Alpha synuclein aggregate binding agents and methods of imaging

Abstract

Provided is an alpha-synuclein aggregate binding agent having high binding selectivity to alpha-synuclein aggregates. An alpha-synuclein aggregate binding agent containing a compound represented by formula (I) (in formula (I), R1 and R2 are each independently selected from the group consisting of hydrogen, an alkyl group, an alkenyl group, an acyl group, and a hydroxyalkyl group, R3 is hydrogen or a halogen, ring A is a benzene ring or a pyridine ring, ring B is represented by formula (i) or formula (ii), and R1 and R2 are each independently selected from the group consisting of hydrogen, an alkyl group, an alkenyl group, an acyl group, and a hydroxyalkyl group. R4 and R5 are each independently selected from hydrogen, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a halogenated hydroxyalkoxy group, and an aminoalkyl group. > # imgabs0 #

Description

This application is a divisional application of the invention patent application with application number 2020800170701, application date January 24, 2020, and invention name “α-synuclein aggregate binding agent and imaging method”. Technical Field

[0001] The present invention relates to an α-synuclein aggregate binding agent, a composition for optical imaging of α-synuclein aggregates, a composition for radiological imaging of α-synuclein aggregates, a diagnostic drug for a disease associated with α-synuclein aggregates, or a companion diagnostic drug for the treatment or prevention of the disease, a diagnostic kit for a disease associated with a substance accumulated in the brain, an optical imaging method, a radiological imaging method, a method for screening a therapeutic or preventive drug for a disease associated with α-synuclein aggregates in the brain, a method for quantifying or determining the accumulation of α-synuclein aggregates in the brain, a method for classifying substances accumulated in the brain and determining their accumulation, an α-synuclein aggregation inhibitor, and a novel compound. Background Art

[0002] Alpha synuclein aggregates constitute the core pathology of Parkinson's disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and have a close causal relationship with neurodegeneration. The diagnosis of these diseases is based on the presence of alpha synuclein aggregates in brain anatomical pathological analysis, so it is impossible to confirm the diagnosis before death. However, if alpha synuclein aggregates in the brain of a living organism can be visualized, it is possible to obtain information (confirmation) related to the diagnosis of these diseases that is close to confirmation at an early stage. In addition, if alpha synuclein aggregates in the brain of a disease model animal can be visualized, it may be helpful to evaluate the efficacy of candidate substances for therapeutic or preventive drugs that target alpha synuclein aggregates through imaging over time.

[0003] Examples of known PET (positron emission tomography) probes that bind to α-synuclein in the brain of a living organism include: 11 C) BF-227. But 11 C) BF-227 has insufficient binding affinity to α-synuclein aggregates, and among these diseases, α-synuclein lesions can only be detected in some MSA patients. 11 C) BF-227 has the problem of non-specific brain accumulation and low selectivity for binding to α-synuclein aggregates due to binding to amyloid β aggregates.

[0004] The present inventors have developed a new compound that can image (image) Tau protein accumulated in the brain (see Patent Document 1). The compound described in Patent Document 1 can image Tau protein accumulated in the brain, and therefore, the technology of Patent Document 1 can be applied to the treatment and prevention of diseases caused by the accumulation of Tau protein, such as Alzheimer's disease (AD). However, Patent Document 1 does not describe binding to α-synuclein aggregates. (Prior art literature) (Patent Document)

[0005] Patent Document 1: International Publication No. 2014 / 097474 Pamphlet Summary of the invention (Problem to be solved by the invention)

[0006] The present inventors have found that among the compounds described in Patent Document 1, (2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol (PBB3) can bind to α-synuclein aggregates with a certain affinity.

[0007] However, the binding selectivity of PBB3 to α-synuclein aggregates is lower than that of PBB3 to Tau aggregates, and therefore PBB3 is not very suitable as an α-synuclein aggregate probe. Therefore, an α-synuclein aggregate binder with high binding selectivity to α-synuclein aggregates is desired.

[0008] In addition, if it is not only possible to detect and diagnose α-synuclein aggregates, but also to inhibit (inhibit) the aggregation of α-synuclein, diseases caused by α-synuclein aggregates can be prevented or treated. Therefore, α-synuclein aggregation inhibitors that can inhibit α-synuclein aggregation are desired.

[0009] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an α-synuclein aggregate binding agent having high binding selectivity to α-synuclein aggregates, an imaging method using the α-synuclein aggregate binding agent, a novel compound that can be used as an α-synuclein aggregate binding agent, and an α-synuclein aggregation inhibitor. (Technical means to solve the problem)

[0010] The present inventors have found that among the compounds described in Patent Document 1, the compound represented by the following formula (I) having a butenyl structure and a benzothiazole structure or a benzofuran structure has high binding selectivity to α-synuclein aggregates, and have completed the present invention after further repeated studies. More specifically, the present invention provides the following scheme.

[0011] [1] An alpha-synuclein aggregate binding agent comprising: A compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, (In formula (I), R1 and R2 are each independently selected from hydrogen, alkyl, alkenyl, acyl, and hydroxyalkyl, R3 is hydrogen or halogen, Ring A is a benzene ring or a pyridine ring, Ring B is the following formula (i) or formula (ii), R4 and R5 are each independently selected from hydrogen, hydroxy, alkoxy, haloalkoxy, halohydroxyalkoxy, and aminoalkyl.).

[0012] [2] The binder according to [1], wherein ring A is a pyridine ring.

[0013] [3] The binder according to [1] or [2], wherein ring B is of formula (i).

[0014] [4] The binder according to [1], wherein the compound represented by formula (I) is selected from the following group:

[0015] [5] The binder according to any one of [1] to [4], wherein One or more atoms of the compound represented by the formula (I) are radioactive isotopes of the atom.

[0016] [6] A composition for optical imaging of alpha-synuclein aggregates, comprising: The binder according to any one of [1] to [4].

[0017] [7] A composition for radiographic imaging of α-synuclein aggregates, comprising: The binder described in [5].

[0018] [8] A diagnostic drug comprising the binding agent described in any one of [1] to [5], The diagnostic drug is a diagnostic drug for a disease associated with alpha-synuclein aggregates, or a companion diagnostic drug for the treatment or prevention of the disease.

[0019] [9] A diagnostic kit for a disease associated with a substance accumulated in the brain, comprising: The binder described in any one of [1] to [5]; and a binder selected from 2-((1E, 3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazole-6-ol, 2-((1E, 3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazole-6-ol, 1-fluoro-3-( At least one of 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol and 1-(18)F-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol.

[0020]

[10] A method for optical imaging of α-synuclein aggregates in the brain, comprising the following steps: The brain of a subject organism to which the binding agent according to any one of [1] to [4] is administered is irradiated with light of a first wavelength from outside the brain, and then light of a second wavelength different from the first wavelength emitted from the brain is detected.

[0021]

[11] A method for radiological imaging of α-synuclein aggregates in the brain, comprising the following steps: Detecting radiation emitted from the brain of a test organism to which the binding agent described in [5] has been administered.

[0022]

[12] A method for screening a therapeutic or preventive drug for a disease associated with α-synuclein aggregates in the brain, comprising the following steps: The candidate substance is screened based on the difference in the amount and / or distribution of light or radiation detected in the subject organism before and after administration of the candidate substance using the imaging method described in

[10] or

[11] .

[0023]

[13] A method for quantifying or determining the accumulation of alpha-synuclein aggregates in the brain, The method comprises the following steps: detecting radiation emitted from the brain of a test organism to which the binding agent described in [5] is administered, and Based on the amount and / or distribution of the detected radiation, the accumulation of α-synuclein aggregates in the brain is quantified or determined.

[0024]

[14] A method for classifying and determining the accumulation of substances accumulated in the brain, comprising: The first step is to detect radiation emitted from the brain of a test organism to which the binding agent described in [5] has been administered; The second step is to detect radiation emitted from the brain of the test organism to which at least one selected from 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol and 1-(18)F-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol is administered at a different time from that of the first step, and Based on the amount and / or distribution data of the radiation detected in the first step and the amount and / or distribution data of the radiation detected in the second step, the classification and accumulation of the substance accumulated in the brain are determined.

[0025]

[15] An alpha synuclein aggregation inhibitor comprising: A compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, (In formula (I), R1 and R2 are each independently selected from hydrogen, alkyl, alkenyl, acyl, and hydroxyalkyl, R3 is hydrogen or halogen, Ring A is a benzene ring or a pyridine ring, Ring B is the following formula (i) or formula (ii), R4 and R5 are each independently selected from hydrogen, hydroxy, alkoxy, haloalkoxy, halohydroxyalkoxy, and aminoalkyl.).

[0026]

[16] An α-synuclein aggregation inhibitor as described in

[15] , wherein ring A is a pyridine ring.

[0027]

[17] The α-synuclein aggregation inhibitor according to

[15] or

[16] , wherein ring B is of formula (i).

[0028]

[18] The α-synuclein aggregation inhibitor according to

[15] , wherein The compound represented by formula (I) is selected from the following groups:

[0029]

[19] A compound represented by the following formula, a pharmaceutically acceptable salt thereof, or a solvate thereof,

[0030]

[20] A compound represented by the following formula, a pharmaceutically acceptable salt thereof, or a solvate thereof, (In the formula, at least one of the atoms marked with * is a radioactive isotope of the atom.)

[0031]

[21] An intermediate represented by the following formula, which is used to synthesize the compound represented by

[19] ,

[0032]

[22] An intermediate represented by the following formula, which is used to synthesize the compound represented by

[20] , (Effects of the Invention)

[0033] According to the present invention, an α-synuclein aggregate-binding agent having high binding selectivity to α-synuclein aggregates can be provided. Furthermore, it is possible to provide an imaging method using the α-synuclein aggregate binding agent. In addition, it is possible to provide a novel compound that can be used as an α-synuclein aggregate binding agent and other uses. In addition, it can inhibit the aggregation of alpha-synuclein. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1A The results of fluorescence microscopy measurements of the brains of DLB ​​patients and AD patients are shown. Figure 1B The results of fluorescence microscopy measurements of the brains of DLB ​​patients and AD patients are shown. Figure 2 The quantitative results of the fluorescence brightness of the lesion area and the lesion-free area are shown. Figure 3 Shown are the results of fluorescence microscopy measurements of mice after α-synuclein fibril inoculation. Figure 4 Shown are the results of two-photon laser scanning fluorescence microscopy examination of model mice 6 weeks after injection of α-synuclein fibril solution. Figure 5 PET imaging results are shown. Figure 6 PET imaging results are shown. Figure 7 Shown are the results of fluorescence microscopy of mice after α-synuclein fibril inoculation. Figure 8 PET imaging results are shown. Fig. 9 PET imaging results are shown. Fig.10 PET imaging results are shown. Fig.11 PET imaging results are shown. Fig.12 PET imaging results are shown. Fig.13 The results showed an α-synuclein aggregation inhibitory effect. Fig.14 The results showed an α-synuclein aggregation inhibitory effect. DETAILED DESCRIPTION

[0035] <Definition> The term "alkyl" refers to a monovalent group formed by losing one hydrogen atom from an aliphatic saturated hydrocarbon. The alkyl group has, for example, 1 to 15 carbon atoms, typically 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 2 to 6 carbon atoms. The alkyl group may be straight chain, branched, or cyclic. The alkyl group is not limited, and examples thereof include methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. The alkyl group may be substituted with a suitable substituent.

