shaping through the pipeline.
  • the body 30b, the reactor neutron source 10b and the neutron source of the accelerator 10a all generate a mixed radiation field, and the higher energy fast neutrons in the mixed radiation field are retarded by the retarding body 32b in the beam shaping body 30b.
  • the thermal neutron absorber 33b in the beam shaping body can be Absorbing the lower energy thermal neutrons in the mixed radiation field to make the ultrathermal neutron content in the neutron beam N higher, the neutron beam N being formed by the convergence of the collimator 40b can be used for more accurate Irradiation contains heat
  • the compound 52 capable of specifically binding to the pathogenic protein 53 of the nuclide 51 having a large cross section is more fully utilized for the epithermal neutron beam.
  • the neutron capture therapy system shown in Figures 1 and 2 further comprises a compound 52 capable of specifically binding to amyloid beta 53 and further comprising a nuclide 51 having a large cross section for thermal neutron capture.
  • Compound 52 acts as an intermediate in the process of neutron capture therapeutic system to eliminate amyloid beta, first of which compound 52 recognizes and binds to amyloid beta according to its properties of specific binding to amyloid beta 53 whereby the thermal neutron capture cross section will be larger nuclide (10 B) 51 and 53 amyloid ⁇ bind, at 50 to thermal neutron irradiation, thermal neutrons produced in the reaction and 10 B of the composition Energy destroys amyloid beta 53.
  • the compound specifically binding to amyloid ⁇ as described in the preferred embodiment of the present invention refers to 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole, wherein the boron element on the compound It is 10 B and the compound may contain a radioactive element 11 C. Unless otherwise specified, the boron element in the boron-containing compound described in the preferred embodiment of the present invention contains 10 B.
  • the compound 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole having the formula I can be produced by the following reaction:
  • 2-(4-nitrophenyl)-6-bromobenzothiazole can be prepared by the following steps:
  • C in methyl iodide may be radioactive 11 C, and 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole synthesized therefrom also has a radioactive element 11 C, so the radioactive
  • the compound can be used in combination with PET to track the location of beta amyloid deposition in the brain and the diagnosis of AD.
  • SAMP8 mice are currently the most common animal model for studying AD (Alzheimer's disease), and there are a large number of amyloid deposit plaques in the brain.
  • SAMP8 mice were used as model mice.
  • Ordinary experimental mice were used as control mice, and both model and control mice were 10 months old.
  • Two kinds of mice were injected with 11 C-labeled 2-(4-methylaminophenyl)-6-dihydroxyborylbenzene.
  • Thiazole was further examined by Micro-PET scanning to investigate whether 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole and amyloid beta have specific binding properties.
  • Model rats and control rats weighing 31.5 ⁇ 0.3g were selected and injected with 31.0 ⁇ 0.6 ⁇ Ci of 11 C-labeled 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole.
  • the Siemens model scans INVEON's Micro-PET with a scan energy window of 350-650KeV.
  • the ratio of cerebral cortex uptake of model rats to control rats at the 35th minute after radiopharmaceutical injection can reach 2.7, which is higher than the target and non-target boron concentration of effective boron neutron capture therapy.
  • the ratio (2.5) indicates that the radioactive 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole can effectively bind to the amyloid beta deposit and accumulate in the lesion. It is also expected that patients with Alzheimer's disease can be treated with boron neutron capture, which can receive a large amount of radiation dose for therapeutic purposes and reduce radiation damage from normal brain tissue.
  • SAMP8 model mice accumulate a large number of amyloid beta deposits in the lesions of Alzheimer's disease in the cerebral cortex and hippocampus, through the model rats and controls in Tables 1 and 2.
  • the experimental data of the rats showed that the cerebral cortex and hippocampus of the SAMP8 model rats had stronger absorption of 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole than the normal control mice.
  • the ability therefore, further illustrates the specificity of 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole and amyloid beta, and in the future, boron neutron capture therapy can be used to treat Alzheim.
  • Mohs disease provides another advanced treatment for patients with Alzheimer's disease.
  • the radioactive drug was administered to the hippocampus of the model rat brain and the control mice 25 to 35 minutes after the injection of radioactive 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole.
  • the ratio was 3.2, so a further comparison of the micro-PET image with a median value of 30 min was performed in the case where the radioactive 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole accumulated in the brain.
  • Figure 4 is a PET scan of the radioactive 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole at 30 min and processed by AMIDE software, wherein Figure A shows the control mice injected with radiopharmaceuticals.
  • Figure A shows the control mice injected with radiopharmaceuticals.
  • Figure A shows the control mice injected with radiopharmaceuticals.
  • Figure A shows the control mice injected with radiopharmaceuticals.
  • (1) is the scanned image of the coronal section of the control mouse
  • the figure is (1) the scanning view of the section along the Y axis
  • the figure is (1) the image along the X axis.
  • Figure B is the image of the SAMP8 model mice injected with radioactive drugs for 30 min.
  • Figure B (1) is the model mouse coronal section scan image
  • the figure is (1)
  • (3) is (1) the brain section scan along the X-axis.
  • (3) in Figure A and (3) in Figure B can reflect the absorption of radioactive drugs in the brain. Comparing the two images, it can be seen that the brain of SAMP8 model mice in Figure B (3) is relatively The control mice in Figure A (3) accumulate a large amount of radiopharmaceuticals in the brain, while the brains of known model mice have a large number of beta amyloid deposits, which can explain 2-(4-methylaminobenzene).
  • -6-Dihydroxyborylbenzothiazole is specific for beta amyloid deposition plaques, and future 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole can be used for boron neutron capture treatment.
  • boric acid H 3 10 BO 3
  • 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole wherein the boron element in boric acid (H 3 10 BO 3 ) is 10 B.
  • BSA bovine serum albumin
  • a mixed solution of boric acid and bovine serum albumin was placed in a neutron capture treatment device to generate a neutron beam environment, and analyzed by SDS-PAGE gel electrophoresis. The effect of neutrons on bovine serum albumin and the effect of neutrons on bovine serum albumin in the presence of H 3 10 BO 3 .
  • the BSA solution with a concentration of 0.01% (w/w) was placed in ultrapure water.
  • the prepared solution was stored at 4 ° C and experimentally operated.
  • 1 mL of BSA solution was placed on the center line of the collimator outlet of the neutron capture treatment device. Wherein the solution is 2 cm from the collimator exit distance, and the neutron capture treatment device is arranged such that the neutron intensity at the outlet of the collimator is 2.4 ⁇ 10 11 /s, and the BSA solution is in the neutron environment Irradiation for 2 h; another 1 mL of BSA solution was used as a control solution without neutron irradiation.
  • the BSA solution and the control solution which were irradiated with neutrons for 2 hours were stained with Coomassie brilliant blue and subjected to SDS-PAGE gel electrophoresis.
  • the color of the protein bands in the electrophoresis patterns of the above sample solution and the control solution were quantified by Image J software.
  • the value is used to indicate the relative content of the protein, wherein the BSA content in the control solution is defined as 1.
  • the content of BSA after neutron irradiation for 2 hours is 0.8, and its content is about 20%. The reduction, as can be seen, the radiation containing the neutron beam can affect the protein content.
  • a solution of BSA and H 3 10 BO 3 was prepared with ultrapure water, wherein the concentration of BSA in the solution was 0.01% (w/w), and the concentration of H 3 10 BO 3 was 0.18 M;
  • Store at 4 ° C and experimental operation take 8 parts from the solution (numbered A, B, C, D, E, F, G, H), and each 1 mL solution is treated with a neutron capture treatment device. Irradiation, respectively, 8 solutions were placed on the center line of the collimator outlet of the neutron capture treatment device, the distance of the solution A from the exit of the collimator was 2 cm, and the solution B was 4 cm from the outlet of the collimator.
  • the outlet of the straightener is 6cm, and so on.
  • the beam at the exit of the collimator includes gamma rays and other radiation in addition to the neutron rays.
  • the neutron rays are mainly used to destroy the protein.
  • the neutrons in the beam are used.
  • the intensity of the beam is described in terms of intensity, wherein the neutron intensity used in this embodiment is 2.4 x 10 11 /s, 8 parts of the solution are irradiated in the neutron environment for 2 h; and from the BSA and H 3 10 1 mL of the BO 3 solution was used as a control solution, and the control solution was not irradiated with neutrons.
  • control solution and the 8 solutions irradiated by the radiation received by the neutron capture treatment device were stained with Coomassie brilliant blue and subjected to SDS-PAGE gel electrophoresis.
  • Figure 5 shows the SDS-PAGE of the control solution and 8 parts of the solution. Electropherogram.
  • the first two protein bands in Figure 5 are BSA in the control solution, and the rest are BSA after irradiation with the radiation, and 8 solutions are placed on the center line of the collimator exit, due to the center line
  • the solution contains H 3 10 BO 3
  • the 10 B element has a large capture cross section for the thermal neutrons, so the neutrons in the radiation from the exit of the collimator pass through the solution containing H 3 10 BO 3
  • the sub-dose is drastically reduced, and the farther away from the collimator outlet, the less neutron radiation dose the BSA receives.
  • the color of the protein bands irradiated by the eight neutron-irradiated solutions is shallower to varying degrees compared to the control, and the closer to the outlet of the collimator, the solution is in the solution.
  • the lighter the color of the protein band the more the protein content is reduced, and the closer the outlet is to the collimator, the larger the neutron radiation dose of the solution, further indicating that the size of the neutron dose affects the BSA content in the solution.
  • the stronger the neutron dose the less the BSA content in the solution after the neutron irradiation.
  • the color of the BSA protein band in the electrophoresis pattern corresponding to the control solution and the 8 parts solution was quantified by Image J software, and the value was used to indicate the relative content of the protein, wherein the BSA content in the control solution was defined as 1.
  • the content of BSA after neutron irradiation for 2 hours is shown in Table 3.
  • the compound 2-(4-methylaminophenyl)-6-dihydroxyborylbenzothiazole provided by the present invention carries a radionuclide 10 B having a large thermal neutron capture cross section like H 3 10 BO 3 , and the compound can Binding to amyloid beta, placing the compound in an environment containing amyloid beta, which forms a higher concentration around amyloid beta, which is then emitted by a neutron capture therapy device The neutron beam illuminates the area where the compound accumulates, and the energy released can destroy the structure of the protein.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pathology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Radiation-Therapy Devices (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

