WO2001070667A1 - Sonde de diagnostic par image, a base d'azobenzene substitue ou d'un analogue de celui-ci, pour les maladies imputables a l'accumulation d'amyloide et composition pour le diagnostic par image le contenant - Google Patents
Sonde de diagnostic par image, a base d'azobenzene substitue ou d'un analogue de celui-ci, pour les maladies imputables a l'accumulation d'amyloide et composition pour le diagnostic par image le contenant Download PDFInfo
- Publication number
- WO2001070667A1 WO2001070667A1 PCT/JP2001/002204 JP0102204W WO0170667A1 WO 2001070667 A1 WO2001070667 A1 WO 2001070667A1 JP 0102204 W JP0102204 W JP 0102204W WO 0170667 A1 WO0170667 A1 WO 0170667A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solvate
- compound
- salt
- group
- amyloid
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
- C07C211/50—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton with at least two amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
- C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
- C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/20—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups being part of rings other than six-membered aromatic rings
- C07C251/22—Quinone imines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/46—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/47—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having at least one of the sulfo groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/78—Halides of sulfonic acids
- C07C309/86—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/88—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
- C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/38—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with the sulfur atom of the thio group bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
Definitions
- Probe for diagnostic imaging of a disease in which amyloid accumulates by substituted azobenzene and similar compounds and diagnostic imaging composition containing the same
- the present invention relates to an imaging diagnostic probe for a disease in which amyloid accumulates, in particular, a probe labeled with a positron emitting nuclide, and an imaging diagnostic composition containing the probe.
- an imaging diagnostic probe for a disease in which amyloid accumulates in particular, a probe labeled with a positron emitting nuclide, and an imaging diagnostic 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 the greatest risk factor for dementia represented by Alzheimer's disease is aging. Therefore, the increase in the number of patients accompanying the aging population is particularly remarkable in aging societies such as Japan, the United States, and European countries, and the cost of medical care for these increases is due to the health care system in these countries. We are in crisis.
- the number of Alzheimer's disease patients in Japan is estimated to be about 100,000, and it is expected that the number of Alzheimer's disease patients will increase as the population ages in the future. Since the cost of patients with Waltz-heimer's disease, including nursing care costs, is considered to exceed 250 million yen per patient per year, socioeconomic costs exceeding 2.5 trillion yen have already been paid in Japan. Will be. 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. Senile plaques and neurofibrillary tangles.
- the main component of the former is an amyloid 3 protein with 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 protein in the pathogenesis of Alzheimer's disease is as follows (Katsuhiko Yanagisawa, Yasuo Ihara: Advances in Neuroscience, Vol. 41, pp. 70-79, 199, Mikio Tokaibayashi: Dementia Japan, Vol. 11, pp. 43-50, 1990, Akira Tamaoka: Dementia Japan, Vol. 11, pp. 51-57, pp. 197 ).
- Diffuse deposition of amyloid protein ( ⁇ ) 3) is considered to be the earliest neuropathological change in the brain of Alheimer's disease.
- the gene encoding APP is present. 2. Neuropathological changes similar to Alzheimer's disease brain appear early in Alzheimer's disease brain in the syndrome of Dund syndrome with trisomy on chromosome 1.
- amyloid i3 protein is characteristic of a disease in which amyloid accumulates, including Alzheimer's disease, and is closely related. Therefore, detection of the amyloid / 3 protein having a three-sheet structure as a marker in the body, especially in the brain, is one of the important diagnostic methods for diseases in which amyloid accumulates, especially Alzheimer's disease.
- amyloid accumulation diseases such as Alzheimer's disease
- substances that specifically bind to and stain the amyloid 3 protein in the body, especially in the brain have been conventionally searched.
- Such substances include Congo Red (Puchtler et al., Journal of Hist Chemistry and Site Chemistry, Vol. 10, pp. 35, 1962) and Thioflavin S (Pachitra). I. (Puchtler) et al., Journal Op. Hist Chemistry and Site Chemistry, Vol. 77, pp.
- the present invention provides a substance which has high binding specificity to amyloid protein and blood-brain barrier permeability, and can be used as an imaging diagnostic probe for a disease in which amyloid is accumulated. Provide a different group of substances.
