WO2001070699A1 - Analogues d'azur a utilises comme sondes dans l'imagerie diagnostique des maladies dues a l'accumulation d'amyloide, et compositions renfermant ces analogues destinees a l'imagerie diagnostique - Google Patents

Analogues d'azur a utilises comme sondes dans l'imagerie diagnostique des maladies dues a l'accumulation d'amyloide, et compositions renfermant ces analogues destinees a l'imagerie diagnostique Download PDF

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WO2001070699A1
WO2001070699A1 PCT/JP2001/002205 JP0102205W WO0170699A1 WO 2001070699 A1 WO2001070699 A1 WO 2001070699A1 JP 0102205 W JP0102205 W JP 0102205W WO 0170699 A1 WO0170699 A1 WO 0170699A1
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Prior art keywords
compound
solvate
salt
amyloid
disease
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PCT/JP2001/002205
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English (en)
Japanese (ja)
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Yukitsuka Kudo
Masako Suzuki
Takahiro Suemoto
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Bf Research Institute, Inc.
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Priority claimed from JP2000080083A external-priority patent/JP2000344685A/ja
Application filed by Bf Research Institute, Inc. filed Critical Bf Research Institute, Inc.
Priority to AU2001244549A priority Critical patent/AU2001244549A1/en
Publication of WO2001070699A1 publication Critical patent/WO2001070699A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • 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
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds

Definitions

  • Imaging diagnostic probe for diseases in which amyloid accumulates due to azul A-like compound and diagnostic imaging compositions containing the same
  • the present invention relates to a diagnostic probe for a disease in which amyloid accumulates, in particular, a probe labeled with a positron emitting nuclide, and a diagnostic imaging composition containing the probe.
  • a diagnostic probe for a disease in which amyloid accumulates in particular, a probe labeled with a positron emitting nuclide, and a diagnostic imaging composition containing the probe.
  • Alzheimer's disease is currently regarded as one of the most difficult to treat, and accurate early diagnosis is desired.
  • Alzheimer's disease is a disease characterized by progressive dementia that occurs primarily from the old age to the old age. Pathologically, it is characterized by general atrophy of the cerebrum, marked degeneration and loss of nerve cells, neurofibrillary tangles and the appearance of senile plaques. It is known that aging is the largest risk factor for dementia represented by Alzheimer's disease. Therefore, the increase in the number of patients as the aging population increases is particularly noticeable in aging societies in Japan, the United States, and European countries. We are in crisis.
  • Alzheimer's disease patients In Japan, the number of Alzheimer's disease patients is estimated to be about 100,000, and it is certain that the number of Alzheimer's disease patients will increase as the population ages in the future. It is thought that the cost for patients with Alzheimer's disease, including nursing care costs, is expected to exceed 250 million yen per patient per year, so that in Japan, socio-economic costs exceeding 2.5 trillion yen have already been achieved. You are paying. It is now common knowledge in the world that treating Alzheimer's disease before or as soon as dementia manifests can have significant medical and economic benefits. However, at present It is extremely difficult to accurately diagnose these stages of Alzheimer's disease.
  • Alzheimer's disease is represented by two main features. That is, senile plaques and neurofibrillary tangles.
  • the main component of the former is an amyloid protein having a ⁇ -sheet structure, and the latter is a hyperphosphorylated tau protein. Definitive diagnosis of Alzheimer's disease relies on the appearance of these pathological features in the patient's brain.
  • amyloid] 3 protein in the pathogenesis of Alzheimer's disease is known as follows (Katsuhiko Yanagisawa, Yasuo Ihara: Advances in Neuroscience, Vol. 41, pp. 70-79, 1997) Year, Tokai Hayashi Mikio: Dementia Japan, Vol. 1, Volume 43, 50, pp. 1997, Akira Tamaoka: Dementia ⁇ Japan, Vol. Year).
  • Diffuse deposition of [amyloid] 3 protein ( ⁇ / 3) is considered to be the earliest neuropathological change in Alzheimer's disease brain.
  • APP amyloid breaker protein-1
  • the [amyloid] 3 protein is characteristic of a disease in which amyloid accumulates, including Alzheimer's disease, and is closely related. Therefore, detection of ⁇ -sheet-structured amyloid] 3 protein as a marker in the body, particularly in the brain, is one of the important diagnostic methods for diseases in which amyloid is accumulated, particularly Alzheimer's disease.