[0036] In the present specification, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 8, 2 to 6, 2 to 4, 3 to 8, 3 to 6, 4 to 8, 4 to 6, etc. carbon atoms are respectively referred to as C 1-15 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-8 , C 2-6 , C 2-4 , C 3-8 , C 3-6 , C 4-8 , and C 4-6 wait.

[0037] The term "cycloalkyl" refers to a monovalent group formed by losing one hydrogen atom from an aliphatic saturated hydrocarbon formed as a carbocyclic ring. The cycloalkyl group has, for example, 3 to 10 carbon atoms, typically 3 to 8, 3 to 6, 3 to 5, 3 to 4, 4 to 5, 4 to 6, or 4 to 8 carbon atoms. The cycloalkyl group is not limited, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. The cycloalkyl group may also be substituted by a suitable substituent.

[0038] The term "alkenyl" refers to an aliphatic unsaturated hydrocarbon group having at least one double bond. Alkenyl groups have, for example, 2 to 15 carbon atoms, and typically have 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 8, 4 to 6, 4 to 7, or 4 to 8 carbon atoms. Alkenyl groups may be straight chain or branched. The alkenyl group is not limited, and specific examples thereof include vinyl (i.e., -CH=CH2), allyl (i.e., -CH2CH=CH2), -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, 1,3-butadienyl (i.e., -CH=CH-CH=CH2), and hept-1,6-dien-4-yl (i.e., -CH2-(CH2CH=CH2)2), etc. The alkenyl group may be further substituted by a suitable substituent.

[0039] The term "alkynyl" refers to an aliphatic unsaturated hydrocarbon group having at least one triple bond. The alkynyl group has, for example, 2 to 15 carbon atoms, typically 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 4 to 6, 4 to 7, or 4 to 8 carbon atoms. The alkynyl group may be straight chain or branched. The alkynyl group is not limited, and examples thereof include ethynyl (i.e., -C≡CH), -C≡CH(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3). The alkynyl group may also be substituted by a suitable substituent.

[0040] The term "acyl" refers to a group represented by -CO-R. Here, R is, for example, an alkyl, alkenyl, or alkynyl group. The acyl group is not limited, and examples thereof include acetyl (i.e., -COCH3), ethylcarbonyl, propylcarbonyl, pentylcarbonyl, cyclohexylcarbonyl, octylcarbonyl, 2-ethylhexylcarbonyl, dodecylcarbonyl, phenylcarbonyl, benzylcarbonyl, naphthylcarbonyl, and pyridylcarbonyl. The acyl group may also be substituted by a suitable substituent.

[0041] The term "hydroxy" or "hydroxyl" refers to -OH.

[0042] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group (i.e., -OH). The hydroxyalkyl group is not limited, and examples thereof include hydroxymethyl (i.e., -CH2OH), 2-hydroxyethyl (i.e., -CH2CH2OH), 1-hydroxyethyl (i.e., -CH(OH)CH3), 3-hydroxypropyl (i.e., -CH2CH2CH2OH), 2-hydroxypropyl (i.e., -CH2CH(OH)CH3), and 1-hydroxypropyl (i.e., -CH(OH)CH2CH3). The hydroxyalkyl group may also be substituted with a suitable substituent.

[0043] The term "halogen" or "halo" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0044] The term "alkoxy" refers to an alkyl group bonded to another group via an oxygen atom (i.e., -O-alkyl). The alkoxy group is not limited, and examples thereof include methoxy (i.e., -O-methyl), ethoxy (i.e., -O-ethyl), propoxy (i.e., -O-propyl), -O-isopropyl, -O-2-methyl-1-propyl, -O-2-methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl-1-propyl, -O-2-methyl-1-pentyl, 3- -O-methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O-3-methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-1-butyl, -O-2-ethyl-1-butyl, -O-butyl, -O-isobutyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, and -O-hexyl. Alkoxy may also be substituted by a suitable substituent.

[0045] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. As haloalkyl, there are fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl. If the example of haloalkyl is cited, it is not limited to fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoroethyl, chloroethyl, bromoethyl, iodoethyl, fluoropropyl, chloropropyl, bromopropyl, iodopropyl, fluorobutyl, chlorobutyl, bromobutyl, iodobutyl, fluoropentyl, chloropentyl, bromopentyl, iodopentyl, fluorohexyl, chlorohexyl, bromohexyl, iodohexyl, fluoroheptyl, chloroheptyl, bromoheptyl, iodoheptyl, fluorooctyl, chlorooctyl, bromooctyl and iodooctyl etc. Haloalkyl can also be substituted by a suitable substituent.

[0046] The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen (ie, -O-haloalkyl). Examples of the haloalkoxy group include a fluoroalkoxy group, a chloroalkoxy group, a bromoalkoxy group, and an iodoalkoxy group.

[0047] The term "halogenated hydroxyalkoxy" refers to a halogenated alkoxy group substituted with a hydroxyl group. Examples of the halogenated hydroxyalkoxy group include a fluorohydroxyalkoxy group, a chlorohydroxyalkoxy group, a bromohydroxyalkoxy group, and an iodohydroxyalkoxy group. Examples of halogenated hydroxyalkoxy groups include -O-CH(F)(OH), -O-CH2CH(F)(OH), -O-CH(OH)-CH2(F), -O-CH2-CH(F)(OH), -O-CH(OH)-CH2-CH2(F), -O-CH2-CH(OH)-CH2(F), -O-CH(CH2-F)(CH2OH), and -O-CH2-CH2-CH(F)(OH).

[0048] The term "nitro" refers to -NO2.

[0049] The term "amino" refers to -NH2.

[0050] The term "aminoalkyl" refers to an alkyl group substituted with an amino group. The aminoalkyl group is not limited, and examples thereof include aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminopentyl, aminohexyl, and aminooctyl.

[0051] The term "substituent" refers to one or more atoms or groups of atoms introduced into a chemical structural formula. Examples of substituents include C 1-8 Alkyl (methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, or n-hexyl or isomers thereof), C 2-8 alkenyl (vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), and -C(CH2CH3)=CH2, etc.), C 2-8 Alkynyl (ethynyl, -C≡CH(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3)), alkoxy, hydroxy, halogen, haloalkyl, cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), amino, nitro, acyl (acetyl (i.e., -COCH3)), carboxyl (i.e., -COOH), ester (i.e., -COOR x , where R x It is C 1-6 alkyl, etc.), amide (i.e. -CONR y R z , where R y and Rz independently H or C 1-6 alkyl, etc.), mercapto (i.e. -SH), sulfonic acid (i.e. -SO3H), nitrile (i.e. -CN), aromatic ring (aryl, phenyl, benzyl, or naphthyl, etc.), heterocyclic group (pyrrolidinyl, tetrahydrofuranyl, pyrrolyl, furanyl, thienyl, piperidinyl, oxanyl, or pyridyl, etc.), etc.

[0052] The term "pharmaceutically acceptable salt" refers to a salt that is harmless to mammals, especially humans. Pharmaceutically acceptable salts can be formed using non-toxic acids or bases including inorganic acids or inorganic bases or organic acids or organic bases. Examples of pharmaceutically acceptable salts include: metal salts formed with aluminum, calcium, lithium, magnesium, potassium, sodium and zinc; or organic salts formed with lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (i.e., N-methylglucamine) and procaine. In addition, pharmaceutically acceptable salts include acid addition salts and base addition salts.

[0053] The term "pharmaceutically acceptable carrier" refers to physiological saline solution; liquid or solid fillers, diluents, solvents, or packaging materials and other pharmaceutically acceptable materials, compositions, or excipients. Examples of pharmaceutically acceptable carriers include water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose, and lactated Ringer's injection.

[0054] The term "effective amount" refers to the amount of a compound or composition that can achieve the desired effect. For example, in some embodiments, the effective amount refers to the amount of a compound or composition that can successfully perform optical imaging and radiological imaging of brain accumulation substances such as α-synuclein aggregates.

[0055] The term "solvate" refers to a solvent-containing compound formed by the association of one or more solvent molecules with a compound. Solvates include, for example, monosolvates, disolvates, trisolvates, and tetrasolvates. In addition, solvates include hydrates.

[0056] The term "hydrate" refers to a compound or a salt thereof that further contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. Hydrates include, for example, monohydrates, dihydrates, trihydrates, and tetrahydrates.

[0057] The term "treat" refers to reducing or ameliorating the worsening, severity and / or duration of a disease or condition.

[0058] The terms "prevent" and "preventing" refer to reducing the risk of developing or worsening a given disease or condition, or to reducing or inhibiting the recurrence, onset, or worsening of a given disease or symptom of one or more conditions.

[0059] <α-synuclein aggregate binding agent> The α-synuclein aggregate binding agent of the present invention (hereinafter also referred to as a binding agent) comprises a compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound represented by the following formula (I) has a butene structure and a benzothiazole structure or a benzofuran structure instead of a butadiene structure, based on the compound described in Patent Document 1; it is known that the compound represented by the following formula (I) has a higher binding selectivity to α-synuclein aggregates than the binding selectivity to Tau protein and amyloid β aggregates. Similarly, the compound represented by the following formula (I) has a higher binding selectivity to α-synuclein aggregates than the binding selectivity to Tau protein and amyloid β aggregates, and the solvate of the compound represented by the following formula (I) has a higher binding selectivity to α-synuclein aggregates. In addition, the compound represented by the following formula (I) emits fluorescence. In addition, one or two or more atoms in the compound represented by the following formula (I) may be a radioactive isotope of the atom. Therefore, the binding agent of the present invention can be used as a molecular probe for optical imaging and radiological imaging of α-synuclein aggregates accumulated in the brain. Furthermore, as described above, the compound represented by the following formula (I), its pharmaceutically acceptable salt, and its solvate have high binding selectivity to α-synuclein aggregates and can inhibit the aggregation of α-synuclein as described in detail below. α-synuclein is also present in some neuronal synapses in the normal brain, and α-synuclein aggregates are formed by aggregation of α-synuclein.

[0060] (In formula (I), R1 and R2 are each independently selected from hydrogen, alkyl, alkenyl, acyl, and hydroxyalkyl, R3 is hydrogen or halogen, Ring A is a benzene ring or a pyridine ring, Ring B is the following formula (i) or formula (ii), R4 and R5 are each independently selected from hydrogen, hydroxy, alkoxy, haloalkoxy, halohydroxyalkoxy, and aminoalkyl.)

[0061] In one embodiment, ring B is of formula (i). In another embodiment, ring B is of formula (ii).

