JP2007106755A - Probe for amyloid imaging - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a probe for amyloid imaging, which solves the defects of a conventional method, has excellent amyloid β recognition ability and higher functionality. <P>SOLUTION: The compound is represented by formula (I) [n is an integer of 1 or 2; -CH=CH- is E isomer or Z isomer; R<SB>1</SB>is a monocyclic or bicyclic aromatic group which may be substituted with a substituent group; R<SB>2</SB>is a monocyclic or bicyclic nitrogen-containing aromatic group in which a nitrogen atom may be substituted with an N oxide group]. The probe for amyloid imaging contains the compound. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an amyloid imaging probe. More particularly, the present invention relates to a probe that enables highly selective amyloid imaging that cannot be achieved with conventional methods.

  Alzheimer's disease (AD) is characterized by the observation of senile plaques in which amyloid β (Aβ) protein aggregates and accumulates in the brain. Conventionally, methods for diagnosing Alzheimer's disease include 1) evaluation of cognitive function, 2) biochemical diagnostic method for demonstrating increased tau protein and decreased Aβ protein in cerebrospinal fluid using ELISA, etc. 3) MRI Neurological image morphological evaluation by Physiology, Positron emission tomography (PET), Single photoemission computed tomography (SPECT) functional image diagnosis method, etc. are known, and Alzheimer's disease is currently diagnosed using these techniques Has been done.

  Techniques such as 1) to 3) above have significantly advanced diagnosis related to brain disease. However, although neuropathologically, many senile plaques appear in the brain from the stage of mild cognitive impairment, the above technique allows diagnosis at a very early stage and sporadic Alzheimer's in the asymptomatic stage. It is difficult to predict the onset of disease, and even if a therapeutic drug for Alzheimer's disease is developed, more effective treatment cannot be performed. Therefore, a probe for amyloid imaging having a highly selective Aβ recognition ability for Alzheimer's disease is required.

  Non-Patent Document 1 reviews amyloid imaging probes. Existing probes for amyloid imaging are not satisfactory in terms of selectivity.

Japan Geriatrics Society Journal, Vol. 41, No. 2, p. 175-178 (2004)

  The present invention has been made in view of the circumstances as described above, and provides an amyloid imaging probe with higher functionality and excellent amyloid β recognition ability, which can eliminate the drawbacks of conventional methods. With the goal.

  The present invention includes the following inventions.

［式中、ｎは１又は２である整数であり、
−ＣＨ＝ＣＨ−は、Ｅ体であってもＺ体であってもよく、
Ｒ_１は、置換基により置換されていてもよく、環原子として酸素、窒素及び硫黄からなる群から選択される１〜３個のヘテロ原子を有していてもよい、単環式又は二環式の芳香族基であり、
Ｒ_２は、窒素原子がＮオキシド基により置換されていてもよい単環式又は二環式の含窒素芳香族基であって、環原子として酸素、窒素及び硫黄からなる群から選択される１〜３個のヘテロ原子を更に有していてもよく、更なる置換基により置換されていてもよい、前記含窒素芳香族基である］
で表される化合物、又は該化合物の薬学的に許容される塩、若しくは溶媒和物を含有するアミロイドイメージング用プローブ。 (1) Formula (I):

[Wherein n is an integer of 1 or 2,
-CH = CH- may be E-form or Z-form,
R ₁ may be substituted by a substituent, and may have 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur as ring atoms, monocyclic or bicyclic An aromatic group of formula
R ₂ is a monocyclic or bicyclic nitrogen-containing aromatic group in which the nitrogen atom may be substituted with an N oxide group, and is selected from the group consisting of oxygen, nitrogen and sulfur as a ring atom The nitrogen-containing aromatic group which may further have ˜3 heteroatoms and may be substituted by a further substituent]
Or a pharmaceutically acceptable salt or solvate of the compound.

(2) R ₁ may have 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur as ring atoms, substituted with an electron donating group, The probe for amyloid imaging according to (1), which is a bicyclic aromatic group.
(3) The probe for amyloid imaging according to (1) or (2), wherein R ₂ is a 3- or 4-pyridyl group in which a nitrogen atom may be substituted with an N oxide group.
(4) The amyloid imaging according to any one of (1) to (3), wherein the compound represented by formula (I) or a pharmaceutically acceptable salt or solvate of the compound is labeled. Probe.
(5) The probe for amyloid imaging according to (4), wherein the label is derived from a radionuclide.
(6) The probe for amyloid imaging according to (5), wherein the radionuclide is a γ-ray emitting nuclide.
(7) The amyloid imaging according to (6), wherein the γ-ray emitting nuclide is selected from the group consisting of 51Cr, 59Fe, 57Co, 67Ga, 75Se, 81mKr, 99mTc, 111In, 123I, 131I, 133Xe, and 201Tl. Probe.
(8) The probe for amyloid imaging according to (4), wherein the label is derived from a positron emitting nuclide.
(9) The positron emitting nuclide is selected from the group consisting of 11C, 13N, 15O, 18F, 35mCl, 76Br, 45Ti, 48V, 60Cu, 61Cu, 62Cu, 66Ga, 89Zr, 94mTc, and 124I. ) The probe for amyloid imaging of description.
(10) An amyloid imaging composition comprising the amyloid imaging probe according to any one of (1) to (9) and a pharmaceutically acceptable carrier.
(11) Formula (I):