一种能够消除β淀粉样蛋白的中子捕获治疗系统，该系统包括中子捕获治疗装置以及含有对热中子捕获截面大的核素的能够和β淀粉样蛋白特异性结合的化合物。该中子捕获治疗装置包括中子源、射束整形体和准直器，该中子源释放的中子通过该射束整形体缓速为一定能量范围内的中子射束，该中子射束照射该化合物，其反应所产生的的能量能够破坏β淀粉样蛋白的结构，该中子捕获治疗系统能够有针对性的消除β淀粉样蛋白，并且很大程度上降低了对β淀粉样蛋白周围组织的伤害。

Description

用于消除β淀粉样蛋白的中子捕获治疗系统 技术领域
本发明涉及一种中子捕获治疗系统，尤其是一种能够消除β淀粉样蛋白的中子捕获治疗系统。
背景技术
阿尔兹海默症(Alzheimer’s disease，通常简写为AD)是老年人中最常见的一种痴呆症，其组织病理学表现主要为老年斑，神经元纤维缠结以及由凋亡引起的区域性神经细胞死亡等。
有研究表明β淀粉样蛋白(Amyloidβ-protein，通常简写为Aβ)的异常沉积是阿尔兹海默症主要发病机制之一。β淀粉样蛋白是由淀粉样前体蛋白(APP)经β和γ分泌酶的蛋白水解作用而产生的含有39～43个氨基酸的多肽，人体内常见的是含有40(Aβ1～40)或42(Aβ1～42)个氨基酸的多肽，其中Aβ1～42具有更强的毒性，更容易聚积成β淀粉样蛋白沉积斑块的核心，β淀粉样蛋白沉积后形成的β淀粉样蛋白沉积斑块能够引发神经毒性作用。在正常的生理状态下，β淀粉样蛋白在血液和脑脊液中都能被检测出，由此可说明β淀粉样蛋白本身不会导致阿尔兹海默症，而β淀粉样蛋白的沉积是导致阿尔兹海默症的原因之一。
有研究表明阿尔兹海默症患者脑部的海马区和皮层区聚积有大量β淀粉样蛋白沉积斑块，并且降低β淀粉样蛋白在大脑内的蓄积量可延缓或者减轻阿尔兹海默症的症状。
β淀粉样蛋白可被多种肽酶降解，如胰岛素降解酶(IDE)和中性肽链内切酶(NEP)，这两种酶均是锌依赖性内切蛋白酶，有研究表明，在IDE和NEP存在的条件下，β淀粉样蛋白会显著减少，然而在IDE和NEP缺失的条件下，如何破坏β淀粉样蛋白的结构，减少β淀粉样蛋白的聚积成为研究阿尔兹海默症发病机制乃至于治疗阿尔兹海默症的手段之一，目前尚没有一种方法能够有效的破坏β淀粉样蛋白的结构。
发明内容
为了能够破坏β淀粉样蛋白的结构，消除β淀粉样蛋白，本发明的一方面提供了一种用于消除β淀粉样蛋白的中子捕获治疗系统，包括：中子捕获治疗装置以及能和所述β淀粉样蛋白特异性结合的化合物，
其中，所述化合物包含对热中子捕获截面大的核素；
所述中子捕获治疗装置产生的中子束作用到所述化合物上的核素后产生的能量破坏β淀 粉样蛋白的结构，从而实现消除这些致病蛋白质的目的。
实际应用中，所述中子捕获治疗装置产生的射束为包括中子射线、伽马射线及其他辐射线的混合射束，然而在运用所述射束消除β淀粉样蛋白的过程中用到的主要是混合射束中的中子射束。
对热中子捕获截面大的核素包含但不限于10B、155Gd或157Gd。其中所述的对热中子捕获截面大的核素是指在相同能量的热中子照射下，中子捕获截面大于等于人体基本组成元素(C、H、O、N、P、S)的中子捕获截面的100倍及以上的核素，其中在相同能量的热中子照射下构成人体基本组成元素中的H的中子捕获截面最大，在热中子能量为0.025eV的条件下H的热中子捕获截面为0.2barn，10B的热中子捕获截面为3800barn，155Gd的热中子捕获截面为60700barn，而157Gd的热中子捕获截面为254000barn，均大于在相同能量的热中子照射下的H元素的热中子捕获截面的100倍。
这种热中子捕获截面大的核素能够与热中子作用发生核反应，释放出至少一种有杀伤力的射线，该射线射程短，基本上只破坏和所述化合物特异性结合的β淀粉样蛋白的结构，而并不破坏其他正常组织，对正常组织的危害很小。
优选的是，用于消除β淀粉样蛋白的中子捕获治疗系统中，所述对热中子捕获截面大的核素为10B、155Gd或157Gd。
对热中子捕获截面大的核素10B在中子射线的照射下发生如下反应，放射能量：
Figure PCTCN2016111811-appb-000001
利用含硼(10B)化合物对热中子具有高捕获截面的特性，借由10B(n,α)7Li中子捕获及核分裂反应产生4He和7Li两个重荷粒子。如反应式I所示，两荷电粒子的平均能量约为2.33MeV，具有高线性转移(Linear Energy Transfer,LET)、短射程特征，α粒子的线性能量转移与射程分别为150keV/μm、8μm，而7Li重荷粒子则为175keV/μm、5μm，两粒子的总射程约相当于一个细胞大小，因此对于生物体造成的辐射伤害能局限在细胞层级，当含硼化合物与β淀粉样蛋白特异性结合时，搭配适当的中子射源，便能在不对正常组织造成太大伤害的前提下，达到局部破坏β淀粉样蛋白的结构的目的。
所述用于消除β淀粉样蛋白的中子捕获治疗系统中，优选的是，所述中子捕获治疗装置包括中子源、射束整形体和准直器。其中所述中子源用于产生中子射束。所述射束整形体位于所述中子源后部并将所述中子源产生的具有较宽能谱的中子射束中的快中子调整为超热中子或热中子，一般情况下，定义快中子为能区大于40keV的中子，超热中子能区在0.5eV到40keV之间，热中子能区小于0.5keV。所述准直器位于射束整形体后部用于汇聚所述超热中子或热中子以使治疗更有针对性，对于不同大小的β淀粉样蛋白沉积斑块采用合适口径的准直器。
优选的是，所述用于消除β淀粉样蛋白的中子捕获治疗系统中，所述中子源包括加速器中子源或反应堆中子源。
其中，所述加速器中子源通过加速带电粒子(如质子束)轰击适当的靶核(如锂靶或铍靶)，通过核反应产生中子，最常用的核反应有(d，n)、(p，n)和(γ，n)等。
所述反应堆中子源是利用原子核裂变反应堆产生大量中子，此类中子源是最强的热中子源，在反应堆的壁上开孔，即可把中子引出，所得的中子能量是连续分布的，很接近麦克斯韦分布，采取一定的措施，可获得各种能量的中子束。
优选的是，所述用于消除β淀粉样蛋白的中子捕获治疗系统中，所述射束整形体包括反射体和缓速体，其中所述反射体包围所述缓速体，用于将向射束整形体外扩散的中子反射回所述缓速体中，所述缓速体用于将快中子缓速为超热中子或热中子。其中，反射体由Pb或Ni中的至少一种制成；缓速体的材料可以由Al2O3、BaF2、CaF2、CF2、PbF2、PbF4以及D2O中的一种或者几种结合而成，也可以由上述缓速体的材料添加含锂物质后组成，如含有6Li的LiF或Li2CO3。
其中，所述射束整形体还包括热中子吸收体和辐射屏蔽等，其中，热中子吸收体由6Li制成，辐射屏蔽包括由Pb制成的光子屏蔽和由PE制成的中子屏蔽。
热中子吸收体邻接于缓速体，用于吸收热中子以避免治疗时与浅层正常组织造成过多剂量；辐射屏蔽包括由Pb制成的光子屏蔽和由PE制成的中子屏蔽，用于屏蔽渗漏的中子或光子以减少非照射区的正常组织剂量，其中光子屏蔽可以与反射体设为一体，中子屏蔽可以设置在射束整形体中临近射束出口的位置。