[0062] If ring B is of formula (i), R4 and R5 may be present at a substitutable position on the benzothiazole ring of formula (i). Preferably, R4 and R5 are present at the 6-position and 5-position of the benzothiazole ring of formula (i), respectively. If ring B is of formula (ii), R4 and R5 may be present at a substitutable position on the benzofuran ring of formula (ii). Preferably, R4 and R5 are present at the 5-position and 6-position of the benzofuran ring of formula (ii), respectively.

[0063] In one embodiment, ring A is a pyridine ring. In another embodiment, ring A is a benzene ring. Preferably, in the direction of the structural formula represented by formula (I), ring A is a pyridine ring as shown in the following structural formula.

[0064] In one embodiment, R1 and R2 are both hydrogen. In one embodiment, R1 and R2 are each independently hydrogen or alkyl, especially C 1-8 In other embodiments, R1 is hydrogen, R2 is alkyl, especially C 1-6 In other embodiments, R1 and R2 are both alkyl groups, preferably C 1-6 The alkyl groups are more preferably methyl groups.

[0065] In one embodiment, R1 and R2 are each independently hydrogen or alkenyl, especially C 2-8 Alkenyl, preferably allyl (ie, -CH2CH=CH2) or hept-1,6-dien-4-yl (ie, -CH2-(CH2CH=CH2)2). In other embodiments, R1 is hydrogen, R2 is alkenyl, especially C 2-8 The alkenyl group is preferably an allyl group (ie, -CH2CH=CH2) or a hept-1,6-dien-4-yl group (ie, -CH2-(CH2CH=CH2)2). In another embodiment, R1 and R2 are both alkenyl groups, preferably both C 2-8 Alkenyl, more preferably allyl (ie, -CH2CH2CH=CH2) or hepta-1,6-dien-4-yl (ie, -CH2-(CH2CH=CH2)2).

[0066] In one embodiment, R1 and R2 are each independently hydrogen or acyl, especially C 1-8 In other embodiments, R1 is hydrogen, R2 is acyl, and particularly C 1-8Acyl, preferably acetyl (ie, -COCH3). In other embodiments, R1 and R2 are both acyl, preferably C 1-8 The acyl group is more preferably acetyl (ie, -COCH3).

[0067] In one embodiment, R1 and R2 are each independently hydrogen or hydroxyalkyl, especially hydroxyC 1-8 Alkyl, preferably hydroxypropyl, more preferably 3-hydroxypropyl (ie, -CH2CH2CH2OH). In other embodiments, R1 is hydrogen, R2 is hydroxyalkyl, especially hydroxyC 1-8 In another embodiment, R1 and R2 are both hydroxyalkyl, preferably hydroxypropyl, more preferably 3-hydroxypropyl (ie, -CH2CH2CH2OH). 1-8 The alkyl groups are more preferably all hydroxypropyl groups, and even more preferably all 3-hydroxypropyl groups (ie, -CH2CH2CH2OH).

[0068] In one embodiment, R3 is hydrogen. In other embodiments, R3 is halogen, i.e., F, Cl, Br or I. Preferably, R3 is F. Preferably, R3 is 18 F. It is preferred that R3 exists at the following positions in the direction of the structural formula represented by formula (I).

[0069] Preferably, in the direction of the structural formula represented by formula (I), the relationship between ring A and R3 is as shown below.

[0070] In one embodiment, R4 and R5 are both hydrogen. In one embodiment, R4 and R5 are each independently hydrogen or hydroxyl. In other embodiments, R4 is hydroxyl and R5 is hydrogen. In other embodiments, R4 is hydrogen and R5 is hydroxyl. In other embodiments, R4 and R5 are both hydroxyl.

[0071] In one embodiment, R4 and R5 are each independently hydrogen or alkoxy, especially methoxy. In other embodiments, R4 is alkoxy, especially methoxy, and R5 is hydrogen. In other embodiments, R4 is hydrogen and R5 is alkoxy, especially methoxy. In other embodiments, R4 and R5 are both alkoxy, preferably both methoxy.

[0072] In one embodiment, R4 and R5 are each independently hydrogen or a haloalkoxy group, in particular a fluoroalkoxy group, a chloroalkoxy group, a bromoalkoxy group, or an iodoalkoxy group. In other embodiments, R4 is a haloalkoxy group, in particular a fluoroalkoxy group, a chloroalkoxy group, a bromoalkoxy group, or an iodoalkoxy group, and R5 is hydrogen. In other embodiments, R4 is hydrogen, and R5 is a haloalkoxy group, in particular a fluoroalkoxy group, a chloroalkoxy group, a bromoalkoxy group, or an iodoalkoxy group. In other embodiments, R4 and R5 are both haloalkoxy groups, in particular both fluoroalkoxy groups, a chloroalkoxy group, a bromoalkoxy group, or an iodoalkoxy group. In one embodiment, the fluoroalkoxy group contains a radioactive isotope.

[0073] In one embodiment, R4 and R5 are each independently hydrogen or halogenated hydroxyalkoxy, especially fluorohydroxyalkoxy, preferably fluorohydroxy C 1-3 Alkoxy, more preferably -O-CH2-CH(OH)-CH2(F) or -O-CH(CH2-F)(CH2OH). In other embodiments, R4 is a halogenated hydroxyalkoxy, especially a fluorohydroxyalkoxy, preferably a fluorohydroxy C 1-3 Alkoxy, more preferably -O-CH2-CH(OH)-CH2(F), or -O-CH(CH2-F)(CH2OH), R5 is hydrogen. In other embodiments, R4 is hydrogen, R5 is halogenated hydroxyalkoxy, especially fluorohydroxyalkoxy, preferably fluorohydroxy C 1-3 Alkoxy, more preferably -O-CH2-CH(OH)-CH2(F), or -O-CH(CH2-F)(CH2OH). In addition, in other embodiments, R4 and R5 are both halogenated hydroxyalkoxy, more preferably both fluorohydroxyalkoxy, more preferably both fluorohydroxyC 1-3 Alkoxy, and more preferably -O-CH2-CH(OH)-CH2(F), or -O-CH(CH2-F)(CH2OH). In one embodiment, the fluorohydroxyalkoxy contains a radioactive isotope. Preferably, the fluorohydroxyalkoxy is -O-CH2-CH(OH)-CH2( 18 F), or -O-CH(CH2- 18 F)(CH2OH).

[0074] In one embodiment, R4 and R5 are each independently hydrogen or aminoalkyl, especially aminomethyl or aminoethyl. In other embodiments, R4 is aminoalkyl, especially aminomethyl or aminoethyl, and R5 is hydrogen. In other embodiments, R4 is hydrogen, and R5 is aminoalkyl, especially aminomethyl or aminoethyl. In other embodiments, R4 and R5 are both aminoalkyl, preferably both aminomethyl or aminoethyl.

[0075] In one embodiment, the compound represented by formula (I) is a compound represented by the following formula (II). (In the formula, R1, R2, R3, R4, and R5 are respectively the same as R1, R2, R3, R4, and R5 in formula (I).)

[0076] In one embodiment, the compound represented by formula (I) is a compound represented by the following formula (III). (In the formula, R1, R2, R3, R4, and R5 are respectively the same as R1, R2, R3, R4, and R5 in formula (I).)

[0077] In one embodiment, the compound represented by formula (I) is a compound represented by the following formula (IV). (In the formula, R1, R2, R3, R4, and R5 are respectively the same as R1, R2, R3, R4, and R5 in formula (I).)

[0078] In one embodiment, the compound represented by formula (I) is a compound represented by the following formula (V). (In the formula, R1, R2, R3, R4, and R5 are respectively the same as R1, R2, R3, R4, and R5 in formula (I).)

[0079] In one embodiment, in the compounds of formula (I) to (V), one or more atoms are radioactive isotopes of the atom. The radioactive isotopes are selected from 15 O. 13 N. 11 C. and 18 F, etc., are not particularly limited. Preferably, the radioactive isotope is 11 C or 19 F. Among these, considering 11 The half-life of C is about 20 minutes. 18 The half-life of F is about 110 minutes, so 18 The compounds labeled with F have higher commercial value. Therefore, most preferably, the radioisotope is 18 F.

[0080] Preferably, at least one of R1 to R5 is a group containing a radioactive isotope. Further preferably, R1 and / or R2 is a group containing a radioactive isotope, for example, 11 The base of C (including 11 CH3 11 More preferably, R3 is a group containing a radioactive isotope, for example - 18More preferably, R4 and / or R5 is a group containing a radioactive isotope, for example, 11 C base (including -O 11 CH3 11 C〕alkoxy, etc.), or containing 18 F group (-O-CH2-CH(OH)-CH2( 18 F), and containing -O-CH(CH2- 18 F)(CH2OH)〔 18 F〕fluorohydroxyalkoxy etc.) wherein 11 C) Alkyl refers to a group in which one or more carbon atoms among the carbon atoms constituting the alkyl group are 11 C. 11 C) Alkoxy refers to a group in which one or more carbon atoms among the carbon atoms constituting the alkoxy group are 11 C. 18 F) Fluorohydroxyalkoxy means 18 A group formed by bonding F to a hydroxyalkoxy group.

[0081] Specific examples of the compound represented by formula (I) include the following compounds.

[0082] In one embodiment, in the above specific compound, one or more atoms are radioactive isotopes of the atom. Preferably, in the aminobenzyl or aminopyridyl group bonded to the benzene ring or pyridine ring, the carbon atom bonded to the nitrogen atom of the amino group is a radioactive isotope. 11 C. Preferably, F in the above specific compound is a radioactive isotope 18 F. Preferably, the carbon atom of the methoxy group bonded to the benzothiazole ring is a radioactive isotope 11 C. Furthermore, preferably, the atom marked with * in the above specific compound structure (if there are two * marks in the structure, it refers to any one or two of them) is a radioactive isotope of the atom, for example 11 C or 18 F. In this manual, 11 C〕C05-04 etc. means that the atom marked with * in the structural formula numbered C05-04 etc. is 11 C.

[0083] The method for synthesizing the compound represented by formula (I) is not particularly limited, and the compound can be produced by referring to the synthesis method described in Patent Document 1, for example.

[0084] In addition, among the compounds represented by the above formula (I), the compound represented by the following formula, its pharmaceutically acceptable salt, or its solvate is a novel compound. The compound represented by the following formula can be used as the above α-synuclein aggregate binder, and can also be used for purposes other than the above α-synuclein aggregate binder. (In the formula, at least one of the atoms marked with * is a radioactive isotope of the atom.)

[0085] For example, the novel compound can be synthesized through the following intermediates according to the synthesis method of the examples described below.

[0086] The α-synuclein aggregate binding agent may be contained in a pharmaceutically acceptable carrier. Examples of the pharmaceutically acceptable carrier include water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose, and lactated Ringer's injection.