- the present invention also provides a diagnostic imaging probe for a disease in which amyloid is accumulated. Also provided are such labeled substances used, as well as diagnostic imaging compositions comprising such probes. Means for solving the problem
- the present inventors have conducted intensive studies to solve the above problems, and as a result, have found that the compound represented by the formula I or a salt or solvate thereof has a very high binding specificity to a / 3 amyloid protein, and They have found that they have brain barrier permeability, and have completed the present invention.
- X is CH, N or S
- Y is a force that is CH, N or S ⁇ or is absent
- a and B are each independently a carbocyclic group selected from a benzene ring, a naphthalene ring, an anthracene ring or a phenanthrene ring, or one to three heterogeneous groups selected from N, 0, and S
- the carbocyclic group containing an atom
- P and Q are independently alkyl having 1 to 4 carbons
- n is an integer from 1 to 7
- n 1 to 7
- a compound for imaging diagnostic probe of a disease in which amyloid accumulates or a salt or solvate thereof
- N-039 N— [4— (2- ⁇ 6- [4- (dimethylamino) styryl] —1-methylinopyridinium-1-2-yl ⁇ butyl) phenyl] —N-methinole Methanamine,
- the label is a radionuclide, the compound of (3) or a salt or solvate thereof, (5) The compound according to (4), wherein the substituent R i or R 2 is labeled with a radiation-emitting nuclide, 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,
- a kit for imaging diagnosis of a disease in which amyloid is accumulated comprising the compound according to any of the above (1) to (12) or a pharmaceutically acceptable salt or solvate thereof as an essential component; (1 7) 99m T c or 123 N_039 labeled with I, BF-064 and the compound is selected from the group consisting of SA-215 or essential components a pharmaceutically acceptable salt thereof also properly solvate.
- the substance used as an imaging diagnostic probe for a disease in which amyloid accumulates is a substituted azobenzene and a similar compound, specifically, a compound represented by the above general formula I or a salt or solvate thereof.
- alkyl having 1 to 4 carbon atoms includes methinole, ethyl, propynole, butyl, and structural isomers thereof.
- X is CH, N or S
- Y is a force or absent which is CH, N or S
- X indicates a single or double bond.
- a preferred ring as ring A and ring B is a benzene ring.
- benzene rings naphthalene rings, anthracene rings or phenanthrene rings containing one to three hetero atoms selected from N, 0 and S, preferred are a benzene ring and a pyridine ring.
- R 2 are 1 to at most 7 substituents on ring A and ring B, respectively, and may be substituted at any position on the ring, but the onoleto position or the para position is preferred.
- ring A or ring B is a heterocyclic ring, a substituent or R 2 may be present on the heteroatom (N, S or O).
- R 2 is alkyl having 1 to 4 carbon atoms, methyl, ethyl and propyl are preferred.
- R 2 when R 2 is halogen, fluorine, chlorine or iodine is preferred.
- R i or R 2 which is an amino mono-substituted with an alkyl having 1 to 4 carbon atoms, include a methylamino group and an ethylamino group. Dimethylcarbamoyl Ruamino group and Jechiruamino group, etc.
- Examples of some or R 2 in Amino which is di-monosubstituted number 1 at 4 alkyl carbons.
- 2 or 1 ⁇ 6 is an amino di-substituted by an alkyl having 1 to 4 carbon atoms, it forms an onion at its nitrogen and forms an ionic salt with anion as described later. You may.
- R 2 is a carboxyl or sulfonic acid group
- a salt may be formed at the sulfonic acid group (the salt will be described later).
- the compound of Formula I may contain a hydroxy group (eg, or when R 2 is a hydroxy group), the compound of Formula I may give rise to keto-enol tautomers at this moiety.
- the strong isomers are also included in the present invention.
- the hydrogen of the hydroxy group may be replaced by a metal (eg, sodium or potassium).
- ring A and ring B are pyridine rings
- R i and R 2 are Preferred is a compound represented by the formula: N-039, that is, N— [4- (2- ⁇ 6- [4- (dimethylamino) styryl] —1—methylpyridinium-1— Bil) phenyl) -N-methylmethanamine (see Table I).
- ring A and ring B are pyridine rings
- 1 ⁇ and R 2 are
- a typical example of such a compound is BF-064, that is, N— [4- (2- ⁇ 6- [4-1 (Jetylamino) styryl] —— 11-methylpyridinium —2 —Yl ⁇ vinyl) phenyl] _N_ethylethanamine (see Table I).
