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WO2019168170A1 - Dérivé de chromone et composition pour le diagnostic d'une maladie liée à l'amyloïde - Google Patents

Dérivé de chromone et composition pour le diagnostic d'une maladie liée à l'amyloïde Download PDF

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Publication number
WO2019168170A1
WO2019168170A1 PCT/JP2019/008168 JP2019008168W WO2019168170A1 WO 2019168170 A1 WO2019168170 A1 WO 2019168170A1 JP 2019008168 W JP2019008168 W JP 2019008168W WO 2019168170 A1 WO2019168170 A1 WO 2019168170A1
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group
amyloid
compound
pharmaceutically acceptable
acceptable salt
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PCT/JP2019/008168
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English (en)
Japanese (ja)
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剛志 淵上
守雄 中山
さくら 吉田
史博 片山
真理 中家
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国立大学法人 長崎大学
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Priority to JP2020503654A priority Critical patent/JPWO2019168170A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a chromone derivative useful for diagnosis of amyloid-related diseases such as Creutzfeldt-Jakob disease, a composition for diagnosing amyloid-related diseases containing the same, and a method for screening a therapeutic or prophylactic agent for amyloid-related diseases using the same And a method for evaluating a therapeutic or prophylactic agent for amyloid-related diseases using the same.
  • Prion disease represented by Creutzfeldt-Jakob disease (CJD)
  • CJD Creutzfeldt-Jakob disease
  • prion disease is a fatal neurodegenerative disease classified as sporadic, acquired, or hereditary, and effective diagnosis and treatment methods are still established.
  • the incidence of prion disease in Japan is about 1 in 1 million per year, although the incidence is low, but the incidence rate is such as BSE infection due to the increase in imported beef in the future and hospital infection accidents from surgical instruments due to the increase in the elderly There is concern about the danger of the increase.
  • PrP C normal prion protein
  • PrP Sc abnormal prion protein aggregate
  • Non-patent Document 1 As imaging drugs for diagnosis of amyloid-related diseases such as Alzheimer's disease, flavone derivatives and styrylchromone (SC) derivatives have been reported (Patent Document 1). Recent studies show that SC derivatives show good binding to prion deposition in PrP Sc aggregates and mouse-adapted BSE (mBSE) infected mice, and SPECT / CT also clearly differs between mBSE infected and uninfected mice It has been found that non-patent literature 1 shows the accumulation. However, when aiming at practical application, all of the SC derivatives are prone to photoisomerization (cis-trans photoisomerization), and it is difficult to obtain a single component. There is a problem that it is difficult to obtain, which has been an obstacle to imaging not only prions but also other amyloids.
  • the present invention has been made based on the technical background as described above, and aims to develop a molecular probe for nuclear medicine diagnosis that can non-invasively visualize PrP Sc for early diagnosis of prion disease.
  • Properties required for such molecular probes include 1) permeability of the blood-brain barrier, 2) selective binding of PrP Sc , and 3) rapid disappearance of unbound body from the brain.
  • the molecular probe that achieves the above conditions binds to PrP Sc , and the radiation emitted from the target site is detected using PET or SPECT, so that PrP Sc in vivo can be tracked over time. Be expected.
  • the present invention provides the following [1] to [15].
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom; halogen atom; hydroxy group; carboxy group; sulfo group; nitro group; amino group; C 1-6 alkyl group; An optionally substituted C 1-6 alkoxy group; a mono (C 1-6 alkyl) amino group; or a di (C 1-6 alkyl) amino group, and R 5 , R 6 , R 7 and R 8 are , each independently, a hydrogen atom; a halogen atom; hydroxy group; a carboxy group; a sulfo group; a nitro group; an amino group; C 1-6 alkyl group; a halogen atom or a hydroxy which may be substituted by a group C 1-6 An alkoxy group; a mono (C 1-6 alkyl) amino group; or a di (C 1-6 alkyl) amino group.
  • X 1 in the formula (I) is O
  • X 2 is CH
  • R 1 , R 2 , R 4 , R 5 and R 8 are hydrogen atoms
  • R 3 is An iodine atom and R 6 is a hydrogen atom; a C 1-4 alkyl group; a C 1-4 alkoxy group optionally substituted by a hydroxy group; a mono (C 1-4 alkyl) amino group; or a di (C 1-4 alkyl) amino group
  • R 7 is hydroxy group; C 1-4 alkoxy group optionally substituted by hydroxy group; amino group; mono (C 1-4 alkyl) amino group; or di
  • [6] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [5], which is labeled with a radionuclide.