[0087] The amount of the compound represented by formula (I), its pharmaceutically acceptable salt, or its solvate, and the pharmaceutically acceptable carrier contained in the α-synuclein aggregate binder is not particularly limited, and can be determined based on the following factors, etc.: the type of compound used; the age, weight, health status, sex, and dietary content of the mammal to be administered; the number of administrations and the route of administration; the treatment period; and other drugs used simultaneously. The amount of the pharmaceutically acceptable carrier can be 1 to 99% by weight of the α-synuclein aggregate binder. The α-synuclein aggregate binder can be prepared, for example, in such a manner that the compound represented by formula (I) can be administered in an amount of 5 ng / kg to 5 mg / kg per unit body weight (kg) of the subject, wherein the lower limit is preferably 5 ng / kg, 0.01 mg / kg, 0.05 mg / kg and 0.1 mg / kg, and the upper limit is preferably 5 mg / kg, 3 mg / kg, 1 mg / kg and 20 μg / kg.

[0088] <Composition for optical imaging of α-synuclein aggregates> The composition for optical imaging of α-synuclein aggregates of the present invention (hereinafter also referred to as the composition for optical imaging) comprises the above-mentioned binding agent of the present invention. The optical imaging includes in vitro imaging, in vitro imaging, and in vivo imaging.

[0089] Examples of optical imaging include fluorescence microscopy, multiphoton imaging, two-photon imaging, and near-infrared fluorescence imaging.

[0090] The composition for optical imaging may contain a pharmaceutically acceptable carrier. Examples of the pharmaceutically acceptable carrier include water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose, and lactated Ringer's injection.

[0091] The amount of the compound represented by formula (I), its pharmaceutically acceptable salt, or solvate thereof, and pharmaceutically acceptable carrier contained in the composition for optical imaging is not particularly limited, and their amounts can be determined according to the following factors, etc.: the type of compound used; the age, weight, health status, gender and dietary content of the mammal to be administered; the number of administrations and the route of administration; the treatment period; other drugs used simultaneously. The amount of the pharmaceutically acceptable carrier can be 1 to 99% by weight of the composition for optical imaging. The composition for optical imaging can be prepared, for example, so that the compound represented by formula (I) can be administered in a dosage (mg) of 0.01 mg / kg to 5 mg / kg, preferably 0.05 mg / kg to 3 mg / kg, and more preferably 0.1 mg / kg to 1 mg / kg of the compound represented by formula (I) per unit body weight (kg) of the administered subject.

[0092] <Composition for radiographic imaging of α-synuclein aggregates> The composition for radiographic imaging of α-synuclein aggregates of the present invention (hereinafter also referred to as a composition for radiographic imaging) comprises the above-mentioned binding agent of the present invention. The radiographic imaging includes in vitro imaging, in vitro imaging, and in vivo imaging.

[0093] Examples of radiological imaging include positron emission tomography (PET), single photon emission computed tomography (SPECT), and autoradiography.

[0094] The composition for radiographic imaging may contain a pharmaceutically acceptable carrier. Examples of the pharmaceutically acceptable carrier include water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose, and lactated Ringer's injection.

[0095] The amount of the compound represented by formula (I), its pharmaceutically acceptable salt, or its solvate, and the pharmaceutically acceptable carrier contained in the composition for radiography is not particularly limited, and their amounts can be determined according to the following factors, etc.: the type of compound used; the age, weight, health status, gender and food content of the mammal to be administered; the number of administrations and the route of administration; the treatment period; other drugs used at the same time. The amount of the pharmaceutically acceptable carrier can be 1 to 99% by weight of the composition for radiography. The composition for radiography can be prepared, for example, so that the compound represented by formula (I) can be administered in a dosage of 5 ng / kg to 5 mg / kg, preferably 5 ng to 20 μg / kg, per unit body weight (kg) of the subject to be administered.

[0096] <Diagnostic drug for a disease associated with α-synuclein aggregates, or companion diagnostic drug for the treatment or prevention of such a disease> The diagnostic drug for a disease associated with α-synuclein aggregates of the present invention, or the companion diagnostic drug for the treatment or prevention of the disease (hereinafter, also referred to as the companion diagnostic drug) comprises the above-mentioned binding agent of the present invention. The companion diagnostic drug for treatment refers to a diagnostic drug used to determine whether treatment is expected when the disease is identified. In addition, the companion diagnostic drug for prevention refers to a diagnostic drug used to predict future onset or to determine whether preventive onset inhibition is expected when the precursor symptoms of the disease are identified. By comparing the data related to the amount and / or distribution of α-synuclein aggregates in the brain obtained from the subject using the above-mentioned diagnostic drug with the previously known correlation between the above-mentioned disease and the amount and / or distribution of α-synuclein aggregates, the subject can be diagnosed with the above-mentioned disease (specifically, whether the subject suffers from the above-mentioned disease, its severity, the possibility of onset, etc.). In addition, by comparing the data related to the amount and / or distribution of α-synuclein aggregates in the brain obtained from the subject using the above-mentioned companion diagnostic drug with the previously known correlation between the above-mentioned disease and the amount and / or distribution of α-synuclein aggregates in the brain, the above-mentioned disease state of the subject can be grasped, and therefore a prevention / treatment plan for the above-mentioned disease (types and combinations of preventive / therapeutic drugs, dosages, usage, etc.) can be formulated based on this. One embodiment of the present invention is a medicine for treating or preventing a disease associated with α-synuclein aggregates, and also relates to a medicine administered according to an administration plan based on data related to the amount and / or distribution of α-synuclein aggregates in the brain obtained in the above-mentioned companion diagnosis.

[0097] <Diagnostic kit for diseases related to substances that accumulate in the brain> The diagnostic kit for a disease associated with a substance accumulated in the brain of the present invention (hereinafter, also referred to as a diagnostic kit) comprises: the above-mentioned binding agent of the present invention; and a compound selected from 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol, 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol, at least one of 1-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol and 1-(18)F-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol.

[0098] Examples of substances accumulated in the brain include α-synuclein aggregates, Tau protein aggregates, and amyloid β aggregates.

[0099] Diseases associated with substances accumulated in the brain include: diseases associated with α-synuclein aggregates, namely Parkinson's disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); and diseases associated with Tau protein and amyloid β aggregates, namely Alzheimer's disease (AD) and frontotemporal lobar degeneration.

[0100] The present invention has found that: compared with the binding selectivity to Tau protein and amyloid β aggregates, the binding agent of the present invention has a higher binding selectivity to α-synuclein aggregates; on the other hand, compared with the binding selectivity to α-synuclein aggregates, 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)butan-1,3-dienyl)benzo[d]thiazol-6-ol, 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)butan-1,3-dienyl)benzo[d]thiazol-6-ol, 1-Fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)butan-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol and 1-(18)F-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)butan-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol have higher binding selectivity for Tau protein aggregates.

[0101] The diagnostic kit of the present invention includes both the above-mentioned former with higher binding selectivity for α-synuclein aggregates and the above-mentioned latter with higher binding selectivity for Tau protein aggregates. Therefore, by comparing the detection results of the former (the amount and / or distribution of the detected light and radiation) with the detection results of the latter, it is possible to distinguish which substance is present in each area imaged, specifically, α-synuclein aggregates and Tau protein aggregates can be distinguished, and their presence amounts can be quantified respectively. Therefore, diseases related to α-synuclein aggregates and / or diseases related to Tau protein aggregates can be diagnosed with high accuracy. For example, the ratio of the binding properties to α-synuclein aggregates and to Tau protein aggregates can be determined in advance for each of the binding agent of the present invention, 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol, 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol, etc., and the light quantity ratio and radiation quantity ratio in each region of the brain of a subject organism after administration of the former and after administration of the latter can be measured. In this way, whether α-synuclein aggregates or Tau protein aggregates are present in the region can be distinguished based on the relationship between the predetermined ratio and the measured quantity ratio, and each quantity can be quantified.

[0102] In addition, the diagnostic kit of the present invention can be a diagnostic kit combined with an imaging agent of amyloid beta. The diagnostic kit formed by combining the diagnostic kit of the present invention with an imaging agent of amyloid beta can be used to distinguish which substance is present in each area imaged, specifically, it can be used to distinguish alpha synuclein aggregates, Tau protein aggregates, amyloid beta aggregates, and their presence can be quantified respectively. Therefore, diseases associated with alpha synuclein aggregates, diseases associated with Tau protein aggregates, and / or diseases associated with amyloid beta can be diagnosed with high accuracy.

[0103] One embodiment of the present invention is a medicine for treating or preventing a disease related to substances accumulated in the brain, and also relates to a medicine administered according to an administration plan based on data related to the amount and / or distribution of substances accumulated in the brain obtained using the above-mentioned diagnostic kit.

[0104] <Optical imaging method> The optical imaging method of the present invention comprises the following steps: irradiating the brain of a subject organism to which the binding agent of the present invention is administered with light of a first wavelength from outside the brain, and then detecting light of a second wavelength different from the first wavelength emitted from the brain. After an effective amount of the binding agent is administered to a subject organism, the binding agent that reaches the subject organism's brain will bind to α-synuclein aggregates present in the subject organism's brain. By irradiating the subject organism's brain to which the binding agent has been administered with light of a first wavelength for exciting the binding agent from outside the brain, and detecting light of a second wavelength (e.g., fluorescence) emitted from the binding agent in the brain, optical imaging (imaging) of α-synuclein aggregates can be performed.

[0105] Examples of the test organism include mammals, such as humans, rats, mice, rabbits, guinea pigs, hamsters, monkeys, dogs, minks, and miniature pigs.

[0106] The method of administration is not particularly limited, and there are, for example, parenteral administration such as oral administration, intravenous administration, or intraperitoneal administration. Intravenous administration or intraperitoneal administration is preferred. Intravenous administration is most preferred. The dosage is preferably 0.01 mg / kg to 5 mg / kg, 0.05 mg / kg to 3 mg / kg, or 0.1 mg / kg to 1 mg / kg, and most preferably 0.1 mg / kg to 1 mg / kg.

[0107] <Radiological imaging method> The radiographic method of the present invention comprises the following steps: Detecting radiation emitted from the brain of a test organism to which the above-mentioned binding agent is administered, wherein the above-mentioned binding agent comprises a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and one or more atoms of the compound represented by formula (I) are radioactive isotopes of the atom. When an effective amount of the binding agent is administered to a subject organism, the binding agent that reaches the subject's brain binds to α-synuclein aggregates present in the subject's brain. By detecting radiation emitted from the binding agent in the brain, radiographic imaging (imaging) of α-synuclein aggregates can be performed.

[0108] As the test organism, mammals can be mentioned. Mammals include, for example, humans, rats, mice, rabbits, guinea pigs, hamsters, monkeys, dogs, minks, or miniature pigs, etc. Preferably, the mammal is a human.

[0109] The method of administration is not particularly limited, and there are non-oral administrations such as oral administration, intravenous administration, or intraperitoneal administration. Intravenous administration or intraperitoneal administration is preferred. Intravenous administration is most preferred. The dosage is preferably 5 ng / kg to 5 mg / kg, and more preferably 5 ng to 20 μg / kg. The radiation energy administered is preferably 37 MBq to 7.4 GBq per individual, and more preferably 370 GBq to 3,700 GBq.