- Typical examples of compounds of Formula I are shown below as Table I.
- the compounds of formula I can form salts with various ions, and these salts are also included in the present invention. Salts may be formed with any of the functional groups in the compounds of Formula I. For example, when a carboxyl group or a sulfonic acid group is present in the compound as described above, a salt may be formed between these and a metal. Examples of such salts include salts with alkali metals such as lithium, sodium and potassium, and salts with alkaline earth metals such as magnesium, calcium and barium. Also, as mentioned above, the compounds of formula I may form onium salts.
- Examples of the anion that forms an onium salt with the compound of the formula I include anions such as halide ions, organic acid ions, and sulfonate ions. Strong onium salts are also included in the present invention. Further, a complex formed with a compound of the formula I and a metal salt (for example, a complex formed with a metal salt such as magnesium chloride or iron chloride) is also included in the present specification as a salt of the compound of the formula I. And When the compound of the present invention is used in the composition or kit of the present invention, Preferably, it is a pharmaceutically acceptable salt.
- Pharmaceutically acceptable salts of the compounds of formula I include, for example, those in the form of onium salts with halide ions such as chlorine, bromine and iodine, as well as metals such as sodium, potassium and calcium. And complexes formed with metal salts such as iron chloride and cobalt chloride.
- solvates of the compounds of formula I are encompassed by the present invention. Examples of solvates include hydrates, methanol solvates, ethanol solvates, and ammonia solvates. When used in the composition or kit of the present invention, a pharmaceutically acceptable solvate is also preferable, and a pharmaceutically acceptable solvate includes hydrate, ethanol solvate and the like.
- the term "the compound of the present invention” is intended to include the compound of the formula I, and salts and solvates thereof.
- 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 Panoletzheimer disease and Down 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, 13 I, and the like are radionuclides that have been used before, and are often used in vitro.
- diagnostic imaging probes and their detection means are that they can be diagnosed in vivo, that they have minimal damage to the patient (especially non-invasive), that they have high detection sensitivity, and that their half-life is appropriate. Length (appropriate label probe preparation time and diagnostic time). Therefore, recently, positron emission tomography (PET) using gamma rays, which has high detection sensitivity and material permeability, or computed tomography (SPE) using gamma-emitting nuclides, CT) has come to be used. Of these, PET detects two y- rays emitted from positron-emitting nuclides in opposite directions by a coincidence method using a pair of detectors, so that information with excellent resolution and quantitative properties can be obtained.
- PET positron emission tomography
- SPE computed tomography
- CT computed tomography
- the use SPEC T can be labeled 99 m Tc, 111 I n, 67 Ga, 201 T 1, 123 ⁇ , the present invention compounds of ⁇ -ray emitting nuclides such as 133 Xe. 99m Tc and 123 I are commonly used for SPEC.
- the PET for can be labeled 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.
- a positron emitting nuclides 11 C, 13 N, 15 0, 18 F are preferred from such half-life is appropriate, 18 F are particularly preferred.
- the substituent or R 2 of the compound of formula I may be labeled with a radionuclide, such as a positron-emitting nuclide, a gamma-emitting nuclide, or the hydrogen on the ring of the compound of formula I may be labeled with a positron-emitting nuclide, gamma-ray It may be replaced with a radiation emitting nuclide such as an emitting nuclide.
- X or ⁇ of the compound of formula I may be a radionuclide.
- labeled compounds of formula I are also included in the present invention.
- the substituent or R 2 may be labeled with 18 F, or a hydrogen on the ring of the compound of Formula I may be replaced with 18 F.
- hydrogen contained in either the substituent of ring A or ring B or R 2 may be replaced by 18 F.
- the compounds of the present invention suitable for labeling with 18 F or other radiation-emitting nuclides include N-039, BF-064, and SA-215 described above, but are not limited thereto. Generally, these nuclides are produced by equipment called cyclotrons or generators.
- 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. Double isotope exchange method, which were transferred 3 H, 35 S, 125 I etc. in the compounds of simple structure in the compounds of complex structures, labeled with these radionuclides This is a method for obtaining a compound having a complicated structure.
- Raw synthesis Ru method der to obtain 1 4 C, 3 5 metabolites of these nuclides are introduced to give a compound labeled in cells, such as microorganisms in S or the like.