  • a composition for diagnosing amyloid-related diseases comprising the compound according to any one of [6] to [9] or a pharmaceutically acceptable salt thereof.
  • Amyloid-related diseases are Creutzfeldt-Jakob disease, Alzheimer's disease, Lewy body dementia, Mediterranean fever, Maccle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile Amyloidosis, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, scrapie, kuru disease, Gerstman-Stroisler-Scheinker syndrome, medullary thyroid cancer, isolated atrial amyloid, ⁇ 2 -microglobulin amyloid in dialysis patients, inclusion body myositis,
  • the composition according to [10] which is selected from the group consisting of ⁇ 2 -amyloid deposition in muscle wasting disease and Langerhans type II diabetes insulinoma.
  • An imaging agent for amyloid deposition comprising the compound according to any one of [6] to [9] or a pharmaceutically acceptable salt thereof.
  • a mammal into which a detectable amount of the compound according to any one of [6] to [9] or a pharmaceutically acceptable salt thereof is introduced is computed tomography (SPECT) or positron tomography
  • SPECT computed tomography
  • PET positron tomography
  • a step of administering a test substance to a model animal of amyloid-related disease a step of administering the amyloid-related disease composition described in [10] or [11] to the model animal, and in the brain of the model animal
  • a method for screening a therapeutic or prophylactic agent for amyloid-related diseases which comprises the step of examining the distribution or amount of the compound represented by formula (I) contained in.
  • a step of administering a therapeutic or prophylactic agent for amyloid-related disease to a model animal of amyloid-related disease a step of administering to the model animal the composition for diagnosing amyloid-related disease according to [10] or [11], and a method for evaluating a therapeutic or prophylactic agent for amyloid-related diseases, which comprises the step of examining the distribution or amount of the compound represented by formula (I) contained in the brain of the model animal.
  • the compound represented by the formula (I) exhibits a high binding affinity for PrP Sc, a high permeability of the blood brain barrier, and a property of rapidly disappearing from a normal tissue, so that it can be used as an amyloid imaging probe. Shows ideal brain behavior. It is useful for diagnosis of amyloid-related diseases such as Creutzfeldt-Jakob disease.
  • the cis and trans isomers derived from photoisomerism observed in SC derivatives are not confirmed in the compound represented by the formula (I). As a result, there is an advantage that the structure is stabilized by changing the styryl group of the SC skeleton to a 5-membered ring.
  • prion protein aggregates PrP Sc
  • a ⁇ amyloid- ⁇
  • ⁇ -Syn ⁇ -synuclein aggregates.
  • AD Alzheimer's disease
  • Parkinson's disease (PD) and Lewy body dementia (DLB) are thought to be caused by the accumulation and aggregation of ⁇ -synuclein ( ⁇ -Syn), a protein localized in neurons. ing.
  • the compound of the present invention has a high affinity for PrP Sc , but does not have a high affinity for other A ⁇ aggregates or ⁇ -Syn aggregates.
  • the compounds of the invention can be useful as imaging probes selective for PrP Sc .
  • some of the compounds of the present invention (for example, Compound 30 in Examples) have an affinity for ⁇ -Syn aggregates and are useful as imaging agents (imaging probes) for ⁇ -Syn aggregates. obtain.
  • the figure which shows the synthesis method (1) of a chromone derivative (the number in a figure shows the number of a compound).
  • the figure which shows the synthesis method (2) of a chromone derivative (the number in a figure shows the number of a compound).
  • the figure which shows the synthesis method (3) of a chromone derivative (the number in a figure shows the number of a compound).
  • the figure which shows the labeling method by the radioactive iodine of a chromone derivative The figure which shows the labeling method by the radioactive iodine of a chromone derivative.
  • the figure which shows the adsorption rate (%) of the [ 125I ] BFC derivative with respect to (alpha) -Syn aggregate (250 nM). Values are mean ⁇ SE, n 3.
  • the “halogen atom” is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl group means, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group Etc.
  • it is “C 1-4 alkyl group”, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group.
  • the “C 1-6 alkoxy group” means, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, Such as a hexyloxy group.
  • the “C 1-6 alkoxy group” is preferably a “C 1-4 alkoxy group”, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, tert-Butoxy group.
  • the “mono (C 1-6 alkyl) amino group” is an amino group substituted with one C 1-6 alkyl group, for example, a methylamino group, an ethylamino group, a propylamino group. Isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, pentylamino group, hexylamino group, and the like.