[0110] <Method for screening therapeutic or preventive drugs for diseases associated with α-synuclein aggregates in the brain> The method for screening a therapeutic or preventive drug for a disease associated with α-synuclein aggregates in the brain of the present invention (hereinafter also referred to as a screening method) comprises the following steps: Candidate substances are screened based on the difference in the amount and / or distribution of light or radiation detected in the subject organism before and after administration of the candidate substance using the imaging method of the above-mentioned <optical imaging method> or the above-mentioned <radiation imaging method>.

[0111] Diseases associated with α-synuclein aggregates in the brain are the same as those described in the above-mentioned <Diagnostic kits for diseases associated with substances accumulated in the brain>. In addition, the test organism and the administration method are the same as those described in the above-mentioned <Optical Imaging Method> and <Radiological Imaging Method>.

[0112] For example, if the amount (intensity) of light or radiation such as fluorescence from the binding agent decreases after administration of the candidate substance compared to before administration of the candidate substance, the candidate substance may be useful as a compound for treating the disease or condition. In addition, the amount and / or distribution of light or radiation from the test subject is compared with other normal mammals. If the results after administration of the candidate compound are closer to those of normal mammals than before administration, the candidate compound may be useful as a therapeutic compound for the disease or symptom.

[0113] <Method for quantifying or determining accumulation of α-synuclein aggregates in the brain> The method of the present invention for quantifying or determining the accumulation of α-synuclein aggregates in the brain comprises the following steps: irradiating the brain of a subject organism to which the above-mentioned binding agent is administered with light of a first wavelength from outside the brain, wherein the above-mentioned binding agent comprises a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and then detecting light of a second wavelength different from the first wavelength emitted from the brain, and Based on the amount and / or distribution of the detected light, the accumulation of α-synuclein aggregates in the brain is quantified or determined. This method quantifies or determines the accumulation of α-synuclein aggregates in the brain by optical imaging.

[0114] The test organism and the administration method are the same as those described in the above-mentioned <Optical Imaging Method> section.

[0115] By determining the difference between the amount and / or distribution of light detected in the test organism and that in other normal mammals, the accumulation of α-synuclein aggregates in the brain can be quantified, and it can be determined whether α-synuclein aggregates are accumulated in the brain.

[0116] In other embodiments, the method of the present invention for quantifying or determining the accumulation of α-synuclein aggregates in the brain comprises the following steps: Detecting radiation emitted from the brain of a test organism to which the above-mentioned binding agent is administered, wherein the above-mentioned binding agent comprises a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein one or more atoms of the compound represented by formula (I) are radioactive isotopes of the atom, and Based on the amount and / or distribution of the detected radiation, the accumulation of α-synuclein aggregates in the brain is quantified or determined. This method quantifies or determines the accumulation of α-synuclein aggregates in the brain by radiographic imaging.

[0117] The test organisms and administration methods are the same as those described in the above-mentioned "Radiological Imaging Methods".

[0118] By determining the difference between the amount and / or distribution of light or radiation detected in the test organism and that of other normal mammals, the accumulation of α-synuclein aggregates in the brain can be quantified, and it can be determined whether α-synuclein aggregates are accumulated in the brain.

[0119] <Classification of substances accumulated in the brain and method of determining accumulation> The method of the present invention for classifying substances accumulated in the brain and determining their accumulation comprises: The first step comprises irradiating a brain of a subject organism to which the binding agent is administered with light of a first wavelength from outside the brain, and then detecting light of a second wavelength different from the first wavelength emitted from the brain, wherein the binding agent comprises a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof; and The second step comprises irradiating the brain of the subject organism to which at least one selected from 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol and 1-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol has been administered at a different time from that in the first step with light of a third wavelength from outside the brain, and then detecting light of a fourth wavelength different from the third wavelength emitted from the brain, and The classification and accumulation of substances accumulated in the brain are determined based on the amount and / or distribution data of light detected in step 1 and the amount and / or distribution data of light detected in step 2. This method determines the classification and accumulation of substances accumulated in the brain by optical imaging.

[0120] The test organism and the administration method are the same as those described in the above-mentioned <Optical Imaging Method> section.

[0121] Since the method includes a first step of detecting light emitted from the brain of a test organism to which a binding agent with high binding selectivity to α-synuclein aggregates is administered, and a second step of detecting light emitted from the brain of a test organism to which the above-mentioned substance with high binding selectivity to Tau protein aggregates is administered, by comparing the detection result of the first step (the amount and / or distribution of the detected light) with the detection result of the second step, it is possible to distinguish whether the substance accumulated in the brain is α-synuclein aggregates and / or Tau protein aggregates and determine their accumulation.

[0122] In another embodiment, the method of the present invention for classifying and determining the accumulation of substances accumulated in the brain comprises: The first step is to detect radiation emitted from the brain of a test organism to which the above-mentioned binding agent is administered, wherein the above-mentioned binding agent comprises a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and one or more atoms of the compound represented by formula (I) are radioactive isotopes of the atom; and The second step is to detect radiation emitted from the brain of the subject organism to which at least one selected from 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol and 1-(18)F-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol is administered at a different time from that of the first step, and The classification and accumulation of substances accumulated in the brain are determined based on the amount and / or distribution data of radiation detected in step 1 and the amount and / or distribution data of radiation detected in step 2. This method determines the classification and accumulation of substances accumulated in the brain by radiographic imaging.

[0123] The test organism and the administration method are the same as those described in the above <Radiological imaging method>.

[0124] Since the method includes a first step of detecting radiation emitted from the brain of a test organism to which a binding agent with high binding selectivity to α-synuclein aggregates is administered, and a second step of detecting radiation emitted from the brain of a test organism to which the above-mentioned substance with high binding selectivity to Tau protein aggregates is administered, by comparing the detection result of the first step (the amount and / or distribution of the detected radiation) with the detection result of the second step, it is possible to distinguish whether the substance accumulated in the brain is α-synuclein aggregates and / or Tau protein aggregates and determine their accumulation.

[0125] <α-synuclein aggregation inhibitor> The α-synuclein aggregation inhibitor of the present invention (hereinafter also referred to as an aggregation inhibitor) contains the compound represented by the above formula (I), its pharmaceutically acceptable salt, or its solvate. The compound represented by formula (I), its pharmaceutically acceptable salt, and its solvate contained in the α-synuclein aggregation inhibitor of the present invention are the same as the compound represented by formula (I), its pharmaceutically acceptable salt, and its solvate in the above-mentioned <α-synuclein aggregate binding agent> column.

[0126] As shown in the examples described below, the α-synuclein aggregation inhibitor of the present invention can inhibit the formation of α-synuclein aggregates. Therefore, when the α-synuclein aggregation inhibitor of the present invention is administered to a mammal, the aggregation inhibitor that reaches the brain of the organism can hinder the aggregation of α-synuclein present in the brain of the organism, thereby preventing or treating diseases caused by α-synuclein aggregates in mammals, such as Parkinson's disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).

[0127] As described above, the compound represented by the above formula (I), its pharmaceutically acceptable salt, and its solvate have high binding selectivity to α-synuclein aggregates. The compound represented by formula (I), its pharmaceutically acceptable salt, and its solvate have high binding selectivity to α-synuclein aggregates, so it can be inferred that the compound represented by formula (I), its pharmaceutically acceptable salt, and its solvate will bind to α-synuclein aggregates when α-synuclein aggregates, thereby being able to inhibit and hinder the aggregation of α-synuclein.

[0128] Examples of mammals to which the aggregation inhibitor is administered include humans, rats, mice, rabbits, guinea pigs, hamsters, monkeys, dogs, minks, and minipigs.

[0129] The method of administration of the aggregation inhibitor is not particularly limited, for example, there are oral administration, and non-oral administration such as intravenous administration or intraperitoneal administration. It can also be directly administered to the local area (brain) where the α-synuclein aggregates exist. Intravenous administration or intraperitoneal administration is preferred. Intravenous administration is most preferred. The dosage is preferably 0.01 mg / kg to 5 mg / kg, 0.05 mg / kg to 3 mg / kg, or 0.1 mg / kg to 1 mg / kg, and most preferably 0.1 mg / kg to 1 mg / kg. Example

[0130] Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited to these examples. The following compounds were used.

[0131] (BF-227 preparation) BF-227 (i.e., 2-(2-[2-dimethylaminothiazol-5-yl]vinyl)-6-(2-[fluoro]ethoxy)benzoxazole) was produced by NARD Research Institute, catalog number NP039-0.

[0132] (Synthesis of PBB3) PBB3 (i.e., (2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol) was synthesized by the method described in Synthesis Example 3 of Patent Document 1.

[0133] (Synthesis of C05-01) C05-01 (i.e., ((E)-2-(4-(2-fluoro-6-(methylamino)pyridin-3-yl)but-1-en-3-ynyl)benzo[d]thiazol-6-ol) was synthesized by the method described in Synthesis Example 23 of Patent Document 1.

[0134] (Synthesis of C05-02) C05-02 (i.e., ((E)-5-(4-(6-(aminomethyl)benzo[d]thiazol-2-yl)but-3-en-1-ynyl)-N-methylpyridin-2-amine) was synthesized by the method described in Synthesis Example 11 of Patent Document 1.

[0135] (Synthesis of C05-03) C05-03 (i.e., ((E)-2-(4-(6-(methylamino)pyridin-3-yl)but-1-en-3-ynyl)benzo[d]thiazol-6-ol) was synthesized by the method described in Synthesis Example 10 of Patent Document 1.

[0136] (Synthesis of C05-05) C05-05 (i.e., ((E)-1-fluoro-3-(2-(4-(6-(methylamino)pyridin-3-yl)but-1-en-3-ynyl)benzo[d]thiazol-6-yloxy)propan-2-ol) was synthesized by the method described in Synthesis Example 21 of Patent Document 1.

[0137] (Synthesis of C05-08) C05-08 (ie, ((E)-2-(4-(4-(dimethylamino)phenyl)but-1-en-3-ynyl)benzo[d]thiazol-6-ol) was synthesized by the method described in Synthesis Example 6 of Patent Document 1.

[0138] (Synthesis of C05-09) C05-09 (ie, ((E)-2-(4-(4-(methylamino)phenyl)but-1-en-3-ynyl)benzo[d]thiazol-6-ol) was synthesized by the method described in Synthesis Example 7 of Patent Document 1.

[0139] (Synthesis of C06-01) C06-01 (i.e., 2-((1E,3E)-4-(2-fluoro-6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzofuran-5-ol) was synthesized by the method described in Synthesis Example 24 of Patent Document 1.

[0140] (Synthesis of C05-04) C05-04(TM2) was synthesized by the following scheme.

[0141] (Step 1) Compound 1 (5.01 g, manufactured by Tokyo Chemical Industry) was reacted with tert-butyl nitrite (t-BuONO) and CuBr2 in acetonitrile (MeCN) to obtain yellow oily Compound 2 (amount 5.94 g, yield 87.5%). The obtained Compound 2 solidified during storage.