  • amyloid-accumulating diseases such as Panorezheimer's disease
  • substances that specifically bind to and stain the amyloid / 3 protein in the body, particularly in the brain have been conventionally searched.
  • Such materials include Congo Red (Puchtler et al., Giannareo's Hist Chemistry and Cytology, Vol. 10, p. 35, 1962) and Thioflavin S (Puchtler I. ) Et al., Journal Nanohistohistory 'and Cytochemistry, Vol. 77, p. 431, 1983), Thioflavin T (LeVine), Protein Science, Vol. 2, p.
  • the present invention is a substance having high binding specificity to amyloid protein, high blood-brain barrier permeability, and which can be used as an imaging diagnostic probe for a disease in which amyloid accumulates. It offers a different group of substances.
  • the present invention also provides a labeled such substance used as an imaging diagnostic probe for a disease in which amyloid accumulates, and a diagnostic imaging set containing such a probe. Also provide products ( Summary of the Invention)
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that the compound represented by the formula I or a salt or solvate thereof is very high.] 3 Specificity of binding to amyloid protein, They have found that they have brain barrier permeability, and have completed the present invention.
  • R 4 are each independently hydrogen, halogen, or alkyl having 1 to 4 carbons,
  • R 2 and R 3 are each independently hydrogen, halogen, amino, amino mono-substituted with alkyl having 1 to 4 carbon atoms, amino amino di-substituted with alkyl having 1 to 4 carbon atoms, or
  • R 5 and R 6 are each independently hydrogen, halogen, or alkyl having 1 to 4 carbons,
  • R 4 Oyopi 1 5 rather good also form a connexion benzenesulfonic acid group together, or R E and R 6 may form a connexion benzenesulfonic acid group together.
  • the sulfonic acid group may be attached to any position of the formed benzene ring.
  • R 7 and R 8 are each independently hydrogen, halogen, or alkyl having 1 to 4 carbons,
  • R 9 is hydrogen, halogen, amino, amino mono-substituted with alkyl having 1 to 4 carbons, amino mono-disubstituted with alkyl having 1 to 4 carbons,
  • X is CH or N
  • Y is N, S, or
  • R i Is hydrogen, halogen or alkyl having 1 to 4 carbons.
  • a compound for imaging diagnostic probe of a disease in which amyloid accumulates or a salt or solvate thereof
  • nc, 13 N, 15 0, 18 or a salt or solvate thereof above which is labeled with a positron emitting nuclide (1) is selected from the group consisting of F,
  • composition for diagnostic imaging of a disease in which amyloid is accumulated comprising the compound of the above (1) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier;
  • composition (6) that is labeled with a positron release out nuclide is selected from the group consisting of F, (10) The composition according to (6) above, wherein the compound is selected from atalizine orange, atalizine orange hydrochloride, BF-009, neutral red salt and new methylene pull, and is labeled with 18 F. object,
  • a kit for imaging diagnosis of a disease in which amyloid accumulates comprising the compound of the above (1) or a pharmaceutically acceptable salt or solvate thereof as an essential component,
  • R a , R b , R c and R d each independently represent an alkyl group having 2 to 4 carbon atoms
  • 3,6-bis (getylamino) ataridine hydrochloride is the most preferred.
  • 3,6_bis (getylamino) ataridine hydrochloride is referred to as “compound BF-009” or “BF-009”.
  • R a , R b , R c and R d are each independently an alkyl having 2 to 4 carbon atoms. Represents a radical
  • a compound for imaging diagnostic probe of a disease in which amyloid accumulates or a salt or solvate thereof
  • the label is a radionuclide, the compound of (3) or a salt or solvate thereof,
  • gamma-ray emitting nuclides 99 m T c, 111 I n , 67 Ga, 201 T 1, 123 I and 1 33 are selected from the group consisting of Xe (7)
  • positron emission nuclide 11 C, 13 N, 15 0 and 18 are selected from the group consisting of F (10) or a salt or solvate thereof as claimed,
  • composition comprising BF-009 labeled with 99m Tc or 123 I or a pharmaceutically acceptable salt or solvate thereof.
  • composition according to (13) comprising BF-009 labeled with 18 F or a pharmaceutically acceptable salt or solvate thereof.