  • the “mono (C 1-6 alkyl) amino group” is preferably a “mono (C 1-4 alkyl) amino group”, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, A butylamino group, an isobutylamino group, a sec-butylamino group, and a tert-butylamino group;
  • the “di (C 1-6 alkyl) amino group” is an amino group substituted by two C 1-6 alkyl groups, and the two C 1-6 alkyl groups are the same as or May be different.
  • the “di (C 1-6 alkyl) amino group” is preferably a “di (C 1-4 alkyl) amino group”, for example, a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, And dibutylamino group, diisobutylamino group, di-sec-butylamino group, di-tert-butylamino group, N-ethyl-N-methylamino group, and N-methyl-N-propylamino group.
  • “optionally substituted with a halogen atom” means that it may be substituted with at least one (preferably 1 to 5, more preferably 1 to 3) halogen atoms. To do.
  • “optionally substituted by a hydroxy group” means that it may be substituted by at least one (preferably 1 to 5, more preferably 1 to 3) hydroxy group. To do.
  • halogen atom or a hydroxy group means that it is substituted by at least one (preferably 1 to 5, more preferably 1 to 3) halogen atom or hydroxy group. It means you may.
  • the “C 1-6 alkoxy group optionally substituted by a halogen atom” includes a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a trifluoromethoxy group, and a 2-fluoroethoxy group. , 3-fluoropropoxy group, 4-fluorobutoxy group, 5-fluoropentyloxy group and the like.
  • the “C 1-4 alkoxy group optionally substituted by a hydroxy group” includes a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a 2-hydroxyethoxy group, a 3-hydroxypropoxy group, 4- Examples thereof include a hydroxybutoxy group.
  • X 1 is preferably O.
  • X 2 is preferably CH.
  • X 2 is N.
  • X 1 is more preferably O and X 2 is CH.
  • X 1 is O and X 2 is N.
  • any one of R 1 , R 2 , R 3 and R 4 is a halogen atom, and more preferably any one of R 1 , R 2 , R 3 and R 4 .
  • R 5 and R 8 are preferably a hydrogen atom, and R 6 is a hydrogen atom; a C 1-4 alkyl group; a C 1-4 alkoxy optionally substituted by a hydroxy group A mono (C 1-4 alkyl) amino group; or a di (C 1-4 alkyl) amino group, and R 7 is a hydroxy group; a C 1-4 alkoxy group optionally substituted by a hydroxy group Amino group; mono (C 1-4 alkyl) amino group; or di (C 1-4 alkyl) amino group;
  • Preferable examples of the compound represented by the formula (I) include the following compounds.
  • X 1 is O
  • X 2 is CH
  • R 1 , R 2 , R 4 , R 5 and R 8 are hydrogen atoms
  • R 3 is an iodine atom
  • R 6 is a hydrogen atom; a C 1-4 alkyl group; a C 1-4 alkoxy group optionally substituted by a hydroxy group; a mono (C 1-4 alkyl) amino group; or a di (C 1-4) Alkyl) amino group
  • R 7 is hydroxy group; C 1-4 alkoxy group optionally substituted by hydroxy group; amino group; mono (C 1-4 alkyl) amino group; or di (C 1 -4 alkyl) compound or a pharmaceutically acceptable salt thereof is an amino group.
  • X 1 is O
  • X 2 is CH
  • R 1 , R 2 , R 4 , R 5 and R 8 are hydrogen atoms
  • R 3 is an iodine atom
  • R 6 is a hydrogen atom
  • R 7 is a C 1-4 alkoxy group (eg, methoxy group); an amino group; a mono (C 1-4 alkyl) amino group (eg, a methylamino group); Or a compound which is a di (C 1-4 alkyl) amino group (eg, dimethylamino group) or a pharmaceutically acceptable salt thereof.
  • More preferable examples include compounds 30, 33, 36, or 39 described in Examples described later, or pharmaceutically acceptable salts thereof.
  • the compound represented by the formula (I) can be synthesized according to the description in the examples described later.
  • compound (I) -1 in which X 1 is O and X 2 is CH can be produced by the method shown in the following scheme.
  • Process 1 Compound (IV) can be produced by subjecting compound (II) and compound (III) to cyclization and dehydration reaction in a solvent in the presence of a base.
  • the base include potassium carbonate.
  • the solvent include N, N-dimethylformamide (DMF).