优选的是，所述用于消除β淀粉样蛋白的中子捕获治疗系统中，所述能和β淀粉样蛋白特异性结合的化合物具有如结构式I的机构：
Figure PCTCN2016111811-appb-000002
结构式I所示的化合物是2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑，其中，所述化合物中的B(OH)2-基团中的B为10B；10B核素在自然界中的丰度为19.2％，在实际应用所述化合物消除β淀粉样蛋白的过程中，所述2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑中的B(OH)2-中的硼元素可以为10B也可以为11B，其中含有10B元素的化合物的含量根据实际需要而定。
2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑中甲胺基的C为12C或11C，具有11C的2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑除了可以应用在中子捕获治疗系统中消除β淀粉样蛋白外，还可以判定β淀粉样蛋白在脑部的部位，用来做PET的显像剂。
结构式I所示的化合物在所述用于消除β淀粉样蛋白的中子捕获治疗系统中起到中间体的作用，在中子捕获治疗系统中结构式I所示的化合物上的10B能够捕获所述中子捕获治疗装置发射的中子并发生核反应产生能量，该能量能够破坏和结构式I所示的化合物特异性结合的β淀粉样蛋白的结构，从而降低β淀粉样蛋白的含量。由于结构式I所示的化合物是和β淀粉样蛋白特异性结合的，并且化合物上的10B能够捕获热中子，从而使所述中子捕获治疗系统消除β淀粉样蛋白时具有高效性和靶向性。
其中，在用于消除β淀粉样蛋白的中子捕获治疗系统中，所示结构式I所示的化合物是由结构式II所示的化合物制备而成：
Figure PCTCN2016111811-appb-000003
优选的是，由结构式II所示的化合物制备结构式I所示的化合物的方法包括：
由结构式II所示的化合物2-(4-硝基苯)-6-溴苯并噻唑经还原反应生成2-(4-氨基苯)-6-溴苯并噻唑的步骤；
2-(4-氨基苯)-6-溴苯并噻唑加入甲醛反应生成2-(4-甲胺基苯)-6-溴苯并噻唑的步骤；
2-(4-甲胺基苯)-6-溴苯并噻唑加入联硼酸频那醇酯反应生成2-(4-甲胺基苯)-6-硼酸频哪醇酯苯并噻唑的步骤，其中所述联硼酸频那醇酯中的硼为10B；
2-(4-甲胺基苯)-6-硼酸频哪醇酯被氧化剂氧化为由结构式I所示的化合物2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑的步骤，其中氧化剂可以优选为偏高碘酸钠，或氧化性和偏高碘酸钠类似的其他氧化剂。
所示结构式I所示的化合物还可以由结构式II所示的化合物通过如下反应制备而成：
由结构式II所示的化合物2-(4-硝基苯)-6-溴苯并噻唑和联硼酸频那醇酯反应生成2-(4-硝基苯)-6-硼酸频哪醇酯苯并噻唑的步骤，其中联硼酸频那醇酯中的硼为10B；
2-(4-硝基苯)-6-硼酸频哪醇酯苯并噻唑被氧化剂氧化为2-(4-硝基苯)-6-二羟基硼基苯并噻唑的步骤；
2-(4-硝基苯)-6-二羟基硼基苯并噻唑被还原剂还原为2-(4-氨基苯)-6-二羟基硼基苯并噻唑的步骤；
2-(4-氨基苯)-6-二羟基硼基苯并噻唑、碘甲烷和三氟甲基磺酸银在高温条件下反应生成由结构式I所示的化合物2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑的步骤，其中所述的氧化剂优选为偏高碘酸钠。
上述两种合成2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑的步骤中，结构式I中的化合物的10B来源于所使用的反应剂联硼酸频那醇酯中的10B，如上所述的，10B的含量可以根据需要进行调整。
另外，碘甲烷中的C可以为12C，也可以为11C，当碘甲烷中的C为11C时，所述2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑为具有放射性元素11C标记过的化合物，该化合物除了可以用于中子捕获治疗系统中消除β淀粉样蛋白外，还可以用来制备PET显像剂以进一步用于定位追踪β淀粉样蛋白在脑部的位置。
当结构式I所示的化合物中的甲胺基中的C为11C时，由于结构式I所示的化合物具有特异性结合β淀粉样蛋白的性质，将结构式I所示的化合物用11C标记后可以利用其放射性结合正电子发射型计算机断层显像(Positron Emission Computed Tomography，简称PET)用以追踪β淀粉样蛋白沉积于脑部的部位，用以对AD诊断。需要说明的是，即便用11C标记了结构式I所示的化合物，所述化合物仍然具有和β淀粉样蛋白特异性结合的性质，并且所述化合物仍然含有对热中子捕获截面大的核素10B，因此用11C标记的结构式I所示的化合物仍然具有用于所述中子捕获治疗系统中消除β淀粉样蛋白的功能。
本发明中所述能和β淀粉样蛋白特异性结合的化合物不限于结构式I所示的化合物，其他具有热中子捕获截面大的核素并且能够和β淀粉样蛋白特异性结合的化合物均在本发明的保护范围之内。例如，本领域技术人员熟知地，AV-45也能够与β淀粉样蛋白特异性结合，将该化合物某些元素或官能团被含有10B的基团取代同时未改变其与β淀粉样蛋白特异性结合的性质，则其与入射的中子束照射也能够破坏β淀粉样蛋白的结构。
本发明的一方面提供一种利用中子捕获治疗装置消除β淀粉样蛋白的中子捕获治疗系统，该系统的有益效果是有针对性并高效的消除β淀粉样蛋白；本发明的另一方面还针对和阿尔兹海默症发病机理有关的β淀粉样蛋白提供了一种能和β淀粉样蛋白特异性结合的化合物。
附图说明
图1是加速器中子源的中子捕获治疗系统的平面示意图；
图2是反应堆中子源的中子捕获治疗系统的平面示意图；
图3是和β淀粉样蛋白特异性结合的化合物(2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑)的1HNMR图谱；
图4中的A图和B图分别是注射用11C标记的2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑30min后的对照鼠和SAMP8模型鼠的PET影像；
图5是BSA和H3 10BO3的混合溶液分别在距离准直器出口不同位置处经辐射线照射后的SDS-PAGE电泳图谱。
具体实施方式
下面结合附图对本发明做进一步的详细说明，以令本领域技术人员参照说明书文字能够据以实施。
应当理解，本文所使用的诸如“具有”、“包含”以及“包括”术语并不排除一个或多个其它成分或其组合的存在或添加。
本文所述的快中子为能区大于40keV的中子，超热中子能区在0.5eV到40keV之间，热中子能区小于0.5keV。