  • a kit for imaging diagnosis of a disease in which amyloid accumulates comprising the compound according to any of the above (1) to (12) or a pharmaceutically acceptable salt or solvate thereof as an essential component.
  • the substance used as an imaging diagnostic probe for a disease in which amyloid accumulates according to the present invention is the compound represented by the above general formula I or a salt or solvate thereof.
  • alkyl having 1 to 4 carbon atoms includes methyl, ethyl, propyl, butyl, and structural isomers thereof.
  • R 2 or R 3 is Amino which is mono- substituted numbers 1 to 4 alkyl carbons. Dimethylcarbamoyl Ruamino group and Jechiruamino group, etc.
  • R 2 or R 3 is Amino which is di-substituted by C1-4 alkyl carbons. When R 2 or R 3 is an amino di-substituted by an alkyl having 1 to 4 carbon atoms, it forms an onion at its nitrogen and forms an anion capable of forming an onium salt as described later. Pum salts may be formed.
  • R 2 or R 3 is
  • a salt may be formed at the sulfonic acid group (the salt will be described later).
  • substituents R 9 may be in any position of the phenyl ring.
  • R 5 is hydrogen, but R 4 and R 5 may be linked to form a benzenesulfonic acid group, and the sulfonic acid group may be bonded to any position of the formed benzene ring. Alternatively, a salt may be formed (the salt will be described later).
  • X is CH, or N (H), Y is N, S, or
  • Oxygen ions may be formed at the nitrogen or zeolite contained in X or Y, and may form an ionic salt with an anion capable of forming an ionic salt as described later.
  • Y is the above substituent 1 ⁇ .
  • compounds of Formula I include BF-09, a compound such as Atalidine Orange, which is included in Formula (II) [detailed below], or -Eutral Red, Azunole A, euemethylene Pigments such as bunore, phenosafranine, methylene violet 3 RAX, safraencho, azocarmine B and the like.
  • the compound of formula I is in the form of an ammonium salt formed between its nitrogen or iron and the anion.
  • a dimethyl salt may be formed between the nitrogen or the nitrogen or Y contained in R 2 and R 3 of the formula I and the anion.
  • Examples of the anion capable of forming a rhodium salt with the compound of the formula I include anions such as a halide ion, an organic acid ion, a sulfonate ion and a perchlorate ion. Also, other types of salts of the compounds of Formula I are included in this effort. Salts may be formed with any of the functional groups in the compounds of formula I. For example, as described above, When a sulfonic acid group is present in the compound, a salt may be formed between the sulfonic acid group and the metal. Examples of strong salts include salts with alkali metals such as lithium, sodium, and potassium, and salts with alkaline earth metals such as magnesium, calcium, and barium.
  • a compound whose hydrogen is a metal such as sodium or potassium is also included in the present invention.
  • complexes formed with a compound of the formula I and a metal salt are also included in the present specification as salts of the compound of the formula I. I do.
  • the compound of the present invention is used in a composition or kit, it is preferably a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts of the compounds of formula I include, for example, those in the form of oxalate salts with halide ions such as chlorine, bromine and iodine, as well as metals such as sodium, potassium and calcium.
  • solvates of the compounds of formula I are encompassed by the present invention.
  • the solvates include hydrates, methanol solvates, ethanolic solvates, and ammonia solvates.
  • pharmaceutically acceptable ones are also preferred, and pharmaceutically acceptable solvates include hydrates and ethanol solvates.
  • pharmaceutically acceptable solvates include hydrates and ethanol solvates.
  • Preferred compounds of the invention are those of the above formula (II):
  • R a to R d are each independently an alkyl group having 2 to 4 carbon atoms, and also include structural isomers of these alkyl groups, such as i-propyl, sec-butyl, t Monobutyl groups are also included.
  • R a to R d are all ethyl, and the ring
  • the compound in the form of a hydrochloride at the hetero atom N therein, ie, BF-009, is the most preferred compound of the present invention.
  • amiloid accumulates a compound of formula I or formula II, or a salt or solvate thereof, which specifically binds in vivo to amyloid in a body in a disease in which amyloid accumulates, in particular, 3) amyloid protein in vivo.
  • amyloid-accumulating disease refers to a disease characterized by deposition of amyloid protein, in particular, amyloid protein in the body as described above, which can be diagnosed using this as a marker, such as Alzheimer's disease and Danish disease. Syndrome and the like.