- the label can be introduced at a desired position by designing the synthesis scheme according to the purpose as in the ordinary synthesis. Power and design are well known to those skilled in the art.
- 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 Crel, 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, comprising 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.
- radionuclides especially 11 C, 1 3 N, 1 5 0, it is desirable that the labeled with 1 8 F positron emission such as).
- 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 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, dimethyl sulfoxide, 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 further comprises a known antibacterial agent (for example, an antibiotic), a local anesthetic (for example, pro-force hydrochloride, dibu-force hydrochloride, etc.), a knocker (for example, Tris-hydrochloride buffer, And a osmotic pressure regulator (eg, glucose, sorbitol, sodium salt, etc.).
- a known antibacterial agent for example, an antibiotic
- a local anesthetic for example, pro-force hydrochloride, dibu-force hydrochloride, etc.
- a knocker for example, Tris-hydrochloride buffer
- a osmotic pressure regulator eg, glucose, sorbitol, sodium salt, 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 may appropriately include instruments necessary for diagnosis, for example, instruments used for a syringe, an infusion set, or a PET device. Usually, instructions are attached to the kit.
- the compound of the present invention specifically binds to amyloid) 3 protein
- the compound of the present invention should be used without labeling or after labeling, for detection, quantification, etc. of amyloid 3 protein in the in vivo mouth.
- the compound of the present invention may be used for amyloid protein staining of a microscope specimen, colorimetric quantification of amyloid 3 protein in a sample, or quantification of amyloid 3 protein using a scintillation counter. Next, a method for screening the compound of the present invention will be described.
- amyloid 3 protein purchased from Peptide Research Institute was dissolved in potassium phosphate buffer (pH 7.4) and left at 37 ° C for 4 days.
- test compound final concentration: 1 micromolar
- amyloid 3 protein solution left for 4 days
- thioflavin T which emits fluorescence depending on the structure of the amyloid protein
- glycine-NaOH buffer pH 8.5
- the fluorescence was measured at an excitation wavelength of 442 nanometers and a measurement wavelength of 485 nanometers using a fluorescent microplate reader (Molecular Devices, Inc., fmax type).
- the partition coefficient of water 1-octanol was measured and used as an index of blood-brain barrier permeability.
- 1-octanol was used for the oil phase
- 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 aqueous phase and the oil phase were each sampled and transferred to a 96-well microplate.
- test compound binding specificity to amyloid i3 protein and partition coefficient (test compound permeability to blood-brain barrier) is defined as a useful coefficient, this coefficient is actually When a test compound is administered to a subject, the test compound penetrates the blood-brain barrier, It is considered to be an indicator of how much it binds to amyloid J3 protein in the brain.
- mice The acute toxicity of the compound of the present invention was examined by intravenous administration using mice.
- Each compound was dissolved in physiological saline (Otsuka Pharmaceutical Co., Ltd.), and a single intravenous administration of lOOmgZkg was performed via the tail vein and observed until 7 days later.
- SA-215 has a relatively high degree of structure recognition.
- the compound of the present invention tends to have a higher partition coefficient than the control compound.
- the partition coefficient of S S-215 is extremely high, and the partition coefficients of N_039, BF-064, and BF-021 are also high. Therefore, the usefulness coefficient of these compounds is 1-2 orders of magnitude or more higher than the control compound.
- the compounds of the present invention having particularly high useful coefficients are SA-215, BF-064 and N-039, which are 6910 or more, 6830 and 3340, respectively.
- the useful coefficients of SA_169, BF-021 and SA_245 are also high. From these results, 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. .
- Chrysamine G 0.253 As described above, according to the present invention, an image of a disease that belongs to a group different from the conventional compounds, has high binding specificity to amyloid 3 protein, has high blood-brain barrier permeability, and has amyloid accumulation
- a compound for a diagnostic probe, and a composition and a kit for diagnostic imaging of a disease in which amyloid containing the same accumulates are provided.
- a compound, composition or kit accurate diagnosis of a disease at an early stage is possible.