本发明的实施例以能够有针对性的消除β淀粉样蛋白或降低β淀粉样蛋白含量为目的提供了一种中子捕获治疗系统，该系统包括中子捕获治疗装置以及能和所述β淀粉样蛋白特异性结合的化合物，该化合物包含对热中子捕获截面大的核素，常用的核素有10B、155Gd和157Gd。所述中子捕获治疗装置的热中子照射到对热中子捕获截面大的核素时引起核反应，释放的能量破坏β淀粉样蛋白的结构。
如图1或图2所示：所述中子捕获治疗装置包括中子源、射束整形体和准直器，其中射束整形体包括反射体、缓速体、热中子吸收体和辐射屏蔽装置，其中中子源包括加速器中子源和反应堆中子源。
在实际应用中子捕获治疗系统消除β淀粉样蛋白的过程中，通常情况下需要在中子捕获治疗装置的射束整形体内将来自于中子源的混合辐射场中的快中子调整到超热中子并降低混合辐射场中其他有害射线的含量，虽然和β淀粉样蛋白特异性结合的化合物上的核素是对热中子捕获截面大的核素，但是考虑到中子射束从中子捕获治疗装置的准直器到能和β淀粉样蛋白特异性结合的化合物的过程中，中子射束的能量会随着二者距离的增加能量会有一定程度的衰减，并且中子射束在到达和β淀粉样蛋白特异性结合的化合物的过程中往往会有其他物质对中子的能量进行不同程度的缓速，因此为了保证到达和β淀粉样蛋白特异性结合的化合物中子的能量和中子强度，通常情况下需要将射束整形体内的快中子缓速为超热中子，提高从准直器出来的中子射束中的超热中子的含量。
请再次参照图1，中子捕获治疗系统中的中子捕获治疗装置是加速器中子源的中子捕获治疗装置，其中加速器10a将质子加速，通过扩束装置20扩大质子束P的横截面积，使所述质子束P打到靶材T上并产生中子，其反应原理为：质子、氘核等带电粒子经由加速器加速至足以克服靶原子核库仑斥力的能量，与金属靶T发生核反应产生子核和中子，其中常用的金属靶材通常为锂和铍。通过该方法产生的是混合辐射场，在利用该中子捕获治疗装置进行β淀粉样蛋白53时，需要尽可能的降低其他种类的射线，而射束整形体30a中的缓速体32a具有调整所述混合辐射场能量的作用，反射体31a将向其他方向扩散的混合辐射场反射回来，以降低中子的损失，射束整形体30a还可以包括热中子吸收体33a，其能够吸收能量较低的热中子，所述射束整形体30a外部设置一层辐射屏蔽装置34a，以避免射线泄露对附近的人造成伤害。射束整形体30a的后部安装有准直器40a，经过射束整形体30a调整后的射束再通过准直器40a进行汇聚，以更准确的照射含有对热中子捕获截面大的核素51的能够和β淀粉样蛋白53特异结合的化合物52，更加充分的利用超热中子射束。
请再次参照图2，中子捕获治疗系统中的中子捕获治疗装置是反应堆中子源的中子捕获治疗装置，其中反应堆中子源10b通过管道将产生的中子束N传递至射束整形体30b，反应堆中子源10b和加速器10a中子源一样产生的都是混合辐射场，该混合辐射场中的能量较高的快中子通过射束整形体30b中的缓速体32b缓速为能破坏β淀粉样蛋白结构的中子，向其他方向扩散的射线通过反射体31b反射回缓速体32b中，以提高射线的利用率；射束整形体中的热中子吸收体33b可以吸收混合辐射场中能量较低的热中子以使中子射束N中的超热中子含量更高，所述中子射束N经过准直器40b的汇聚形成可以用来更准确的照射含有对热中 子捕获截面大的核素51的能够和致病蛋白质53特异结合的化合物52，更加充分的利用超热中子射束。
图1和图2所示的中子捕获治疗系统还包括一种能和β淀粉样蛋白53特异性结合的化合物52，该化合物52还包括对热中子捕获截面大的核素51，所述化合物52在中子捕获治疗系统消除β淀粉样蛋白的过程中充当中间体的角色，首先所述化合物52根据其具有和β淀粉样蛋白53特异性结合的性质能够识别并结合到β淀粉样蛋白上从而将对热中子捕获截面大的核素(10B)51和β淀粉样蛋白53进行绑定，以便在该组合物50在热中子照射下，热中子和10B反应产生的能量破坏β淀粉样蛋白53。
下面通过实施例进一步说明本发明的技术方案。
本发明优选实施例中所述的和β淀粉样蛋白特异性结合的化合物指的是2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑，其中该化合物上的硼元素为10B并且该化合物上可以含有放射性元素11C。如未做特殊说明，本发明优选实施例中所述的含硼的化合物中的硼元素均含有10B。
<实施例1>和β淀粉样蛋白特异性结合的化合物的制备方法
具有如结构式I所示的化合物2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑可通过如下反应进行制备：
Figure PCTCN2016111811-appb-000004
将1g的2-(4-硝基苯)-6-溴苯并噻唑溶于10mL的乙醇中，再加入5.39g的SnCl2.2H2O，该反应体系于100℃的条件下搅拌1h得到2-(4-氨基苯)-6-溴苯并噻唑；
1H NMR:400MHz DMSO
δ8.29(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)。
向1g的2-(4-氨基苯)-6-溴苯并噻唑中加入16.4mmol甲醛，再向其中加入10mL的四氢呋喃(THF)和20mL的甲醇，再一次性加入0.886g的甲醇钠构成反应液，所述反应液在65℃的条件下搅拌反应12h，然后将反应液降温至25℃，加入620.41mg的硼氢化钠(NaBH4)， 再将反应温度升至65℃，搅拌反应1h得到2-(4-甲胺基苯)-6-溴苯并噻唑；
1H NMR:400MHz CDCl3
δ7.97(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)。
将100mg的2-(4-甲胺基苯)-6-溴苯并噻唑、95.46mg的联硼酸频那醇酯和92.23mg的醋酸钾构成反应体系，向反应体系中加入4mL的THF和2mL的二甲基亚砜(DMSO)，在20℃充氮的条件下加入26.39mg的二氯二(三苯基磷)合钯(Pd(PPh3)2Cl2)，在90℃条件下搅拌反应12h得到2-(4-甲胺基苯)-6-硼酸频哪醇酯苯并噻唑，其中联硼酸频那醇酯中的硼含有10B；
向300mg的2-(4-甲胺基苯)-6-硼酸频哪醇酯苯并噻唑加入20mLTHF和10mL水，再加入875.93mg偏高碘酸钠(NaIO4)构成反应体系，将该反应体系在25℃条件下搅拌反应12h得到结构式I所示的化合物：2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑。该化合物的1HNMR扫描图谱如图3所示。
1H NMR:400MHz MeOH
δ8.27(s,1H),7.83-7.85(m,4H),6.66-6.68(d,J＝7.6Hz,2H),2.85(s,3H)。
其中，2-(4-硝基苯)-6-溴苯并噻唑可通过以下步骤进行制备：
向25mL浓度为10M的氢氧化钾溶液里加入5g的2-氨基-6-溴-苯并噻唑，再加入5mL乙二醇构成的混合溶液于125℃搅拌反应2h，得到2-氨基-5-溴苯硫醇；
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)。