  • Labels include fluorescent substances, affinity substances, enzyme substrates, and radionuclides.
  • a probe labeled with a radionuclide is used for diagnostic imaging of diseases in which amyloid accumulates.
  • the compounds of the present invention can be labeled with various radionuclides by methods well known in the art. For example, 3 H, 14 C, 35 S, 131 I, etc. are radionuclides that have been used for a long time, and are often used in vitro.
  • PET positron emission tomography
  • SPE CT computed tomography with gamma-ray emitting nuclides
  • SPEC is for T 99 "1 T c, 111 I n N 67 Ga, 201 T 1, 123 ⁇ , it can be labeled compound of the present invention with y-ray emitting nuclides such as 133 Xe. 99m T c and 123 I it can be labeled the 11 C, 13 N, 15 0 , 18 F, 62 Cu, 68 G a, 76 B compound of the present invention with a positron emitting nuclide such as r in but for. PET which is commonly used for SPEC . among positive electron emitting nuclide, half-life is appropriate from the viewpoint of the labeled easiness 11 C, 13 N, 15 0, 18 F are preferred, 18 F are particularly preferred.
  • the labeling position of the compound of the present invention on a radiation-emitting nuclide such as a positron-emitting nuclide or a ⁇ -ray-emitting nuclide may be any position of the compound in Formula I or Formula II.
  • the side chain (! ⁇ ⁇ ! ⁇ ; Substituent or R a -R d substituent) may be labeled with a radiation emitting nuclide such as a positron emitting nuclide, ⁇ -ray emitting nuclide, or hydrogen on the ring May be replaced by radiation emitting nuclides such as positron emitting nuclides and 0 ray emitting nuclides. Strongly labeled compounds of Formula I or Formula II are also included in the present invention.
  • the compound of the present invention when labeled with 18 F, it may be labeled with a side chain (! ⁇ -Substituent or! ⁇ -! ⁇ Substituent) of the formula I or II with a force of 8 F, or May be replaced by 18 F.
  • a force of 8 F or May be replaced by 18 F.
  • hydrogen contained in any of them may be replaced by 18 F.
  • Compounds of the present invention suitable for labeling with radiation emitting nuclides, including 18 F include neutral red and -eumethylenepurine, or compounds of formula (II), for example, BF-009, ataridine Examples include orange and acridine orange hydrochloride, but are not limited thereto.
  • the label may be present at any position of the compound of formula (II).
  • the side chain (R a to R d substituent) itself may be labeled, or the ring itself may be labeled.
  • a particularly preferred compound for labeling with 18 F is BF-009.
  • the compounds BF-009 compound is any one of hydrogen is substituted with 1 8 F of R a to R d group (Echiru group) is particularly preferred.
  • these nuclides are produced by equipment called cyclotrons or generators. Those skilled in the art can select a production method and an apparatus according to a produced nuclide. The nuclide thus produced can be used to label the compound of the present invention.
  • Methods for producing labeled compounds labeled with these radionuclides are well known in the art. Typical methods include chemical synthesis, isotope exchange, and biosynthesis. Chemical synthesis has been widely used, and is essentially the same as ordinary chemical synthesis except that radioactive starting materials are used. Various nuclides are introduced into the compound by this method.
  • the isotope exchange method is used for 3 H, 3 5 S, 1 2 5 I like transferred into compounds of complex structure, a method of obtaining a compound of labeled complex structure of these nuclides.
  • the biosynthesis method is a method in which a compound labeled with 14 c, 35 s or the like is given to cells such as a microorganism to obtain a metabolite into which these nuclides have been introduced.
  • the label can be introduced at a desired position by designing the synthesis scheme according to the purpose as in the ordinary synthesis. Powerful designs are well known to those skilled in the art.
  • positron emitting nuclides such as 11 C, 13 N, 15 O, and 18 F, which have relatively short half-lives
  • the desired nuclide can be introduced into the desired position of the compound of the present invention and labeled by these methods known to those skilled in the art.
  • Administration of the labeled compound of the present invention to a subject may be local or systemic.
  • Administration routes include intradermal, intraperitoneal, intravenous, arterial, or spinal fluid injection or infusion, etc., which can be selected according to the type of disease, nuclide used, compound used, target condition, test site, etc. .
  • the test site can be examined by means of PET, SPECT, or the like. These means can be appropriately selected depending on factors such as the type of disease, nuclide used, compound used, condition of the subject, and site to be examined.