  • Process 2 Compound (V) can be produced by hydrolyzing compound (IV) in the presence of a base in a solvent.
  • the base include sodium hydroxide and potassium hydroxide.
  • Examples of the solvent include methanol and ethanol.
  • Process 3 Compound (VII) can be produced by subjecting compound (V) and compound (VI) to an esterification reaction in the presence of a halogenating agent and a base.
  • a halogenating agent include chlorinating agents such as phosphoryl chloride and thionyl chloride.
  • Examples of the base include pyridine.
  • Process 4 Compound (VIII) can be produced by subjecting compound (VII) to a rearrangement reaction in the presence of a base in a solvent. Examples of the base include potassium hydroxide and sodium hydroxide. Examples of the solvent include pyridine.
  • Process 5 Compound (I) -1 can be produced by subjecting compound (VIII) to a dehydration cyclization reaction in a solvent in the presence of an acid. Examples of the acid include concentrated sulfuric acid. Examples of the solvent include acetic acid.
  • compound (I) -2 in which X 1 is O and X 2 is N can be produced by the method shown in the following scheme.
  • Step 6 Compound (X) can be produced by subjecting compound (IX) to an addition reaction with ethyl glyoxylate in a solvent, followed by an oxidation reaction using ammonium cerium nitrate (CAN) or the like.
  • the solvent include dioxane.
  • Step 7 Compound (XI) can be produced by hydrolyzing compound (X) in a solvent in the presence of a base. Examples of the base include sodium hydroxide and potassium hydroxide. Examples of the solvent include methanol and ethanol.
  • Process 8 Compound (XII) can be produced by subjecting compound (XI) and compound (VI) to an esterification reaction in the presence of a halogenating agent and a base.
  • halogenating agent examples include chlorinating agents such as phosphoryl chloride and thionyl chloride.
  • Examples of the base include pyridine.
  • Step 9 Compound (XIII) can be produced by subjecting compound (XII) to a rearrangement reaction in the presence of a base in a solvent. Examples of the base include potassium hydroxide and sodium hydroxide. Examples of the solvent include pyridine.
  • Step 10 Compound (I) -2 can be produced by subjecting compound (XIII) to a dehydration cyclization reaction in a solvent in the presence of an acid. Examples of the acid include concentrated sulfuric acid. Examples of the solvent include acetic acid.
  • the compound represented by formula (I) is preferably labeled with a labeling substance.
  • a labeling substance a fluorescent substance, an affinity substance or the like may be used, but it is preferable to use a radionuclide.
  • the kind of radionuclide used for labeling is not particularly limited, and can be appropriately determined depending on the mode of use.
  • the radionuclide is 99m Tc, 111 In, 67 Ga, 201 Tl, 123 I, 133 Xe (preferably , 99m Tc, 123 I) can be used.
  • 11 C, 13 N, 15 O, 18 F, 62 Cu, 68 Ga, 76 Br preferably 11 C, 13 N, 15 Positron emitting nuclides such as O, 18 F
  • a radionuclide having a longer half-life such as 125 I
  • the radionuclide may be included in the molecule of the compound represented by formula (I) or may be bonded to the compound represented by formula (I).
  • a pharmaceutically acceptable salt instead of the compound represented by the formula (I).
  • pharmaceutically acceptable salts include alkali metal salts (sodium salt, potassium salt, lithium salt), alkaline earth metal salts (calcium salt, magnesium salt), sulfate, hydrochloride, nitrate, phosphate, etc. it can.
  • amyloid-related disease means a disease in which the presence of an amyloid protein aggregate is observed. Since the compound of the present invention binds to a protein having a ⁇ sheet structure, the “amyloid-related diseases” in the present invention include amyloid having a ⁇ sheet structure such as tau, ⁇ -synuclein, prion, etc. in addition to ⁇ -amyloid. Diseases in which the presence of protein aggregates are observed are included.
  • the “amyloid-related disease” in the present invention includes Creutzfeldt-Jakob disease, Alzheimer's disease, Lewy body dementia, Mediterranean fever, Maccle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, Amyloid cardiomyopathy, systemic senile amyloidosis, hereditary cerebral hemorrhage with amyloidosis (including hereditary cerebral hemorrhage with Dutch or Icelandic amyloidosis), Down's syndrome, scrapie, Kourou disease, Gerstmann-Stroisler-Scheinker syndrome, Examples include medullary thyroid cancer, isolated atrial amyloid, ⁇ 2 -microglobulin amyloid in dialysis patients, inclusion body myositis, ⁇ 2 -amyloid deposition in muscle wasting disease, and Langerhans type II diabetes insulinoma.