2g的2-氨基-5-溴苯硫醇中加入1.48g的对硝基苯甲醛，再加入40mL的DMSO构成反应溶液，所述反应溶液于180℃搅拌反应0.5h，得到2-(4-硝基苯)-6-溴苯并噻唑；
1H NMR:400MHz DMSO
δ8.54(s,1H),8.34-8.41(m,4H),8.07-8.09(d,J＝8.8Hz,1H),7.74-7.77(m,1H)。
本实施例中合成所述的2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑的具体反应过程如反应式II所示(该反应式中的硼元素均含有10B)：
Figure PCTCN2016111811-appb-000005
<实施例2>和β淀粉样蛋白特异性结合的化合物的制备方法
本实施例中2-(4-硝基苯)-6-溴苯并噻唑的合成方法和<实施例1>所示的合成方法相同。
向100mg的2-(4-硝基苯)-6-溴苯并噻唑中加入90.91mg的联硼酸频那醇酯和87.84mg的醋酸钾，再加入4mL的THF和2mL的DMSO，在20℃充氮的条件下加入25mg的二氯二(三苯基磷)合钯，反应体系在95℃条件下搅拌反应15h得到2-(4-硝基苯)-6-硼酸频哪醇酯苯并噻唑，其中联硼酸频那醇酯中的硼含有10B；
1H NMR:400MHz CDCl3
δ8.44(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)。
向539.7mg的2-(4-硝基苯)-6-硼酸频哪醇酯苯并噻唑中加入30mL的THF和10mL水，再加入1.51g的偏高碘酸钠，该反应体系在25℃条件下反应23h得到2-(4-硝基苯)-6-二羟基硼基苯并噻唑；
1H NMR:400MHz DMSO
δ8.56(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)。
向100mL甲醇中加入200mg催化剂Pd/C，再加入180mg的2-(4-硝基苯)-6-二羟基硼基苯并噻唑构成反应体系，所述反应体系在氢气环境下真空脱气并在25℃条件下反应10min生成2-(4-氨基苯)-6-二羟基硼基苯并噻唑；
1H NMR:400MHz MeOH
δ8.29(s,1H),7.80-7.84(m,4H),6.74-6.76(d,J＝8.8Hz,2H)。
利用氮气载带碘甲烷通过加热至200℃的三氟甲基磺酸银管后，再将其通入溶解有2-(4-氨基苯)-6-二羟基硼基苯并噻唑的无水丙酮中构成反应液，将反应液在80℃反应5min后加水猝灭，得到2-(4甲胺基苯)-6-二羟基硼基苯并噻唑。
其中碘甲烷中的C可以为具有放射性的11C，由其合成的2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑同样具有放射性元素11C，因此该具有放射性的化合物可以和PET结合用于追踪β淀粉样蛋白沉积于脑部的部位及AD的诊断。
1H NMR:400MHz MeOH
δ8.27(s,1H),7.83-7.85(m,4H),6.66-6.68(d,J＝7.6Hz,2H),2.85(s,3H)。
本实施例的反应过程如反应式III所示(该反应式中的B均含有10B)：
Figure PCTCN2016111811-appb-000006
<实施例3>11C标记的2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑和β淀粉样蛋白特异性结合的实验
SAMP8(senescence accelerated mouse prone 8)小鼠是目前最常见的研究AD(阿尔兹海默症)的动物模型，其脑部存在大量淀粉样蛋白沉积斑块，本实施例采用SAMP8小鼠作为模型鼠，普通实验鼠作为对照鼠，模型鼠和对照鼠均为10月龄，分别向这两种老鼠注射含有11C标记的2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑，再通过Micro-PET扫描来研究2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑和β淀粉样蛋白是否具有特异性结合的性质。
分别选取体重为31.5±0.3g的模型鼠和对照鼠，分别向其注射31.0±0.6μCi的11C标记的2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑，并用西门子型号为INVEON的Micro-PET进行扫描，其中扫描能窗为350-650KeV。
本领域技术人员熟知地，造成阿尔兹海默式症主要的病因为β淀粉样蛋白沉积斑块聚积在脑部的大脑皮层和海马区，本实施例通过Micro-PET扫描并利用PMOD软件对模型鼠和对照鼠脑部进行比对，分析确定了SAMP8模型鼠和对照鼠的大脑皮层和海马区对具有放射性的2-(4-甲胺基苯)-6二羟基硼基苯并噻唑的吸收，以进一步说明该化合物对β淀粉样蛋白沉积斑块能特异性结合，其具体结果如表1和表2所示：
表1，模型鼠和对照鼠大脑皮层对放射性2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑的摄取
Figure PCTCN2016111811-appb-000007
从表1可以看出：在放射性药物注射后第35分钟时，模型鼠与对照鼠大脑皮层摄取量的比值可达2.7，高于有效硼中子捕获治疗的标靶与非标靶的硼浓度比值(2.5)，此结果可说明放射性2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑可有效的与β淀粉样蛋白沉积斑结合，并积聚在病灶处。更可期许使用硼中子捕获治疗阿尔兹海默氏症的病人，病灶处可接受大量的辐射剂量，达到治疗的目的，并降低正常脑组织的辐射伤害。
表2，模型鼠和对照鼠的海马区对放射性2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑的摄取
Figure PCTCN2016111811-appb-000008
从表2可以看出，放射性药物注射后的25及35分钟，模型鼠与对照鼠的海马区比值皆为3.2，高於有效硼中子捕获治疗的标靶与非标靶的硼浓度比值(2.5)，此结果亦可佐证放射性 2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑可有效的与β淀粉样蛋白沉积斑块结合，并积聚在病灶处。
SAMP8模型鼠为加速老化的阿尔兹海默氏症的发病鼠，在大脑皮层和海马区的病灶部位皆聚积了大量的β淀粉样蛋白沉积斑块，通过表1和表2中模型鼠和对照鼠的实验数据可以看出，SAMP8模型鼠的大脑皮层和海马区相较于正常的对照鼠对2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑具有更强的吸收能力，因此也进一步说明了2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑和β淀粉样蛋白具有特异性，将来更可利用硼中子捕获治疗来治疗阿尔兹海默氏症，为阿尔兹海默氏症患者提供另一种先进的治疗方式。