  • the dose of the compound of the present invention labeled with a radionuclide varies depending on the type of disease, nuclide used, compound used, age of the subject, physical condition, gender, degree of the disease, test site, and the like. In particular, careful attention should be paid to the exposure of the target.
  • the amount of radioactivity 1 1 C, 1 3 N, 1 5 0, 1 8 F present compound labeled with a positron emitting nuclide such as is usually, 3.7 to Megabe not Clermont 3.7 Gigabe Turrell, preferably in the range of 18 megabecquerels to 74 megabecquerels.
  • the present invention also provides a composition for diagnostic imaging of a disease in which amyloid accumulates, including the compound of the present invention.
  • the composition of the present invention comprises the compound of the present invention and a pharmaceutically acceptable carrier.
  • the compound of the present invention in the composition is preferably labeled.
  • Above Power labeling method may vary S, it is desirable that the radionuclide-labeled (in particular 1 1 C, 1 3 N, 1 5 0, 1 8 F positron emission such as) in the image diagnostic applications in vivo .
  • the composition of the present invention is preferably in a form that allows injection or infusion.
  • the pharmaceutically acceptable carrier is preferably a liquid, and is preferably an aqueous solvent such as potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, or polyethylene glycol, vegetable oil, ethanol, glycerin.
  • aqueous solvents such as, but not limited to, dimethi / resulfoxide, propylene glycol and the like.
  • the mixing ratio of the carrier and the compound of the present invention can be appropriately selected depending on the application site, detection means, etc., but is usually 100,000 to 1 to 2: 1 and preferably 10,000 to 1 Or a ratio of 10: 1.
  • composition of the present invention may further comprise a known antibacterial agent (for example, an antibiotic), a local anesthetic (for example, pro-force hydrochloride, dibu-force hydrochloride, etc.), a buffer (for example, a tris-hydrochloride buffer).
  • a known antibacterial agent for example, an antibiotic
  • a local anesthetic for example, pro-force hydrochloride, dibu-force hydrochloride, etc.
  • a buffer for example, a tris-hydrochloride buffer.
  • osmotic pressure regulators eg, glucose, sorbitol, sodium chloride, etc.
  • the present invention provides a diagnostic imaging kit for a disease in which amyloid is accumulated, which contains the compound of the present invention as an essential component.
  • the kit contains the compound of the present invention, a solvent for dissolving the compound, a buffer, an osmotic agent, an antibacterial agent, a local anesthetic, and the like separately or in a container together. It is a collection of what you put in.
  • the compound of the present invention may be unlabeled or labeled. If unlabeled, the compounds of the invention can be labeled before use by conventional methods as described above.
  • the compound of the present invention may be provided as a solid such as a lyophilized powder, or may be provided after being dissolved in an appropriate solvent.
  • the solvent may be the same as the carrier used in the composition of the present invention described above.
  • Each component such as a buffer, an osmotic pressure regulator, an antibacterial agent, and a local anesthetic may be the same as those used in the above-mentioned composition of the present invention.
  • Various containers can be selected as appropriate, but they can also be formed into a shape suitable for the operation of introducing the label into the compound of the present invention, and can be made of a light-shielding material according to the properties of the compound, or can be used for patients. For convenience of administration, it may be in the form of a vial or a syringe.
  • the kit contains instruments necessary for diagnosis, such as syringes, infusion sets, and instruments used for PET devices. May be included as appropriate. Usually, instructions are attached to the kit.
  • the compound of the present invention specifically binds to the amyloid) 3 protein
  • the compound of the present invention can be used as it is, without labeling or after labeling, for the detection and quantification of amyloid / 3 protein in vitro. You can also.
  • the compound of the present invention may be used for amyloid] 3 protein staining of a microscope specimen, colorimetric determination of amyloid protein in a sample, or determination of amyloid protein using a scintillation counter.
  • a test compound (final concentration: 1 micromonoliter) dissolved in the same buffer was dispensed into a 96-well microplate at 50 microliters, and 50 microliters of the amyloid jS protein solution that had been allowed to stand for 4 days was added.
  • 100 microliters of Thioflavin T (which emits fluorescence depending on the degree of the structure of amyloid protein) dissolved in glycine-NaOH buffer (pH 8.5) was added in 100 microliters.