  • the diagnostic composition of the present invention is particularly suitable for diagnosis of Creutzfeldt-Jakob disease, Alzheimer's disease, and Lewy body dementia.
  • precursor symptoms of diseases that are generally not recognized as “diseases” are also included in “amyloid-related diseases” in the present invention. Examples of prodromal symptoms of such diseases include mild cognitive impairment (MCI) seen before the onset of Alzheimer's disease.
  • Diagnosis of amyloid-related diseases with the composition of the present invention is usually performed by administering the composition of the present invention to a subject to be diagnosed or a laboratory animal, and then taking a brain image, which is represented by the formula (I) in the image. This is based on the state of the compound (amount, distribution, etc.).
  • the administration method of the composition of the present invention is not particularly limited and can be appropriately determined according to the type of compound, the type of labeling substance, etc., but is usually intradermal, intraperitoneal, intravenous, arterial, or spinal fluid. It is administered by injection or infusion.
  • the dose of the composition of the present invention is not particularly limited and can be determined appropriately according to the type of compound, the type of labeling substance, etc. In the case of an adult, the compound represented by formula (I) is 10 per day. -10 to 10 -3 mg is preferably administered, more preferably 10 -8 to 10 -5 mg.
  • the composition of the present invention since the composition of the present invention is usually administered by injection or infusion, it may contain components usually contained in an injection solution or an infusion solution.
  • Such components include liquid carriers (for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol, etc.), antibacterial agents And local anesthetics (eg, procaine hydrochloride, dibucaine hydrochloride, etc.), buffer solutions (eg, Tris-HCl buffer solution, Hepes buffer solution, etc.), osmotic pressure regulators (eg, glucose, sorbitol, sodium chloride, etc.) .
  • liquid carriers for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol, etc.
  • the present invention also relates to an imaging agent for amyloid deposition, which comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof labeled with a radionuclide.
  • “Amyloid deposition” is formed by aggregation of amyloid proteins having a ⁇ -sheet structure. Examples of amyloid protein include prion, ⁇ -amyloid, tau and ⁇ -synuclein.
  • the imaging agent of the present invention is suitable for imaging amyloid deposits formed by prion, ⁇ -amyloid and ⁇ -synuclein. .
  • the imaging agent of the present invention is particularly suitable for imaging abnormal prion protein aggregates (PrP Sc ) (amyloid deposits formed by prions).
  • the imaging agent for amyloid deposition of the present invention can be prepared and used in the same manner as the composition for diagnosing amyloid-related diseases.
  • the present invention also provides a. Introducing a detectable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof labeled with a radionuclide into a mammal; b. Leaving the compound for a time sufficient to bind to the amyloid deposit; and c. Detecting a compound bound to one or more amyloid deposits; To a method for imaging amyloid deposits.
  • the present invention also provides A mammal introduced with a detectable amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof labeled with a radionuclide is subjected to computed tomography (SPECT) or positron emission tomography (
  • SPECT computed tomography
  • positron emission tomography The present invention relates to a method for imaging amyloid deposits, comprising the step of imaging by PET.
  • “Mammals” include, but are not limited to, humans, mice, rats, rabbits, dogs, monkeys. Preferably, the “mammal” is a human.
  • the labeling with the radionuclide and the detection of the labeled compound may be performed as described above. That is, SPECT and PET can be used for detection, and the radionuclide may be selected according to the detection method. Moreover, introduction into mammals may be performed as described for the composition for diagnosing amyloid-related diseases.
  • Detectable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof labeled with a radionuclide and “a sufficient time for the compound to bind to amyloid deposits”
  • a person skilled in the art can determine appropriately depending on the mammal to be used, the compound used and the detection method. For example, the amount and time of these can be determined by introducing various concentrations of the labeled compound into the mammal of interest, and detecting this labeled compound with the selected detection method at various times after introduction. .
  • the composition for diagnosing amyloid-related diseases of the present invention can also be used for screening for therapeutic or prophylactic agents for amyloid-related diseases.
  • a test substance such as Creutzfeldt-Jakob disease or Alzheimer's disease
  • the model animal is administered with the amyloid-related disease diagnostic composition of the present invention, and then The distribution or amount of the compound represented by formula (I) contained in the brain is examined, and as a result, a significant difference from the control (model animal not administered with the test substance) (for example, reduction of the distribution site) If a decrease in the amount is detected, the test substance can be a candidate for a therapeutic drug for amyloid-related diseases.