依据表2的分析结果，在老鼠注射放射性2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑后的25至35分钟，放射性药物于模型鼠大脑的海马区与对照鼠的比值皆为3.2，因此取中间值30min的Micro-PET影像图的进一步比对放射性的2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑在脑部积聚的情形。
图4是注射放射性的2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑第30min时的PET扫描并经AMIDE软件处理过的影像，其中A图为对照鼠注射放射性药物30min时的影像，A图中(1)图为对照鼠冠状切面扫描影像，(2)图为(1)图沿Y轴向的切面扫描图，(3)图为(1)图沿X轴向的脑部切面扫描图；B图为SAMP8模型鼠注射放射性药物30min时的影像，同样地，B图中(1)图为模型鼠冠状切面扫描影像，(2)图为(1)图沿Y轴向的切面扫描图，(3)图为(1)图沿X轴向的脑部切面扫描图。
其中A图中的(3)和B图中的(3)能反映脑部放射性药物吸收情况的，将这两幅影像对比可以看出，B图(3)中的SAMP8模型鼠的脑部相对于A图(3)中的对照鼠的脑部聚积有大量的放射性药物，而已知模型鼠脑部具有大量β淀粉样蛋白沉积斑块，由此可说明2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑对β淀粉样蛋白沉积斑块有特异性，且未来2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑可用于硼中子捕获治疗。
<实施例4>模拟中子捕获治疗系统消除蛋白质的实验
本实施例用硼酸(H3 10BO3)来代替2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑，其中硼酸(H3 10BO3)中的硼元素为10B，用牛血清白蛋白(BSA)来模拟β淀粉样蛋白，将硼酸和牛血清白蛋白构成的混合溶液置于中子捕获治疗装置产生中子射束环境中，通过SDS-PAGE凝胶电泳分析中子对牛血清白蛋白的作用以及在H3 10BO3存在的条件下，中子对牛血清白蛋白的作用。
一、中子对牛血清白蛋白的作用
用超纯水配置浓度为0.01％(w/w)的BSA溶液，配置的溶液在4℃条件下保存及实验操作，取1mLBSA溶液置于中子捕获治疗装置的准直器出口的中心线上，其中所述溶液距离准直器出口距离为2cm，设置中子捕获治疗装置以使准直器出口处的中子强度为2.4×1011个/s，所述BSA溶液在该中子环境中照射2h；另取1mLBSA溶液作为对照液不进行中子照射。
将用中子照射2h的BSA溶液和对照液分别用考马斯亮蓝染色并做SDS-PAGE凝胶电泳，用Image J软件分别将上述样品液和对照液的电泳图谱中蛋白条带的颜色进行量化，其数值用来表示蛋白质的相对含量，其中定义对照液中的BSA含量为1，在上述中子照射实验条件下，经中子照射2h后的BSA的含量为0.8，其含量大概有20％的减少，由此可见，包含有中子射束的辐射线能够影响蛋白质的含量。
二、在H3 10BO3存在的条件下，中子对牛血清白蛋白的作用
用超纯水配置BSA和H3 10BO3的溶液，其中，在所述溶液中，BSA的浓度为0.01％(w/w)，H3 10BO3的浓度为0.18M；配置的溶液均在4℃保存及实验操作，从所述溶液中分别取8份(编号分别为A、B、C、D、E、F、G、H)，每份1mL的溶液用中子捕获治疗装置进行照射，分别将8份溶液置于中子捕获治疗装置准直器出口的中心线上，溶液A距离准直器出口的距离为2cm，溶液B距离准直器的出口为4cm，溶液C距离准直器的出口为6cm，并以此类推。准直器出口处的射束中除了包括中子射线，还包括伽马射线及其他辐射线，在实际对蛋白质起到破坏作用的主要是中子射线，本实施例用射束中的中子强度来描述所述射束的强度，其中，本实施例采用的中子强度为2.4×1011个/s，8份溶液在该中子环境中照射2h；另从所述BSA和H3 10BO3溶液中取1mL作为对照液，该对照液不经中子照射。
将对照液和经中子捕获治疗装置放射的辐射线照射过的8份溶液分别用考马斯亮蓝染色并做SDS-PAGE凝胶电泳，图5所示为对照液和8份溶液的SDS-PAGE电泳图谱。
图5中前两个蛋白条带为对照液中的BSA，其余分别为经过所述辐射线照射后的BSA，8份溶液均置于准直器出口中心线上，由于在所述中心线上的溶液中均含有H3 10BO3，而10B元素对热中子有较大的捕获截面，因此从准直器出口出来的辐射线中的中子经过含有H3 10BO3的溶液后，其中子剂量大幅度下降，离准直器出口越远的溶液，其BSA接受到的中子辐射剂量越少。
从图5可以看出，8个经中子照射过的溶液相比于对照样，其蛋白条带的颜色均有不同程度的变浅，并且，离准直器出口越近，其溶液内的蛋白条带的颜色越浅，说明蛋白含量减少的越多，而离准直器出口越近，溶液受到的中子辐射剂量越大，进一步说明，中子剂量的大小影响溶液中BSA的含量，中子剂量越强，经所述中子照射后的溶液中BSA的含量越少。
用Image J软件分别将对照液和8份溶液对应的电泳图谱中的BSA蛋白条带的颜色进行量化，其数值用来表示蛋白的相对含量，其中，定义对照液中的BSA含量为1，在上述中子照射实验条件下，经中子照射2h后的BSA的含量如表3所示。
由表3可以看出，经中子照射的溶液中BSA含量均有不同程度的降低，距离准直器出口2cm的溶液经中子强度为2.4×1011个/s的中子照射2h后，其BSA含量仅剩5.3％，说明在H3 10BO3存在的条件下，中子能大幅度破坏BSA结构，降低BSA的含量；并且在实验误差允许的范围内，8个溶液随着溶液距离准直器出口的距离越远，其BSA含量整体呈减少的趋势，进一步说明中子剂量的大小影响BSA的含量。
表3，在H3 10BO3存在条件下，中子对牛血清白蛋白的作用
溶液编号 BSA含量(％)
对照液 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
本发明提供的化合物2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑和H3 10BO3一样携带有热中子捕获截面大的核素10B，并且该化合物能够和β淀粉样蛋白特异性结合，将所述化合物置于含有β淀粉样蛋白的环境中，所述化合物会在β淀粉样蛋白的周围形成较高的浓度，再用中子捕获治疗装置发射的中子射束照射所述化合物聚积的区域，其释放的能量能破坏蛋白质的结构。
以上列举具体实施例对本发明进行说明，需要指出的是，以上实施例只用于对发明作进一步说明，不代表本发明的保护范围，其他人根据本发明的提示做出的非本质的修改和调整，仍属于本发明的保护范围。