[0142] (Step 2) Compound 2 (5.93 g) was reacted with n-butyllithium (n-BuLi) and N,N-dimethylformamide (DMF) in tetrahydrofuran (THF) to obtain compound 5 (amount 3.78 g, yield 80.5%) as a pale yellow solid.

[0143] (Step 3) Compound 5 (3.78 g) was reacted with malonic acid and piperidine in pyridine to obtain Compound 6 (amount 3.71 g, yield 80.6%) as an ochre-colored solid.

[0144] (Step 4) Compound 6 (4.00 g) was reacted with Dess-Martin periodinane (DMP) and tetraethylammonium bromide (TEAB) in dichloromethane (DCM) to obtain compound 7 (amount 1.85 g, yield 40.3%) as a yellow solid.

[0145] (Step 10) Compound 14 (5.00 g, manufactured by Combi-Blocks) was reacted with N-bromosuccinimide (MBS) in acetonitrile (MeCN) to obtain Compound 15 (yield 6.80 g, 79.8%) as a pale pink solid.

[0146] (Step 11) Compound 15 (6.80 g) was reacted with di-tert-butyl dicarbonate (DIBOC) and sodium hexamethyldisilazane (NaHMDS) in tetrahydrofuran (THF) to obtain Compound 16 (amount 2.42 g, yield 23.3%) as a yellow oil.

[0147] (Step 12) Compound 16 (2.75 g) was reacted with methyl iodide (MeI) and sodium hydride (NaH) in N,N-dimethylformamide (DMF) to obtain compound 17 (amount 2.82 g, yield 97.8%) as a colorless oil.

[0148] (Step 13) In a mixture of triethylamine (TEA) and tetrahydrofuran (THF), in the presence of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), copper iodide (CuI), and triphenylphosphine (PPh3), compound 17 (2.81 g) was reacted with trimethylsilylacetylene to obtain a colorless oily compound 18 (yield 2.50 g, yield 84.2%). The obtained compound 18 solidified during storage.

[0149] (Step 14) Compound 18 (2.49 g) was reacted with tetra-n-butylammonium fluoride (TBAF) in tetrahydrofuran (THF) to obtain Compound 19 (amount 1.85 g, yield 95.7%) as a slightly brown oil.

[0150] (Step 17) In a mixture of triethylamine (TEA) and tetrahydrofuran (THF), in the presence of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), copper iodide (CuI) and triphenylphosphine (PPh3), compound 7 (213.0 mg) was reacted with compound 19 (261.8 mg) to obtain compound 21 as a light yellow solid (yield 256.3 mg, yield 74.0%).

[0151] (Step 18) Compound 21 (245.3 mg) was reacted with trifluoroacetic acid (TFA) to obtain yellow solid C05-04 (TM2) (yield 174.2 mg, yield 92.0%). The total yield was 15%.1 H NMR and ESIMS are shown below. 1 H NMR(DMSO-d6,400MHz)δ:2.79(3H,brs),3.84(3H,s),6.40(1H,m),6.93(1H,d, J=16.0Hz),7.12(1H,m),7.21(1H,d,J=16.0Hz),7.58-7.68(3H,m),7.87(1H,m) ESIMS:m / z found 340.09(Calcd for C 18 H 14 FN3OS[M+H] + 340.09)

[0152] (Synthesis of C06-03) C06-03(TM1) was synthesized by the following scheme.

[0153] (Step 5) Compound 8 (24.95 g, manufactured by Tokyo Chemical Industry) was reacted with ethyl bromoacetate and K2CO3 in N,N-dimethylformamide (DMF) to obtain compound 9 as a white solid (amount 26.07 g, yield 72.2%).

[0154] (Step 6) Compound 9 (5.72 g) was reacted with N-methoxy-N-methylamine hydrochloride and lithium bis(trimethylsilyl)amide (LHMDS) in tetrahydrofuran (THF) to obtain compound 10 (amount 5.68 g, yield 93.0%) as a brown oil.

[0155] (Step 7) Compound 10 (5.68 g) was reacted with lithium aluminum hydride (LAH) in diethyl ether (Et2O) to obtain Compound 11 (amount 3.80 g, yield 89.3%) as a yellow solid.

[0156] (Step 8) Compound 11 (3.69 g) was reacted with malonic acid and piperidine in pyridine to obtain Compound 12 (amount 4.41 g, yield 96.5%) as a pale yellow solid.

[0157] (Step 9) Compound 12 (4.40 g) was reacted with Dess-Martin reagent (DMP) and tetraethylammonium bromide (TEAB) in dichloromethane (DCM) to obtain compound 13 (amount 4.49 g, yield 87.9%) as a pale yellow solid.

[0158] (Step 15) In a mixture of triethylamine (TEA) and tetrahydrofuran (THF), in the presence of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), copper iodide (CuI) and triphenylphosphine, compound 13 (596.6 mg) was reacted with compound 19 (765.2 mg) to obtain compound 20 as a light yellow solid (yield 375.5 mg, yield 37.7%).

[0159] (Step 16) Compound 20 (375.5 mg) was reacted with trifluoroacetic acid (TFA) to obtain yellow solid C06-03 (TM1) (yield 149.5 mg, yield 52.2%). The overall yield was 10%. 1 H NMR and ESIMS are shown below. 1 H NMR(DMSO-d6,400MHz)δ:2.78(3H,brs),3.78(3H,s),6.38(1H,m),6.51(1H,d,J=16.0Hz),6 .91(1H,m),6.95(1H,s),6.98(1H,d,J=16.0Hz),7.14(1H,m),7.44-7.49(2H,m),7.59(1H,m) ESIMS:m / z found 323.12(Calcd for C 19 H 15 FN2O2[M+H] + 323.12)

[0160] ( 18 F) Synthesis of C05-01 The synthesis was carried out by the following scheme 18 F〕C05-01. make〔 18F〕F) fluoride ions were dissolved in a 50% acetonitrile solution (0.4 mL) containing K.222 (Kryptofix 222) (7.5 mg) and potassium carbonate (2.77 mg). After the solution was introduced into a reaction vessel, it was heated under a nitrogen stream to dry and solidify the solvent. Then, anhydrous acetonitrile (0.1 mL) was added for azeotropic distillation, and the reaction vessel was fully dried. The following reaction was carried out under light shielding. A DMSO (300 μL) solution containing tert-butyl (E)-(5-(4-(6-(ethoxymethoxy)benzo〔d〕thiazol-2-yl)but-3-ene-1-yn-1-yl)-6-nitropyridine-2-yl)(methyl)carbamate (i.e., precursor C05-01) (1 mg) synthesized by the method of Synthesis Example 38 (pre24) of Patent Document 1 was added to the reaction vessel. The reaction mixture was heated at 110°C for 10 minutes. After the reaction vessel was cooled, 4N hydrochloric acid (0.5 mL) was added and hydrolyzed at 110°C for 10 minutes. After the reaction vessel was cooled, 1N sodium acetate (2 mL) was added and stirred, followed by the addition of HPLC solvent (500 μL). The mixed solution was purified by HPLC (HPLC conditions: CAPCELL PAK C18 UG 80 10 mm × 250 mm, acetonitrile / 50 mM ammonium acetate = 6 / 4, 4 mL / min). 18 The fraction of F〕C05-01 was recovered in a flask containing ethanol (300 μL), 25% ascorbic acid (100 μL) and Tween80 (100 μL), and the solvent was distilled off under reduced pressure. The residue was dissolved in physiological saline (2.5 mL, pH 7.4) to obtain an injection solution of 〔 18 F〕C05-01.

[0161] ( 11 C) Synthesis of C05-04 The synthesis was carried out by the following scheme 11 C〕C05-04. The following synthesis was carried out under light shielding. 11C〕Methane was added to a dimethyl sulfoxide (DMSO) (300 μL) solution containing (E)-6-fluoro-5-(4-(6-methoxybenzo〔d〕thiazol-2-yl)but-3-ene-1-yn-1-yl)pyridine-2-amine (i.e., precursor C05-04-1) (1.5 mg). The reaction mixture was heated at 120°C for 5 minutes. After the reaction container was cooled, a solvent for HPLC (500 μL) was added. The mixture was purified by HPLC (HPLC conditions: Waters Atlantis prepT310mm×150mm, acetonitrile / 50mM ammonium acetate=4 / 6, 5mL / min). The equivalent of〔 11 The C05-04 fraction was recovered in a flask containing ethanol (300 μL), 25% ascorbic acid (100 μL) and Tween 80 (75 μL), and the solvent was distilled off under reduced pressure. The residue was dissolved in physiological saline (3 mL, pH 7.4) to obtain an injection solution. 11 C) C05-04. In addition, the precursor C05-04-1 was synthesized by a method similar to the synthesis of C05-04 (TM2) described above.

[0162] ( 18 F) Synthesis of C05-04 The synthesis was carried out by the following scheme 18 F〕C05-04.

[0163] make〔 18F〕Fluoride ions were dissolved in a 50% acetonitrile solution (0.4 mL) containing K.222 (Kryptofix 222) (7.5 mg) and potassium carbonate (2.77 mg). After the solution was introduced into a reaction vessel, it was heated under a nitrogen stream to dry and solidify the solvent. Then, anhydrous acetonitrile (0.1 mL) was added for azeotropic distillation, and the reaction vessel was fully dried. The following reaction was carried out under light shielding. A DMSO (300 μL) solution containing tert-butyl (E)-(5-(4-(6-methoxybenzo〔d〕thiazol-2-yl)but-3-ene-1-yn-1-yl)-6-nitropyridine-2-yl)(methyl)carbamate (i.e., precursor C05-04-2) (1.5 mg) was added to the reaction vessel. The reaction mixture was heated at 110°C for 10 minutes. After the reaction vessel was cooled, 4N hydrochloric acid (0.3 mL) was added and hydrolyzed at 110°C for 10 minutes. After the reaction vessel was cooled, 2N sodium acetate (0.6 mL) was added and stirred, and then a HPLC solvent (500 μL) was added. The mixed solution was purified by HPLC (HPLC conditions: Waters Atlantis prep T3 10 mm × 150 mm, acetonitrile / 50 mM ammonium acetate = 4 / 6, 5 mL / min). 18 The fraction of F〕C05-04 was recovered in a flask containing ethanol (300 μL), 25% ascorbic acid (100 μL) and Tween80 (75 μL), and the solvent was distilled off under reduced pressure. The residue was dissolved in physiological saline (3 mL, pH 7.4) to obtain an injection solution of 〔 18 F) C05-04. Precursor C05-04-2 was synthesized by a method similar to the synthesis of C05-04(TM2) described above.

[0164] ( 11 C〕Synthesis of C06-03) The synthesis was carried out by the following scheme 11 C〕C06-03.