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01914179A EP1266884A4 (en) | 2000-03-22 | 2001-03-21 | IMAGE DIAGNOSIS PROBE, BASED ON SUBSTITUTED AZOBENZOL OR ITS ANALOGA, FOR DISEASES WHICH ARE ATTRIBUTED TO AMYLOID ACCUMULATION, AND MIXTURES CONTAINING THIS IMAGE |
AU2001239544A AU2001239544A1 (en) | 2000-03-22 | 2001-03-21 | Image diagnosis probe based on substituted azobenzene or analogue thereof for disease attributable to amyloid accumulation and composition for image diagnosis containing the same |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000-80081 | 2000-03-22 | ||
JP2000080081 | 2000-03-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001070667A1 true WO2001070667A1 (fr) | 2001-09-27 |
Family
ID=18597236
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2001/002204 WO2001070667A1 (fr) | 2000-03-22 | 2001-03-21 | Sonde de diagnostic par image, a base d'azobenzene substitue ou d'un analogue de celui-ci, pour les maladies imputables a l'accumulation d'amyloide et composition pour le diagnostic par image le contenant |
Country Status (4)
Country | Link |
---|---|
US (1) | US20030138374A1 (ja) |
EP (1) | EP1266884A4 (ja) |
AU (1) | AU2001239544A1 (ja) |
WO (1) | WO2001070667A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004054978A1 (ja) * | 2002-12-16 | 2004-07-01 | Bf Research Institute, Inc. | タウ蛋白蓄積性疾患の診断プローブとしてのキノリン誘導体 |
EP1630205A1 (en) * | 2004-08-24 | 2006-03-01 | Clariant International Ltd. | New styrylpyridinium imine based dyes and their use in optical layers for optical data recording |
JP2007525441A (ja) * | 2003-03-03 | 2007-09-06 | マイコソル,インコーポレイテッド | ピリジニウム塩、化合物および使用法 |
JP2009532349A (ja) * | 2006-03-30 | 2009-09-10 | ザ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・ペンシルバニア | スチリルピリジン誘導体及びアミロイド斑を結合させ画像化するためのその使用 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050118226A1 (en) * | 2003-11-07 | 2005-06-02 | Kovacs Dora M. | Methods for treating ACAT-related diseases |
US20120237446A1 (en) * | 2005-03-25 | 2012-09-20 | Bayer Pharma Aktiengesellschaft | Compounds for binding and imaging amyloid plaques and their use |
CN100358582C (zh) * | 2005-03-25 | 2008-01-02 | 北京师范大学 | 放射性标记的Schiff碱类早老痴呆Aβ-淀粉斑块显像剂 |
JPWO2007074786A1 (ja) * | 2005-12-26 | 2009-06-04 | 国立大学法人東北大学 | コンフォーメーション病診断プローブ |
WO2008078424A1 (ja) * | 2006-12-25 | 2008-07-03 | Tohoku University | ベンゾキサゾール誘導体 |
JP5322180B2 (ja) * | 2007-07-04 | 2013-10-23 | 国立大学法人東北大学 | フッ素およびヒドロキシ基で置換されたアルコキシ基を有するpetプローブ |
EP2368558A1 (en) * | 2010-03-23 | 2011-09-28 | Mdc Max-Delbrück-Centrum Für Molekulare Medizin Berlin - Buch | Azo compounds reducing formation and toxicity of amyloid beta aggregation intermediates |
CN102557969B (zh) * | 2011-11-01 | 2015-03-18 | 中国科学技术大学 | 环酮类衍生物及其作为淀粉样蛋白沉积物和神经纤维缠结的显像剂和聚集抑制剂的用途 |
US20170176469A1 (en) * | 2012-02-24 | 2017-06-22 | Case Western Reserve University | Molecular Probes for Detecting Lipids |
US9180212B2 (en) * | 2012-05-22 | 2015-11-10 | The Regents Of The University Of California | β-amyloid plaque imaging agents |
CN104151193B (zh) * | 2014-07-10 | 2016-01-20 | 广西华锡集团股份有限公司 | (甲基亚胺基-(4-苯乙烯基-三苄胺))苯酚光敏剂及其合成方法 |
CN112525868B (zh) * | 2019-09-19 | 2022-04-22 | 吉林大学 | 喹哪啶红及其衍生物在制备检测淀粉样纤维的试剂盒中的应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0155551A1 (en) * | 1984-03-06 | 1985-09-25 | Mitsubishi Kasei Corporation | Method for the partial hydrogenation of conjugated dienes |
EP0287909A1 (en) * | 1987-04-08 | 1988-10-26 | Salutar, Inc. | Amyloidosis and Alzheimer's disease diagnostic assay and reagents therefor |
EP0290133A2 (en) * | 1987-04-02 | 1988-11-09 | Minnesota Mining And Manufacturing Company | Ternary photoinitiator system for addition polymerization |