  • the composition for amyloid-related disease diagnosis of the present invention is administered to the model animal, and then the brain of the model animal
  • the distribution or amount of the compound represented by the formula (I) contained in is investigated, and as a result, there is a significant difference from the control (for example, the distribution site is reduced or enlarged, the amount is decreased or increased, etc.) ) Is detected, the test substance can be a candidate for a prophylactic agent for amyloid-related diseases.
  • the composition for diagnosing amyloid-related diseases of the present invention can also be used for evaluation of therapeutic and preventive drugs for amyloid-related diseases whose effects have already been confirmed. That is, after the therapeutic or prophylactic agent for the disease is administered to a model animal for amyloid-related disease, the composition for diagnosing amyloid-related disease of the present invention is administered to the model animal, and then contained in the brain of the model animal. Thus, the distribution or amount of the compound represented by the formula (I) is examined, and thereby the therapeutic agent and the prophylactic agent are evaluated (specifically, effective dose, effective administration method, etc.).
  • Radioiodine-125 is produced by MP Biomedicals, Inc. Iodine-125 (Na 125 I, 100 mCi / ml, pH10 NaOH solution) and Muromachi Yakuhin Iodine-125 (Na 125 I, 3.7 GBq / mL, 0.01 M NaOH solution) ) was used.
  • 1 H-NMR measurement was performed using Varian Gemini 300 or JOEL JNM-AL 400 and tetramethylsilane as an internal standard substance. Mass spectrometry used JOEL JMS-T100TD. For measurement of radioactivity, a Wizard Autowell gamma counter manufactured by PerkinElmer Japan was used. For separation of bound and unbound molecules in binding experiments, Brandel M-24R cell harvester and Whatman GF / B filter (pore size 1 ⁇ m) were used. Leica cryostat CM1900 was used for the preparation of BSE-infected mouse brain sections, and Nikon ECLIPSE 80i was used for the fluorescence microscope.
  • the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 10 Using Synthesis Compound 41 of 6-bromo-2- (6-nitrobenzo [d] oxazol-2-yl) -4H-chromen-4-one , the same as in Production Example 7, Production Example 9 and Example 2 By the method, the title compound is obtained.
  • Radioactive iodine-labeled precursor tributyltin (1 mg / mL) in methanol solution (50 ⁇ L), Na 125 I (0.1-0.2 mCi, specific activity 2200 Ci / mmol), 1.0 M HCl (50 ⁇ L), 3 W / v% hydrogen peroxide solution (50 ⁇ L) was sequentially added, and the mixture was allowed to stand at room temperature for 10 minutes, or stirred for 10 seconds and then left for 15-20 minutes to react.
  • FIG. 7 shows the binding rate of SC, VPC and BFC derivatives to rMoPrP aggregates (250 nM).
  • [ 125 I] 2 which showed the highest binding rate to rMoPrP aggregates among the flavonoid analogues, showed high binding properties of about 10%.
  • [ 125 I] 10 introduced with an ethanolamino group at the 4′-position of the SC skeleton showed a binding rate equivalent to [ 125 I] 2, indicating that it has a high binding property to rMoPrP aggregates.
  • [ 125I ] 30, [ 125I ] 33 in which a methoxy group, an amino group, a monomethylamino group, and a dimethylamino group were introduced at the 4 ′ position of the BFC skeleton obtained by structural conversion of the styryl group of the SC skeleton into a 5-membered ring,
  • the binding rates of [ 125 I] 36 and [ 125 I] 39 were 14.2%, 7.2%, 10.6%, and 18.0%, respectively.
  • [ 125 I] 30 and [ 125 I] 39 were found to have a binding rate to rMoPrPG aggregates equal to or higher than that of the SC derivative.
  • mice Mouse-adapted BSE (mBSE) -infected mice were prepared by inoculating the brain of 20% of 1% brain emulsion of mBSE-infected brain into the right temporal region of 4-week-old ddY male mice. did. Further, 20 ⁇ L of PBS solution as non-infected mice was inoculated in the brain on the right temporal region of 4-week-old ddY male mice. Each group was bred for 20-25 weeks and then used to prepare mouse brain slices.
  • mBSE Mouse-adapted BSE
  • [ 125 I] 30, [ 125 I] 33, and [ 125 I] 39 in which a methoxy group, an amino group, and a dimethylamino group were introduced into the BFC skeleton, exhibited a brain migration property that exceeded the previously reported SC derivatives.