Claims (10)

  1. 一种用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于，包括：中子捕获治疗装置以及能和所述β淀粉样蛋白特异性结合的化合物，
    其中，所述化合物包含对热中子捕获截面大的核素；
    所述中子捕获治疗装置产生的中子束作用到所述化合物上的核素后产生的能量破坏β淀粉样蛋白的结构。
  2. 如权利要求1所述的用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于，所述对热中子捕获截面大的核素为10B、155Gd或157Gd，其中所述中子捕获治疗装置产生的中子束与化合物中核素10B发生硼中子捕获反应以通过产生的4He和7Li两个重荷粒子破坏β淀粉样蛋白的结构。
  3. 如权利要求1所述的用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于，所述中子捕获治疗装置包括中子源、射束整形体和准直器，其中所述中子源用于产生中子射束，所述射束整形体位于所述中子源后部并将所述中子源产生的具有较宽能谱的中子射束中的快中子调整为超热中子或热中子，所述准直器位于射束整形体后部用于汇聚所述超热中子或热中子。
  4. 如权利要求3所述的用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于，所述中子源为加速器中子源或反应堆中子源。
  5. 如权利要求3所述的用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于，所述射束整形体包括反射体和缓速体，其中所述反射体包围所述缓速体，用于将向射束整形体外扩散的中子反射回所述缓速体中，所述缓速体用于将快中子缓速为超热中子或热中子。
  6. 如权利要求1-5中任一项所述的用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于，能和所述β淀粉样蛋白特异性结合的化合物具有如结构式I的结构：
    Figure PCTCN2016111811-appb-100001
    其中，结构式I中B(OH)2-基团中的B为10B。
  7. 如权利要求6所述的用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于，结构式I 所示的化合物由结构式II所示的化合物制备而成：
    Figure PCTCN2016111811-appb-100002
    所述结构式II所示的化合物为2-(4-硝基苯)-6-溴苯并噻唑。
  8. 如权利要求7所述的用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于，由结构式II所示的化合物制备结构式I所示的化合物的方法包括：
    由结构式II所示的化合物经还原反应生成2-(4-氨基苯)-6-溴苯并噻唑；
    2-(4-氨基苯)-6-溴苯并噻唑加入甲醛反应生成2-(4-甲胺基苯)-6-溴苯并噻唑的步骤；
    2-(4-甲胺基苯)-6-溴苯并噻唑加入联硼酸频那醇酯反应生成2-(4-甲胺基苯)-6-硼酸频哪醇酯苯并噻唑的步骤；
    2-(4-甲胺基苯)-6-硼酸频哪醇酯被氧化剂氧化为由结构式I所示的化合物2-(4-甲胺基苯)-6-二羟基硼基苯并噻唑的步骤；
    其中所述的联硼酸频那醇酯中的硼为10B。
  9. 如权利要求7所述的用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于，由结构式II所示的化合物制备结构式I所示的化合物的方法包括：
    由结构式II所示的化合物和联硼酸频那醇酯反应生成2-(4-硝基苯)-6-硼酸频哪醇酯苯并噻唑的步骤；
    2-(4-硝基苯)-6-硼酸频哪醇酯苯并噻唑被氧化剂氧化为2-(4-硝基苯)-6-二羟基硼基苯并噻唑的步骤；
    2-(4-硝基苯)-6-二羟基硼基苯并噻唑被还原剂还原为2-(4-氨基苯)-6-二羟基硼基苯并噻唑的步骤；
    2-(4-氨基苯)-6-二羟基硼基苯并噻唑、碘甲烷和三氟甲基磺酸银在高温条件下反应生成由结构式I所示的化合物2-(甲胺基苯)-6-二羟基硼基苯并噻唑的步骤；
    其中所述的联硼酸频那醇酯中的硼为10B。
  10. 如权利要求9所述的用于消除β淀粉样蛋白的中子捕获治疗系统，其特征在于：所述的碘甲烷中的C为11C。
PCT/CN2016/111811 2015-12-30 2016-12-23 用于消除β淀粉样蛋白的中子捕获治疗系统 WO2017114316A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP16881105.7A EP3384960B1 (en) 2015-12-30 2016-12-23 NEUTRON CAPTURE THERAPY SYSTEM FOR ELIMINATING AMYLOID ß-PROTEIN
RU2018127690A RU2721284C2 (ru) 2015-12-30 2016-12-23 СИСТЕМА НЕЙТРОНОЗАХВАТНОЙ ТЕРАПИИ, ПРИМЕНЯЕМАЯ ДЛЯ УДАЛЕНИЯ β-АМИЛОИДНОГО БЕЛКА
JP2018529662A JP6709284B2 (ja) 2015-12-30 2016-12-23 βアミロイドタンパク質を除去するための中性子捕捉療法システム
US16/010,818 US10709783B2 (en) 2015-12-30 2018-06-18 Neutron capture therapy system for eliminating amyloid β-protein