  • the fluorescence was measured at an excitation wavelength of 442 nanometers and a measurement wavelength of 485 nanometers using a fluorescence microplate reader (Molecular Devices, Inc., fmax type).
  • test compound] 3 Structure recognition degree (%) ⁇ (BC) / (BA) 1 X100 It can be said that the higher the] 3 structure recognition degree, the higher the binding specificity of the test compound to amyloid / 3 protein.
  • Insulin Structural Recognition of Test Compound (%) ⁇ (EF) / (ED) ⁇ XI 00
  • BSAS Biological Statistical Analysis System
  • the partition coefficient of 7k1-otatanol was measured to obtain an index of blood-brain barrier permeability.
  • 11-Otanol was used for the oil phase, and phosphate buffer (pH 7.3) or ultrapure water was used for the aqueous phase.
  • An appropriate amount of the test compound was dissolved in an oil phase or an aqueous phase, and both phases were placed in the same test tube and shaken vigorously at room temperature for 30 minutes. After leaving still at room temperature for 1 hour or more, it was centrifuged at 2,000 rpm for 10 minutes, and left still at room temperature for 1 hour. The ⁇ phase and the oil phase were each sampled and transferred to a 96-well microplate.
  • the absorbance was measured at the maximum absorption wavelength of each test compound using a microphone mouth plate reader (Spectramax 250, manufactured by Molecular Devices Co., Ltd.), and the test compound was determined from the calibration curve previously determined. The concentration was calculated.
  • test compound is as a diagnostic probe for a disease in which amyloid is accumulated.
  • mice Five-week-old Crj: CD1 male mice were used as 4 mice per group (mean weight of each group: 30 to 31 g). Each compound was dissolved in physiological saline (Otsuka Pharmaceutical Co., Ltd.), and a single intravenous administration of 1 O mg / m 1 or 100 mg Z kg was performed via the tail vein, and observation was performed until 7 days later.
  • physiological saline Oleuka Pharmaceutical Co., Ltd.
  • Typical examples of the compound of the present invention include ataridine orange (and its hydrochloride), a compound BF-009 (3,6-bis (getylamino) ataridine hydrochloride, synthesized by Tanabe R & D service), neutral red , Janus Green BS A-171, Phenosafranine, Methylene Violet 3 RAX, Safranin T, Azocarmine ⁇ , Thionine Perchlorate S ⁇ —252, AZUNORE A, AZUL, AZUL CSA 20 2, New methylene blue, Tonoreijin bunore 0, Methylene pull 1, 1,9-Dimethyl-methylene punolay hydrochloride SA-251
  • the / S structure recognition degree was measured by the measurement method described in (1).
  • Ataridine Orange and its hydrochloride
  • Compound BF-00 9 Neutral Red, Phenosafranine, Methylene Violet 3 RAX, Safranin T, Azocanolemin ⁇ , Az / re, Azunole ⁇ , New methylene phenol
  • the partition coefficient was measured by the method described in (3) above, and the useful coefficient was calculated by the method described in (4) above. The results are shown in Table I. The values in Table I are the average of two measurements, while those in bold are the average of three measurements.
  • the compounds of the present invention belonging to a different group from the conventionally reported control compound recognize the structure.
  • the structure recognition degree of the compound of the present invention was in the same order as that of the control compound.
  • the compound of the present invention tends to have a higher partition coefficient than the control compound, and thus the useful coefficient is higher by one order to three orders or more than that of the control compound.
  • the useful coefficient of neutral thread is extremely high.
  • the highest usefulness factor was obtained for compound BF-09.
  • Ataridin orange (and its hydrochloride), new methylene blue and methylene violet 3RAX also have relatively high usefulness coefficients. Therefore, it can be said that the compound of the present invention can specifically bind to the amyloid 3 protein, has extremely high blood-brain barrier permeability, and is extremely useful as a diagnostic probe for diseases in which amyloid is accumulated.
  • Table II shows the results obtained by measuring the degree of recognition of the insulin structure of BF-099, ataridine orange (free form), neutral red, phenosafraen, and safraen T by the method described in (2) above. Congo Red and Chrysami as controls G was measured similarly. The measurement was performed twice and the average value is shown in Table II.
  • the insulin sheet recognition degree of BF-009 was the highest, and the insulin [3] structure recognition degree of the other compounds of the present invention was almost the same as that of the control congoles and chrysamine G.