WO1998040071A1 (en) * | 1997-03-11 | 1998-09-17 | The General Hospital Corporation | Identification of agents for use in the treatment of alzheimer's disease |
WO1999024394A2 (en) * | 1997-11-06 | 1999-05-20 | University Of Pittsburgh | Compounds for the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3085935A (en) * | 1961-04-24 | 1963-04-16 | Burroughs Wellcome Co | Method for the elimination of nematode infestations |
DE69010537T2 (de) * | 1989-04-01 | 1994-12-01 | Nippon Sheet Glass Co Ltd | Verfahren zur Herstellung eines schichtförmig aufgebauten Materials mit einem organischen Farbstoff enthaltenden Siliziumdioxidfilm sowie das somit erzeugte Produkt. |
US5955472A (en) * | 1995-11-02 | 1999-09-21 | Warner-Lambert Company | Naphthylazo inhibition of amyloidosis |
US6001331A (en) * | 1996-01-24 | 1999-12-14 | Warner-Lambert Company | Method of imaging amyloid deposits |
US5958919A (en) * | 1996-09-20 | 1999-09-28 | Washington University | Treatment of presymptomatic alzheimer's disease to prevent neuronal degeneration |
JP2000281591A (ja) * | 1999-03-26 | 2000-10-10 | Bf Kenkyusho:Kk | ベーシックブルー41およびパラチン・ファスト・ブラックwan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 |
PL352430A1 (en) * | 1999-06-10 | 2003-08-25 | Warner Lambert Co | Method of inhibiting agreggation of amyloid proteins and visualising amyloid deposits |
WO2002016333A2 (en) * | 2000-08-24 | 2002-02-28 | University Of Pittsburgh | Thioflavin derivatives and their use in diagnosis and theraphy of alzheimer's disease |
-
2001
- 2001-03-21 AU AU2001239544A patent/AU2001239544A1/en not_active Abandoned
- 2001-03-21 WO PCT/JP2001/002204 patent/WO2001070667A1/ja not_active Application Discontinuation
- 2001-03-21 US US10/239,154 patent/US20030138374A1/en not_active Abandoned
- 2001-03-21 EP EP01914179A patent/EP1266884A4/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0155551A1 (en) * | 1984-03-06 | 1985-09-25 | Mitsubishi Kasei Corporation | Method for the partial hydrogenation of conjugated dienes |
EP0290133A2 (en) * | 1987-04-02 | 1988-11-09 | Minnesota Mining And Manufacturing Company | Ternary photoinitiator system for addition polymerization |
EP0287909A1 (en) * | 1987-04-08 | 1988-10-26 | Salutar, Inc. | Amyloidosis and Alzheimer's disease diagnostic assay and reagents therefor |
WO1998040071A1 (en) * | 1997-03-11 | 1998-09-17 | The General Hospital Corporation | Identification of agents for use in the treatment of alzheimer's disease |
WO1999024394A2 (en) * | 1997-11-06 | 1999-05-20 | University Of Pittsburgh | Compounds for the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition |
Non-Patent Citations (2)
Title |
---|
ATTINA MARINA ET AL.: "Labeled aryl fluorides from the nucleophilic displacement of activated nitro groups by fluoride-18 ion", J. LABELLED COMPD. RADIOPHARM., vol. 20, no. 4, 1983, pages 501 - 514, XP002944123 * |
See also references of EP1266884A4 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004054978A1 (ja) * | 2002-12-16 | 2004-07-01 | Bf Research Institute, Inc. | タウ蛋白蓄積性疾患の診断プローブとしてのキノリン誘導体 |
US7118730B2 (en) | 2002-12-16 | 2006-10-10 | Bf Research Institute, Inc. | Quinoline derivative as diagnostic probe for disease with tau protein accumulation |
JP2007525441A (ja) * | 2003-03-03 | 2007-09-06 | マイコソル,インコーポレイテッド | ピリジニウム塩、化合物および使用法 |
JP4742028B2 (ja) * | 2003-03-03 | 2011-08-10 | マイコソル,インコーポレイテッド | ピリジニウム塩、化合物および使用法 |
EP1630205A1 (en) * | 2004-08-24 | 2006-03-01 | Clariant International Ltd. | New styrylpyridinium imine based dyes and their use in optical layers for optical data recording |