  • the ratio of radioactivity in the brain 2 minutes after administration of [ 125 I] 30, [ 125 I] 33 or 180 minutes after administration of [ 125 I] 39 was calculated as 6.1, 6.7, and 8.9%, respectively. As a result, these compounds were shown to have very high disappearance from the brain.
  • [ 125 I] 30, [ 125 I] 33 and [ 125 I] 39 were compared, it was shown that the lower the lipid solubility, the better the brain migration and disappearance.
  • the ratio of brain accumulation has been reported to be 3.8 (reference 5) and 4.8 (reference 6), respectively. Therefore, it is considered that the compound [ 125 I] 33 of the present invention has a brain behavior useful as a prion imaging agent.
  • radioactive iodine-125 sodium iodide (Na 125 I, 3.7 GBq / mL, 0.01 N NaOH solution) manufactured by PerkinElmer Japan was used. M-24 cell harvester (Brandel, Gaithersburg, MD) and GF / B filter (Whatman, Kent, UK) were used for separation of bound and unbound molecules to amyloid aggregates in adsorption and binding saturation experiments. . 1 H NMR was measured using JEOL JNM-AL 400 using tetramethylsilane (TMS) as an internal standard substance and deuterated chloroform (CDCl 3 ) or deuterated methanol (CD 3 OD) as a solvent.
  • TMS tetramethylsilane
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • DART Direct Analysis in Real Time mass spectrometry was measured using JMS-T100TD manufactured by JEOL Ltd.
  • a Wizard autowell gamma counter manufactured by PerkinElmer Japan was used.
  • Cytation 3 manufactured by Bio Tek was used for measurement of fluorescence intensity.
  • ⁇ 1-42 manufactured by Peptide Institute was used.
  • ⁇ -Syn used was transferred from Nagasaki University School of Medicine.
  • a centrifuge manufactured by Kubota Corporation was used for the centrifugation in the binding saturation experiment for ⁇ -Syn aggregates.
  • the fluorescence image of the compound accumulated in the brain section was observed using a fluorescence microscope (BZ-8100) manufactured by Keyence or a fluorescence microscope (ECLIPSE 80i) manufactured by Nikon.
  • a ⁇ 1-42 aggregates A ⁇ 1-42 is dissolved in 10 mM phosphate buffer (1 mM EDTA, pH 7.4), adjusted to a concentration of 0.25 mg / mL (55.4 ⁇ M), and adjusted to 60 ° C. And shaken for about 30 minutes. Thereafter, A ⁇ 1-42 aggregates were prepared by incubating at 37 ° C. for 42 hours, and stored at ⁇ 80 ° C. until used for experiments.
  • ⁇ -Syn is dissolved in 30 mM Tris-HCl buffer (200 mM NaCl, pH 6.0, 7.0, 8.0) and adjusted to 1.67 mg / mL (115 ⁇ M) at 37 ° C. The mixture was stirred for 72 hours and stored at -80 ° C until used in the experiment. The ⁇ -Syn aggregate is diluted to 1.2 ⁇ M with PBS, then 20 ⁇ M of ThT is added, and the fluorescence intensity at excitation wavelength 440 nm and fluorescence wavelength 485 nm is measured to form a ⁇ -sheet structure. It was confirmed.
  • the fluorescence intensity of ThT when PBS was used instead of the ⁇ -Syn aggregate was measured.
  • dilute the ⁇ -Syn aggregate to a concentration of 0.5 ⁇ M, then centrifuge at 20,000 g for 15 minutes at 20 ° C.
  • Pre-centrifuge ⁇ -Syn precipitated ⁇ -Syn and 20 ⁇ M
  • the fluorescence intensity at an excitation wavelength of 440 nm and a fluorescence wavelength of 485 nm was measured.
  • the fluorescence intensity of ThT when PBS was used instead of the ⁇ -Syn aggregate was measured.
  • Binding saturation experiment for ⁇ -Syn aggregates [ 125I ] BFC derivative and corresponding non-radioactive compound mixed solution (2000 nM) were sequentially diluted with 20% EtOH to prepare final concentration of 24.7-2000 nM did.
  • 400 ⁇ L of the mixed solution of various concentrations and 400 ⁇ L of ⁇ -Syn aggregate (200 nM) were mixed in a polypropylene tube and shaken at 50 rpm at room temperature for 2 hours. After shaking, 200 ⁇ L was collected before centrifugation. The remaining 600 ⁇ L was centrifuged at 20 ° C. and 20,000 g for 15 minutes.