  • the useful coefficient of 09 was about 139 times (> 920 OZ66) of Congo Red and about 14 times (> 9200/649) of Chrysamine G. From the above, BF— 0
  • RAX Generally a total dose of Pojito port down labeled and unlabeled compounds for PET imaging in humans, 1 X 1 0- 1 intravenous administration of 2 from 1 X 1 0 one 5 mg Z kg is employed, in many cases 1 X 1 0- 1 0 from 1 X 1 0- 7 mg / kg intravenous administration is used. Acridine orange, eutranore red, new methylene punoray, methylene bio red 3 Looking at the maximum tolerated dose of intravenous RAX and the total amount of compounds required during PET imaging, there is at least 1 between the two. These compounds are considered to be extremely safe as a probe for PET imaging because there is a difference of more than 100,000 times.
  • amyloid belonging to a group different from conventional compounds, having high binding specificity to amyloid protein, high blood-brain barrier permeability, and extremely high safety A compound for an imaging diagnostic probe for a disease that accumulates is provided.
  • the compound represented by the formula (II) is preferred in the present invention, and particularly the compound BF-09 is a most preferred compound having a high useful coefficient.
  • a compound for imaging diagnosis of a disease in which amyloid represented by the formula (II) accumulates in particular, BF-09
  • a composition for imaging diagnosis of a disease in which amyloid containing them is accumulated Articles and kits are provided. Use of such a compound, composition, or kit enables accurate and early diagnosis of a disease.

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Abstract

La présente invention concerne des composés représentés par la formule générale (II), particulièrement BF-009, utilisés comme sondes dans l'imagerie diagnostique des maladies dues à l'accumulation d'amyloïde. En outre, cette invention concerne des compositions et des kits d'imagerie diagnostique conçues pour les maladies dues à l'accumulation d'amyloïde. Dans ladite formule (II), Ra, Rb, Rc, Rd représentent individuellement C2-4 alkyle.
PCT/JP2001/002205 2000-03-22 2001-03-21 Analogues d'azur a utilises comme sondes dans l'imagerie diagnostique des maladies dues a l'accumulation d'amyloide, et compositions renfermant ces analogues destinees a l'imagerie diagnostique WO2001070699A1 (fr)

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AU2001244549A AU2001244549A1 (en) 2000-03-22 2001-03-21 Azure a analogues useful as probes in the diagnostic imaging for diseases due toaccumulation of amyloid and compositions for diagnostic imaging containing the analogues

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JP2000-80083 2000-03-22
JP2000080083A JP2000344685A (ja) 1999-03-26 2000-03-22 アズールａ類似化合物によるアミロイドが蓄積する疾患の画像診断プローブおよびそれを含む画像診断用組成物

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7371744B2 (en) 2001-05-30 2008-05-13 Photopharmica Limited Biologically active methylene blue derivatives
US7713962B2 (en) 2001-03-20 2010-05-11 Wista Laboratories Ltd. Neurofibrillary labels
US7910579B2 (en) 2006-12-25 2011-03-22 Tohoku University Benzoxazole derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3563751A (en) * 1967-07-20 1971-02-16 Du Pont Hexaarylbiimidazole-acridine dye compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3563751A (en) * 1967-07-20 1971-02-16 Du Pont Hexaarylbiimidazole-acridine dye compositions

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7713962B2 (en) 2001-03-20 2010-05-11 Wista Laboratories Ltd. Neurofibrillary labels
US8097615B2 (en) 2001-03-20 2012-01-17 Wista Laboratories Ltd. Neurofibrillary labels
US7371744B2 (en) 2001-05-30 2008-05-13 Photopharmica Limited Biologically active methylene blue derivatives
US7732439B2 (en) 2001-05-30 2010-06-08 Photopharmica Limited Biologically active methylene blue derivatives
US7855197B2 (en) 2001-05-30 2010-12-21 Photopharmica Limited Biologically active methylene blue derivatives
US7915254B2 (en) 2001-05-30 2011-03-29 Photopharmica Limited Biologically active methylene blue derivatives
US8188074B2 (en) 2001-05-30 2012-05-29 Photopharmica Limited Biologically active methylene blue derivatives
US7910579B2 (en) 2006-12-25 2011-03-22 Tohoku University Benzoxazole derivatives

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