[0165] The following synthesis was carried out under light shielding. 11C〕Methane was added to a dimethyl sulfoxide (DMSO) (300 μL) solution containing (E)-6-fluoro-5-(4-(5-methoxybenzofuran-2-yl)but-3-ene-1-yn-1-yl)pyridin-2-amine (i.e., precursor C06-03-1) (1.5 mg). The reaction mixture was heated at 120°C for 5 minutes. After the reaction container was cooled, a solvent for HPLC (500 μL) was added. The mixture was purified by HPLC (HPLC conditions: Waters Atlantis prepT310mm×150mm, acetonitrile / 50mM ammonium acetate=4 / 6, 5mL / min). The equivalent of〔 11 The C06-03 fraction was recovered in a flask containing ethanol (300 μL), 25% ascorbic acid (100 μL) and Tween 80 (75 μL), and the solvent was distilled off under reduced pressure. The residue was dissolved in physiological saline (3 mL, pH 7.4) to obtain an injection solution. 11 C) C06-03. In addition, the precursor C06-03-1 was synthesized by a method similar to the synthesis of C06-03 (TM1) described above.

[0166] ( 18 F) Synthesis of C06-03 The synthesis was carried out by the following scheme 18 F〕C06-03.

[0167] make〔 18F〕Fluoride ions were dissolved in a 50% acetonitrile solution (0.4 mL) containing K.222 (Kryptofix 222) (7.5 mg) and potassium carbonate (2.77 mg). After the solution was introduced into a reaction vessel, it was heated under a nitrogen stream to dry and solidify the solvent. Then, anhydrous acetonitrile (0.1 mL) was added and azeotropic distillation was performed, and then the reaction vessel was fully dried. The following reaction was carried out under light shielding. A DMSO (300 μL) solution containing tert-butyl (E)-(5-(4-(5-methoxybenzofuran-2-yl)but-3-ene-1-yn-1-yl)-6-nitropyridine-2-yl)(methyl)carbamate (precursor C06-03-2) (1.5 mg) was added to the reaction vessel. The reaction mixture was heated at 110°C for 10 minutes. After the reaction vessel was cooled, 4N hydrochloric acid (0.3 mL) was added and hydrolyzed at 110°C for 10 minutes. After the reaction vessel was cooled, 2N sodium acetate (0.6 mL) was added and stirred, and then a HPLC solvent (500 μL) was added. The mixed solution was purified by HPLC (HPLC conditions: Waters Atlantis prep T3 10 mm × 150 mm, acetonitrile / 50 mM ammonium acetate = 4 / 6, 5 mL / min). 18 The fraction of F〕C06-03 was recovered in a flask containing ethanol (300 μL), 25% ascorbic acid (100 μL) and Tween 80 (75 μL), and the solvent was distilled off under reduced pressure. The residue was dissolved in physiological saline (3 mL, pH 7.4) to obtain an injection solution of 〔 18 F) C06-03. C06-03-2 was synthesized by a method similar to the synthesis of C06-03 (TM1) described above.

[0168] <Optical imaging of the human brain> (Brain Dissection Tissue) Postmortem human brains were obtained by partial autopsy of patients with Lewy body dementia (DLB) and Alzheimer's disease (AD). Frozen DLB tissues were sectioned to 20 μm thickness in a cryostat (HM560, Carl Zeiss). In addition, AD brain tissue was fixed in 10% neutral buffered formalin, embedded in paraffin blocks, and sectioned at 6 μm thickness.

[0169] (In vitro fluorescence microscopy) Post-fixed fresh frozen sections of amygdala tissue from DLB patients and dewaxed formalin-fixed paraffin-embedded sections of middle frontal gyrus tissue from AD patients were used. 30 μM of each of the above compounds and brain sections were incubated in a 50% ethanol solution at room temperature for 30 minutes. Then, the sections were washed twice, i.e., washed with 50% ethanol solution for 5 minutes and then washed with ultrapure water for 3 minutes. After embedding the sections with an embedding agent (VECTASHIELD H-1000, Vector Laboratories), images of the lesion accumulation areas on the sections were obtained using a fluorescence microscope (DM4000, Leica). The fluorescence image is shown in Figure 1 ( Figure 1A and Figure 1B ) is shown in Figure 2. Using analysis software (Image J), ​​the fluorescence brightness of the lesion area and the non-lesion area (background) was quantified. The results are shown in Figure 2. Figure 2 shown.

[0170] As shown in Figure 1 and Figure 2 As shown, it was confirmed that the compounds C05-01, C05-02, C05-03, C05-04, C05-05, C05-08, C05-09 and C06-02 represented by the above formula (I) bind to the α-synuclein aggregates formed in the brains of DLB ​​patients with a strength greater than PBB3. In addition, it was confirmed that the binding of these compounds represented by the above formula (I) to the α-synuclein aggregates is stronger than the binding to the Tau and amyloid β aggregates formed in the brains of AD patients. In addition, the same in vitro fluorescence microscopy measurement as the above DLB patient brain was performed on the brains of MSA patients, and the same results were obtained.

[0171] In addition, the compounds represented by the above formula (I) are superior to the compound C06-01 having a butadiene structure in that the selectivity for α-synuclein aggregates is higher than the selectivity for aggregates formed in the brain of AD patients. In addition, it was confirmed that BF-227, which has been reported as a PET probe for synuclein pathology, mainly binds to amyloid β aggregates of AD, and that the binding of BF-227 to α-synuclein aggregates is weaker than that of the compound represented by the above formula (I).

[0172] <Optical imaging of mouse brain> (Preparation of mouse model after α-synuclein fibril inoculation) First, E. coli was made to express recombinant mouse α-synuclein protein, which was extracted and cultured in a test tube, thereby forming insoluble α-synuclein aggregates. The α-synuclein aggregates were then inoculated into the striatum of mice. The α-synuclein aggregates spread to surrounding areas via the neural network, and α-synuclein pathology was observed in the cerebral neocortex a few months later. Among them, α-synuclein aggregates were inoculated into the striatum of mice using the following method. First, the hair of the head of a 9-week-old C57BL / 6 male mouse anesthetized with 1.5% (v / v) isoflurane was removed, the scalp was disinfected with a disinfectant (isodine; イソジン), and then xylocaine was applied, the scalp was incised and the skull was exposed. Then, the skull was drilled at a position of 0.05mm from the bregma and 2mm laterally, and 3μl of α-synuclein fiber solution (4mg / ml of mouse α-synuclein fibers dissolved in physiological saline) was injected into the position of 2μm deep using a glass pipette, and then the scalp was reset and sutured.

[0173] (In vitro fluorescence microscopy) The brain of the mouse inoculated with the α-synuclein fibers was removed, sliced, and subjected to fluorescent staining analysis. Specifically, the mouse brain slices inoculated with the α-synuclein fibers and 30 μM of the compound were incubated in a 20% ethanol solution at room temperature for 30 minutes. Then, the slices were washed twice, i.e., washed with a 20% ethanol solution for 5 minutes and then washed with ultrapure water for 3 minutes. After embedding the slices with an embedding agent (VECTASHIELD H-1000), images of the α-synuclein aggregate accumulation areas on the slices were obtained using a fluorescence microscope (DM4000). The same slice was washed with a phosphate buffer and then treated with an autoclave to activate antigenicity. Immunohistochemical staining was performed using an anti-phosphorylated α-synuclein monoclonal antibody (pS129, abcam, ab59264) (1:1000). After embedding the slices with an embedding agent (VECTASHIELD H-1000), images of the same areas as above were obtained using a fluorescence microscope (DM4000). The results are as follows. Figure 3 shown. Figure 3 In the middle, the right side shows the result of anti-phosphorylated α-synuclein antibody staining, and the left side shows the result of C05-05 fluorescent staining. according to Figure 3 The results show that the compound C05-05 represented by the above formula (I) binds to the pathological changes caused by phosphorylated α-synuclein.

[0174] (In vivo two-photon laser scanning fluorescence microscopy) Six weeks after the injection of the α-synuclein fibril solution, the model mice were anesthetized with 1.5% (v / v) isoflurane, and a cranial window was set according to the Seylaz-Tomita method (Tomita et al. J Cereb Blood Flow Metab 25, 858-67, 2005). Two weeks after the cranial window was set, the mice were anesthetized with 1.5% (v / v) isoflurane, and 50 μl of DMSO saline solution (DMSO: saline = 1:1) containing 0.05% C05-05 or PBB3 was administered from the tail vein. 90 minutes after the administration of C05-05 or 30 minutes after the administration of PBB3, the mice were fixed under a two-photon laser fluorescence microscope, and 100 μl of saline solution containing 5 mM sulforhodamine 101 was intraperitoneally administered, and then biological two-photon fluorescence imaging was performed at an excitation wavelength of 900 nm. The detection wavelength for C05-05 and PBB3 was 500-550 nm, and the detection wavelength for sulforhodamine 101 was 573-648 nm. Figure 4 shown. like Figure 4 As shown in the results, after intravenous injection of compound C05-05 represented by formula (I), the compound was observed to reach the brain and even the neurons of the organism and bind to each α-synuclein lesion by biological two-photon laser fluorescence microscopy. Therefore, it can be said that even when the density and total number of lesions are small and difficult to detect by PET, lesions can be detected by biological fluorescence imaging. On the other hand, PBB3 was intravenously injected and observed, but no lesions were detected, confirming that the lesion detection contrast of compound C05-05 represented by formula (I) is higher than that of PBB3.

[0175] <In vivo PET (positron emission tomography) imaging> PET scans were performed using a micro PET Focus 220 animal scanner (Siemens Medical Solutions), which provides 95 slices with a thickness of 0.851 mm (center thickness), an axial field of view (FOV) of 19.0 cm, and an intra-sectional FOV of 7.6 cm. C57BL / 6 mice were anesthetized with 1.5% (v / v) isoflurane before scanning. 18F〕C05-01 (C05-01 compound labeled with positron-emitting radionuclides) (24.3±0.7 MBq), an emission scan was immediately performed in 3D list mode with an energy window of 350-750 keV for 90 minutes. In order to avoid photoracemism of the compound, the injection and scanning of the radioactive compound were performed in a dark room. All list mode data were organized into 3D sinograms, and then transformed into 2D sinograms by Fourier-rebining (frames: 10×1, 6×5, 5×10 minutes). By reconstruction processing based on the maximum a posteriori probability method, the addition images of 30 to 60 minutes after the injection of the radioactive compound and 60 to 90 minutes after the injection of the radioactive compound were obtained. In addition, dynamic images were reconstructed by filter-corrected back projection method using a 0.5-mm Hanning filter. Referring to the MRI (magnetic resonance imaging) template, the volume of interest (VOI) was set for the striatum and midbrain using PMOD image analysis software (PMOD Technologies). Figure 5 and Figure 6 shown.

[0176] The compound C05-01 represented by the above formula (I) was labeled with a positron-emitting radionuclide and then intravenously injected into normal mice. PET scanning was performed and the results were as follows: Figure 5 and Figure 6 As shown, it was confirmed that C05-01 has appropriate brain accessibility and clearance rate from the brain, and C05-01 has good properties as a probe for imaging (imaging) α-synuclein aggregates in the brain of a living body in PET. In addition, Figure 5 Shown is intravenous injection 18 F) Two coronal images and one midsagittal image of the normal mouse brain at 1 to 30 minutes after C05-01, respectively, superimposed on the standard brain MRI image. Figure 6 Corresponds to the striatum and midbrain 18 F〕Time-radioactivity curve of C05-01 after intravenous injection.