  • Binding saturation experiment on A ⁇ 1-42 aggregate [ 125 I] BFC derivative and the corresponding non-radioactive compound mixed solution (2000 nM) were sequentially diluted with 20% EtOH to a final concentration of 24.7-2000 nM. .
  • a mixture of 100 ⁇ L of various concentrations and 100 ⁇ L of A ⁇ 1-42 aggregate (200 nM) were mixed in a borosilicate glass tube ( ⁇ 12 ⁇ 75 mm) and shaken at 50 rpm for 2 hours at room temperature.
  • Nonspecific binding was calculated by adding 100 ⁇ L of a phosphate buffer not containing A ⁇ 1-42 aggregates. After shaking, the reaction solution was permeated through a GF / B filter using an M-24R cell harvester.
  • Tg2576 mouse brain sections Frozen brain sections of Tg2576 mice (24 months old) overexpressing amyloid precursor protein (APP) were dissolved in 50% EtOH in each compound (100 ⁇ M). Soaked for 1 hour. After washing with 50% EtOH for 2 minutes ⁇ 2 times, observation was performed using a fluorescence microscope. Further, the adjacent sections were soaked in ThT (100 ⁇ M) dissolved in 50% EtOH for 10 minutes, and washed with 50% EtOH for 1 minute ⁇ 2 times to confirm A ⁇ aggregates in the brain sections.
  • ThT 100 ⁇ M
  • the fluorescence intensity when mixed with the prepared ⁇ -Syn aggregates is pH 6.0, 7.0, 8.0 of the buffer used.
  • the increase by 186, 134, and 47-fold showed that the produced ⁇ -Syn aggregate had an amyloid structure.
  • the binding affinity evaluation with a compound it is necessary to separate a compound that is bound to an aggregate and a compound that is not bound by filtration using a filter or centrifugation. For this reason, it is necessary to produce an aggregate that cannot pass through a filter or precipitates by centrifugation. Therefore, the content ratio of the fraction precipitated by centrifugation of the aggregates prepared by the above three methods was examined, and the aggregates more suitable for the binding experiment were selected. First, the ⁇ -Syn aggregate was centrifuged at 20 ° C. and 20,000 ⁇ g for 15 minutes.
  • BFC derivatives have lower binding properties to amyloid other than PrP Sc compared to existing compounds. Furthermore, since these compounds are excellent in brain migration for deployment as an in vivo imaging probe, the possibility of clinical application as a PrP Sc selective imaging probe was shown.
  • the compound of the present invention exhibits high binding specificity for amyloid protein, high blood brain barrier permeability, and rapid disappearance from normal tissues, and is useful for diagnosis of amyloid-related diseases.
  • the compounds of the present invention can be useful as imaging probes that are selective for abnormal prion protein aggregates (PrP Sc ).

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Abstract

L'objectif de la présente invention est de fournir un composé ayant une spécificité de liaison élevée pour des protéines amyloïdes et une perméabilité élevée pour la barrière hémato-encéphalique, et présentant une élimination rapide des tissus normaux. La présente invention concerne : un composé marqué par un radionucléide représenté par la formule (I) (les symboles dans la formule sont tels que définis dans la description) ou un sel pharmaceutiquement acceptable de celui-ci ; et une composition pour le diagnostic d'une maladie liée à l'amyloïde le comprenant.
PCT/JP2019/008168 2018-03-02 2019-03-01 Dérivé de chromone et composition pour le diagnostic d'une maladie liée à l'amyloïde WO2019168170A1 (fr)

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CN115361961A (zh) * 2020-01-28 2022-11-18 斯坦福大学托管董事会 通过上调人组织蛋白酶抑制素ll-37以抑制胰岛淀粉样蛋白多肽（iapp）自组装来预防或治疗胰腺功能障碍或糖尿病的方法
JP7589356B2 (ja) 2020-12-16 2024-11-25 イーライ リリー アンド カンパニー プレターゲットイメージング剤

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115361961A (zh) * 2020-01-28 2022-11-18 斯坦福大学托管董事会 通过上调人组织蛋白酶抑制素ll-37以抑制胰岛淀粉样蛋白多肽（iapp）自组装来预防或治疗胰腺功能障碍或糖尿病的方法
JP7589356B2 (ja) 2020-12-16 2024-11-25 イーライ リリー アンド カンパニー プレターゲットイメージング剤

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