JP2009532349A (ja) * | 2006-03-30 | 2009-09-10 | ザ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・ペンシルバニア | スチリルピリジン誘導体及びアミロイド斑を結合させ画像化するためのその使用 |
US8506929B2 (en) | 2006-03-30 | 2013-08-13 | The Trustees Of The University Of Pennsylvania | Styrylpyridine derivatives and their use for binding and imaging amyloid plaques |
US8840866B2 (en) | 2006-03-30 | 2014-09-23 | The Trustees Of The University Of Pennsylvania | Styrylpyridine derivatives and their use for binding and imaging amyloid plaques |
Also Published As
Publication number | Publication date |
---|---|
AU2001239544A1 (en) | 2001-10-03 |
US20030138374A1 (en) | 2003-07-24 |
EP1266884A4 (en) | 2003-04-23 |
EP1266884A1 (en) | 2002-12-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Klunk et al. | Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative | |
WO2001070667A1 (fr) | Sonde de diagnostic par image, a base d'azobenzene substitue ou d'un analogue de celui-ci, pour les maladies imputables a l'accumulation d'amyloide et composition pour le diagnostic par image le contenant | |
US10149644B2 (en) | Curcumin derivatives for amyloid-β plaque imaging | |
US7700616B2 (en) | Compounds and amyloid probes thereof for therapeutic and imaging uses | |
AU2008202626B2 (en) | Thioflavin derivatives and their use in diagnosis and therapy of Alzheimer's disease | |
JPWO2004035522A1 (ja) | プリオン蛋白蓄積性疾患の診断プローブおよび治療薬ならびにプリオン蛋白の染色剤 | |
US8986657B2 (en) | Methods and system for detecting soluble amyloid-β | |
JPWO2005016888A1 (ja) | アミロイド蓄積性疾患のプローブ、アミロイド染色剤、アミロイド蓄積性疾患の治療および予防薬、ならびに神経原線維変化の診断プローブおよび染色剤 | |
US20080219922A1 (en) | Alzheimer's Disease Imaging Agents | |
WO2004054978A1 (ja) | タウ蛋白蓄積性疾患の診断プローブとしてのキノリン誘導体 | |
WO2003106439A1 (ja) | アミロイド蓄積性疾患の画像診断プローブ化合物、老人斑/びまん性老人斑染色用化合物、ならびにアミロイド蓄積性疾患の治療薬 | |
Cui et al. | Synthesis and evaluation of novel benzothiazole derivatives based on the bithiophene structure as potential radiotracers for β-amyloid plaques in Alzheimer’s disease | |
JPWO2007074786A1 (ja) | コンフォーメーション病診断プローブ | |
JP2010512325A (ja) | アセチレン誘導体、ならびにアミロイドプラークと結合し、および画像化するためのそれらの使用 | |
EP1655287A1 (en) | Probe for diseases with amyloid accumulation, amyloid-staining agent, remedy and preventive for diseases with amyloid accumulation and diagnostic probe and staining agent for neurofibrillary change | |
Tu et al. | Compounds for imaging amyloid-β deposits in an Alzheimer’s brain: a patent review | |
JP2000344684A (ja) | ピロニンb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 | |
JP2007223952A (ja) | アミロイドβ蛋白が蓄積する疾患の画像診断プローブ | |
Brockschnieder et al. | Preclinical characterization of a novel class of 18F-labeled PET tracers for amyloid-β | |
JP2004250411A (ja) | アミロイドβ蓄積性疾患の診断プローブおよび治療用化合物 | |
JP2000344685A (ja) | 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 | |
Kung et al. | Radioiodinated styrylbenzene derivatives as potential SPECT imaging agents for amyloid plaque detection in Alzheimer’s disease | |
Kawasaki et al. | Development of radioiodinated acridine derivatives for in vivo imaging of prion deposits in the brain | |
JP2002275099A (ja) | ベンゾシアゾリン環またはベンゾオキサゾリン環を含む化合物による、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 | |
JP2004067659A (ja) | タウ蛋白蓄積性疾患の診断プローブとしてのベンゾイミダゾール環含有化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 568879 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2001914179 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10239154 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 2001914179 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2001914179 Country of ref document: EP |