[0177] <Optical imaging of mouse brain> (In vitro imaging) Model mice 6 weeks after injection of the same α-synuclein fibril solution as in the above "(Preparation of mouse model after α-synuclein fibril inoculation)" column were anesthetized with 1.5% (v / v) isoflurane and intraperitoneally administered with C05-05 (1.66 mg / kg) or BF-227 (1.66 mg / kg). 90 minutes after C05-05 administration and 120 minutes after BF-227 administration, the brain was removed and frozen, and 20 μm thick frozen sections were made in a freezing microtome (HM560). After embedding the sections with an embedding agent (VECTASHIELD H-1000), images of the α-synuclein aggregate accumulation areas on the sections were obtained using a fluorescence microscope (DM4000). In addition, the same slice was fixed by immersing it in a phosphate buffer containing 4% paraformaldehyde overnight. The fixed brain was washed with running water and then treated with an autoclave to activate antigenization. Immunohistochemical staining was performed using an anti-phosphorylated α-synuclein monoclonal antibody (pS129, abcam, ab59264) (1:1000). After embedding the slice with an embedding agent (VECTASHIELDH-1000), an image of the same area as above was obtained using a fluorescence microscope (DM4000). The results are as follows Figure 7 shown. Figure 7 (a) is the image of C05-05. Figure 7 (b) is an image in which BF-227 was projected. like Figure 7 As shown in the results, after C05-05 was intravenously injected into mice inoculated with α-synuclein fibrils, it was observed by in vitro imaging that the compound traveled into the brain and even into neurons and bound to each α-synuclein lesion. On the other hand, BF-227 was intravenously injected and observed, but no lesions were detected, confirming that the lesion detection contrast of the compound C05-05 represented by formula (I) was higher than that of BF-227.

[0178] <In vivo PET (positron emission tomography) imaging> PET scans were performed using a micro PET Focus 220 animal scanner (Siemens Medical Solutions), which provides 95 slices with a thickness of 0.851 mm (center thickness), an axial field of view (FOV) of 19.0 cm, and an intra-sectional FOV of 7.6 cm. Before scanning, mice inoculated with α-synuclein fibrils and mice injected with saline (control) were anesthetized with 1.5% (v / v) isoflurane. 18F〕C05-05 (C05-05 compound labeled with positron-emitting radionuclides) (30.8±0.4 MBq), a 120-minute radiation scan was immediately performed in 3D list mode with an energy window of 350-750 keV. In order to avoid photoracemization of the compound, the injection and scanning of the radioactive compound were performed in a dark room. All list mode data were organized into 3D sinograms, and then transformed into 2D sinograms by Fourier-rebining (frames: 10×1, 6×5, 5×10 minutes). Through reconstruction processing based on the maximum a posteriori probability method (maximum a posteriorireconstruction), the addition images of 0-30 minutes after the injection of the radioactive compound, 30-60 minutes after the injection of the radioactive compound, 60-90 minutes after the injection of the radioactive compound, and 90-120 minutes after the injection of the radioactive compound were obtained. In addition, a dynamic image was reconstructed by the filter-corrected back projection method using a 0.5-mm Hanning filter. Referring to the MRI template, the volume of interest (VOI) was set for the striatum and cerebellum using PMOD image analysis software (PMOD Technologies). The results are as follows Figures 8 to 12 shown. Figure 8 (a) is 18 F) Results of the model mice injected with α-synuclein fibril solution 60 to 90 minutes after intravenous injection of C05-05. Figure 8 (b) is the result of mice injected with saline. The upper figures show the images after overlapping the coronal images of the brain containing the striatum with the standard brain MRI images, and the lower figures show the images after overlapping the coronal images of the brain containing the cerebellum with the standard brain MRI images. In addition, Fig. 9 is the corresponding striatum 18 F〕Time-radioactivity curve of C05-05 after intravenous injection, Fig.10 corresponds to the cerebellum 18 F〕Time-radioactivity curve of C05-05 after intravenous injection. Fig.11 The striatum is shown relative to 18 F) Time course of standardized uptake value ratio (SUVR) in the cerebellum after intravenous injection of C05-05. Fig.12 The mean values ​​of SUVR during the period of 90 to 120 minutes are compared between mice injected with α-synuclein fibril solution and mice injected with normal saline (n=4, **p<0.005 by Student's t-test, mean±SEMs).

[0179] The compound C05-05 represented by the above formula (I) was labeled with a positron-emitting radionuclide and then intravenously injected into the α-synuclein fibril solution-injected model mice and the saline-injected mice (control), and PET scanning was performed. The results showed appropriate brain accessibility and clearance rate from the brain. In addition, in the α-synuclein fibril solution-injected model mice, it was found that 18 F) C05-05 obviously accumulated in the striatum rich in α-synuclein lesions, confirming that 18 F〕C05-05 can visualize α-synuclein aggregates in PET.

[0180] <Inhibitory effect of the compound represented by formula (I) on α-synuclein aggregation> Escherichia coli was made to express recombinant protein for A53T mutant human α-synuclein, and the protein was extracted and cultured in a test tube to produce α-synuclein aggregate seeds. C05-05 (its DMSO solution) was added to 0.02μg of α-synuclein aggregate seeds to a final concentration of 20μM or 200μM and stirred. A control experiment was performed with samples to which only DMSO was added. These samples were suspended in 50μL of 1mg / ml A53T mutant human α-synuclein monomer solution and then shaken at 37°C for 1 day. 10μL of the suspension was mixed with 90μL of 1% sarcosine, ultracentrifuged at 100Krpm for 20 minutes, the resulting precipitate was electrophoresed, and then the gel was stained with CBB. The image of the gel was acquired using an imager, and the bands were quantified using analysis software (Image J). The results are as follows. Fig.13 and 14 shown. Fig.13 The insoluble α-synuclein aggregates (indicated by arrows) contained in the sarcosine-insoluble fraction under each condition were observed. Fig.14 The bar graph is a bar graph in which the control experiment (DMSO) is set as 100%.

[0181] like Fig.14 As shown, if C05-05 at a final concentration of 20 μM is added to the α-synuclein aggregate seeds, the formation of insoluble α-synuclein aggregates is reduced by about 20% compared with the control experiment, and if C05-05 at a final concentration of 200 μM is added, the formation of insoluble α-synuclein aggregates is reduced by about 60% compared with the control experiment, so C05-05 has an inhibitory effect on α-synuclein aggregation. (ANOVA F(2,3)=51.57, p=0.0048, *p<0.05 and **p<0.005 by Bonferroni's post hoc test, mean±SEMs).

Claims

1. A binder for alpha-synuclein aggregates, comprising: A compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, In formula (I), R1 and R2 are each independently selected from hydrogen, alkyl, alkenyl, acyl, and hydroxyalkyl, R3 is hydrogen or halogen, Ring A is a benzene ring or a pyridine ring, Ring B is the following formula (i) or formula (ii), R4 and R5 are each independently selected from hydrogen, hydroxy, alkoxy, haloalkoxy, halohydroxyalkoxy, and aminoalkyl.

2. The binder according to claim 1, wherein Ring A is a pyridine ring.

3. The binder according to claim 1 or 2, wherein Ring B is of formula (i).

4. The binder according to claim 1, wherein The compound represented by formula (I) is selected from the following groups:

5. The binder according to any one of claims 1 to 4, wherein One or more atoms of the compound represented by the formula (I) are radioactive isotopes of the atom.

6. A composition for optical imaging of alpha-synuclein aggregates, comprising: The binder according to any one of claims 1 to 4.

7. A composition for radiographic imaging of α-synuclein aggregates, comprising: The binding agent according to claim 5.

8. A diagnostic drug comprising the binding agent according to any one of claims 1 to 5, The diagnostic drug is a diagnostic drug for a disease associated with alpha-synuclein aggregates, or a companion diagnostic drug for the treatment or prevention of the disease.

9. A diagnostic kit for a disease associated with substances accumulated in the brain, comprising: The binder according to any one of claims 1 to 5; and At least one selected from 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol, 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol, 1-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol and 1-(18)F-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol.

10. A method for optical imaging of α-synuclein aggregates in the brain, comprising the following steps: The brain of a subject organism to which the binding agent according to any one of claims 1 to 4 has been administered is irradiated with light of a first wavelength from outside the brain, and then light of a second wavelength different from the first wavelength emitted from the brain is detected.

11. A method for radiological imaging of α-synuclein aggregates in the brain, comprising the following steps: Detecting radiation emitted from the brain of a subject organism to which the binding agent according to claim 5 has been administered.

12. A method for screening a therapeutic or preventive drug for a disease associated with α-synuclein aggregates in the brain, comprising the following steps: The candidate substance is screened based on the difference in the amount and / or distribution of light or radiation detected in a test organism before and after administration of the candidate substance using the imaging method according to claim 10 or claim 11.

13. A method for quantifying or determining the accumulation of alpha-synuclein aggregates in the brain, The method comprises the steps of: detecting radiation emitted from the brain of a test organism to which the binding agent according to claim 5 is administered, and Based on the amount and / or distribution of the detected radiation, the accumulation of α-synuclein aggregates in the brain is quantified or determined.

14. A method for classifying and determining the accumulation of substances accumulated in the brain, comprising: The first step is to detect radiation emitted from the brain of a subject organism to which the binding agent according to claim 5 is administered; The second step is to detect radiation emitted from the brain of the test organism to which at least one selected from 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol and 1-(18)F-fluoro-3-(2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-yloxy)propan-2-ol is administered at a different time from that of the first step, and Based on the amount and / or distribution data of the radiation detected in the first step and the amount and / or distribution data of the radiation detected in the second step, the classification and accumulation of the substance accumulated in the brain are determined.

15. An alpha synuclein aggregation inhibitor comprising: A compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, In formula (I), R1 and R2 are each independently selected from hydrogen, alkyl, alkenyl, acyl, and hydroxyalkyl, R3 is hydrogen or halogen, Ring A is a benzene ring or a pyridine ring, Ring B is the following formula (i) or formula (ii), R4 and R5 are each independently selected from hydrogen, hydroxy, alkoxy, haloalkoxy, halohydroxyalkoxy, and aminoalkyl.

16. The α-synuclein aggregation inhibitor according to claim 15, wherein Ring A is a pyridine ring.

17. The α-synuclein aggregation inhibitor according to claim 15 or 16, wherein Ring B is of formula (i).

18. The α-synuclein aggregation inhibitor according to claim 15, wherein The compound represented by formula (I) is selected from the following groups:

19. A compound represented by the following formula, a pharmaceutically acceptable salt thereof, or a solvate thereof:

20. A compound represented by the following formula, a pharmaceutically acceptable salt thereof, or a solvate thereof: In the formula, at least one of the atoms marked with * is a radioactive isotope of the atom.

21. An intermediate represented by the following formula, which is used to synthesize the compound represented by claim 19, 22. An intermediate represented by the following formula, which is used to synthesize the compound represented by claim 20,

Images