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201511018353.5 2015-12-30
CN201511018353 2015-12-30

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/010,818 Continuation US10709783B2 (en) 2015-12-30 2018-06-18 Neutron capture therapy system for eliminating amyloid β-protein

Publications (1)

Publication Number Publication Date
WO2017114316A1 true WO2017114316A1 (zh) 2017-07-06

Family

ID=58920104

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/111811 WO2017114316A1 (zh) 2015-12-30 2016-12-23 用于消除β淀粉样蛋白的中子捕获治疗系统

Country Status (7)

Country Link
US (1) US10709783B2 (zh)
EP (1) EP3384960B1 (zh)
JP (1) JP6709284B2 (zh)
CN (2) CN106730414B (zh)
RU (1) RU2721284C2 (zh)
TW (1) TWI607756B (zh)
WO (1) WO2017114316A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10462893B2 (en) 2017-06-05 2019-10-29 Neutron Therapeutics, Inc. Method and system for surface modification of substrate for ion beam target
US11024437B2 (en) 2015-05-06 2021-06-01 Neutron Therapeutics Inc. Neutron target for boron neutron capture therapy

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3385266B1 (en) * 2015-12-30 2019-08-14 Neuboron Medtech Ltd. Compound for specific binding with amyloid beta-protein
EP3895760B1 (en) * 2017-08-24 2024-02-28 Neuboron Medtech Ltd. Neutron capture therapy system
CN109464749B (zh) * 2017-09-07 2024-02-23 南京中硼联康医疗科技有限公司 中子捕获治疗系统
US11517769B2 (en) * 2019-07-10 2022-12-06 Ricoh Company, Ltd. Neutron beam transmission adjusting device comprising a neutron beam transmission unit including a neutron reactant, method for producing neutron beam transmission adjusting device, and neutron beam adjusting method
WO2023100942A1 (ja) * 2021-12-02 2023-06-08 国立大学法人 東京大学 光酸素化触媒用化合物及びこれを含有する医薬組成物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006027877A1 (ja) * 2004-09-08 2006-03-16 Sharp Kabushiki Kaisha 物体の物性または機能を変化させる方法および細胞の生体機能を消失させる方法
CN101426517A (zh) * 2006-02-28 2009-05-06 遗传工程与生物技术中心 用于预防和消除组织中纤维样和其他病理性沉积的、含ghrp-6的药物组合物
CN103127530A (zh) * 2013-01-31 2013-06-05 中国人民解放军第三军医大学第二附属医院 靶向β淀粉样蛋白显像剂的应用
CN105658244A (zh) * 2013-05-23 2016-06-08 诺罗森公司 使用放射性核素标记的膜联蛋白诊断和治疗阿尔茨海默病

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5630786A (en) * 1994-06-27 1997-05-20 Ionix Corporation Boron neutron capture enhancement of fast neutron therapy
RU2191610C2 (ru) * 2000-04-12 2002-10-27 Медицинский радиологический научный центр РАМН Способ формирования поглощенной дозы излучения при нейтронной терапии
TWI245764B (en) * 2001-04-23 2005-12-21 Hank F Kung Amyloid plaque aggregation inhibitors and diagnostic imaging agents
US8703096B2 (en) * 2006-04-21 2014-04-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Beta-amyloid PET imaging agents
JP5054335B2 (ja) * 2006-07-18 2012-10-24 株式会社日立製作所 ホウ素中性子捕捉療法用の医療装置
US20100183513A1 (en) * 2006-11-24 2010-07-22 Wolfgang Froestl N-(methyl) -1h-pyrazol-3-amine, n-(methyl)-pyridin-2-amine and n-(methyl)-thiazol-2-amine derivatives for the treatment of diseases associated with amyloid or amyloid-like proteins, like e.g. alzheimer's
JP5490651B2 (ja) 2010-09-01 2014-05-14 住友重機械工業株式会社 中性子線照射システム
US20130323166A1 (en) * 2010-09-10 2013-12-05 William Beaumont Hospital Radiation Therapy for Treating Alzheimer's Disease
CN103127877B (zh) * 2013-03-05 2015-09-09 山东东岳高分子材料有限公司 一种含氟表面活性剂及其制备方法
JP6042269B2 (ja) * 2013-05-22 2016-12-14 住友重機械工業株式会社 中性子捕捉療法装置、及び中性子線の測定方法
CN104059028B (zh) * 2014-06-06 2020-10-16 北京智博高科生物技术有限公司 与Aβ斑块具有亲和力的含手性侧链取代的氟代2-芳基苯并杂环化合物、其制备方法及应用
EP3316665B1 (en) 2014-12-08 2019-10-09 Neuboron Medtech Ltd. Beam shaping assembly for neutron capture therapy
CN107497060B (zh) * 2014-12-08 2020-02-28 南京中硼联康医疗科技有限公司 用于中子捕获治疗的射束整形体
EP3385266B1 (en) * 2015-12-30 2019-08-14 Neuboron Medtech Ltd. Compound for specific binding with amyloid beta-protein

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006027877A1 (ja) * 2004-09-08 2006-03-16 Sharp Kabushiki Kaisha 物体の物性または機能を変化させる方法および細胞の生体機能を消失させる方法
CN101426517A (zh) * 2006-02-28 2009-05-06 遗传工程与生物技术中心 用于预防和消除组织中纤维样和其他病理性沉积的、含ghrp-6的药物组合物
CN103127530A (zh) * 2013-01-31 2013-06-05 中国人民解放军第三军医大学第二附属医院 靶向β淀粉样蛋白显像剂的应用
CN105658244A (zh) * 2013-05-23 2016-06-08 诺罗森公司 使用放射性核素标记的膜联蛋白诊断和治疗阿尔茨海默病

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11024437B2 (en) 2015-05-06 2021-06-01 Neutron Therapeutics Inc. Neutron target for boron neutron capture therapy
US10462893B2 (en) 2017-06-05 2019-10-29 Neutron Therapeutics, Inc. Method and system for surface modification of substrate for ion beam target
US11553584B2 (en) 2017-06-05 2023-01-10 Neutron Therapeutics, Inc. Method and system for surface modification of substrate for ion beam target

Also Published As

Publication number Publication date
CN108187044B (zh) 2021-03-09
EP3384960A1 (en) 2018-10-10
TW201722441A (zh) 2017-07-01
RU2721284C2 (ru) 2020-05-18
TWI607756B (zh) 2017-12-11
CN106730414B (zh) 2017-10-10
RU2018127690A3 (zh) 2020-01-31
RU2018127690A (ru) 2020-01-31
EP3384960B1 (en) 2019-06-05
JP2019506915A (ja) 2019-03-14
CN108187044A (zh) 2018-06-22
US10709783B2 (en) 2020-07-14
US20180360963A1 (en) 2018-12-20
EP3384960A4 (en) 2018-12-19
JP6709284B2 (ja) 2020-06-10
CN106730414A (zh) 2017-05-31

Similar Documents

Publication Publication Date Title
WO2017114316A1 (zh) 用于消除β淀粉样蛋白的中子捕获治疗系统
WO2017114317A1 (zh) 和β淀粉样蛋白特异性结合的化合物
TWI642437B (zh) 含&lt;sup&gt;１０&lt;/sup&gt;Ｂ的化合物在製備和β澱粉樣蛋白特異性結合藥物中的應用
CN108239101B (zh) 用于制备和β淀粉样蛋白特异性结合的化合物的化合物、制备方法及其应用
CN108239100B (zh) 用于制备和β淀粉样蛋白特异性结合的化合物的化合物、制备方法及其应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16881105

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2018529662

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016881105

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2016881105

Country of ref document: EP

Effective date: 20180703