からなる群から選択される化合物を除く）、又は該化合物の薬学的に許容される塩、若しくは溶媒和物。 [Wherein n is an integer of 1 or 2,
-CH = CH- may be E-form or Z-form,
R ₁ may be substituted by a substituent, and may have 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur as ring atoms, monocyclic or bicyclic An aromatic group of formula
R ₂ is a monocyclic or bicyclic nitrogen-containing aromatic group in which the nitrogen atom may be substituted with an N oxide group, and is selected from the group consisting of oxygen, nitrogen and sulfur as a ring atom The nitrogen-containing aromatic group which may further have ˜3 heteroatoms and may be substituted by a further substituent]
A compound represented by (however,

Or a pharmaceutically acceptable salt or solvate of the compound.

［式中、Ｒ_３及びＲ_４は、互いに独立に、水素、メチル又はエチルである（ただしＲ_３とＲ_４が同時に水素である場合は除く）］
で表される化合物、若しくは該化合物のピリジル基上の窒素原子がＮオキシド基により置換された化合物、又はこれらの化合物の薬学的に許容される塩、若しくは溶媒和物。 (12) Formula (II):

[Wherein R ₃ and R ₄ are independently of each other hydrogen, methyl or ethyl (except when R ₃ and R ₄ are simultaneously hydrogen)]
Or a compound in which the nitrogen atom on the pyridyl group of the compound is substituted with an N oxide group, or a pharmaceutically acceptable salt or solvate of these compounds.

  According to the present invention, an amyloid imaging probe having a highly selective amyloid β recognition ability is provided.

  The present invention relates to a compound of formula (I):

で表される化合物のアミロイドイメージング用プローブとしての新規用途に関する。本発明はまた上記式（Ｉ）で表される化合物に包含される新規化合物に関する。

To a novel use as a probe for amyloid imaging. The present invention also relates to a novel compound included in the compound represented by the above formula (I).

  In the above formula (I), n is an integer of 1 or 2, preferably 2. When n is 2, the above compound becomes a dienone derivative, and an α, β, γ, δ-unsaturated conjugated system is formed, and this unsaturated conjugated system functions as an electron withdrawing group, thereby further increasing the amyloid β specificity. Rise.

  In the above formula (I), —CH═CH— may be independently E-form or Z-form for each —CH═CH— when n is 2, preferably E-form. (When n is 2, E, E body).

R ₁ may be substituted with a substituent and may have 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur as ring atoms, preferably 5 to 10 members Is a monocyclic or bicyclic aromatic group. R ₁ is preferably an aromatic hydrocarbon group such as a phenyl group, 1- or 2-naphthynyl group, 2- or 3-furyl group, 2- or 3-thienyl group, which may be substituted with a substituent, It is a heteroaromatic group such as 2- or 3-pyrrolyl group, 1-, 2- or 3-indolyl group, 2- or 3-benzofuranyl group, and more preferably a phenyl group.

The substituent on R ₁ is preferably an electron donating group, for example, —NR ₃ R ₄ , wherein R ₃ and R ₄ are independently of each other hydrogen, methyl or ethyl (provided that R ₃ and R ₄ is simultaneously hydrogen))), alkyl groups such as methyl, ethyl, propyl, butyl and pentyl, alkoxyl groups such as methoxy, aromatic groups such as phenyl and benzyl, fluoroethyl, p-fluorobenzyl and the like In particular, the above-described —NR ₃ R ₄ (particularly, those in which R ₃ and R ₄ are both methyl) are preferable.

In the above formula (I), R ₂ is a monocyclic or bicyclic nitrogen-containing aromatic group in which the nitrogen atom may be substituted with an N oxide group, preferably 5 to 10 members. The nitrogen-containing aromatic group may further have 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur as ring atoms, and further substituents (for example, methyl, ethyl, etc.) A lower alkyl group, an aromatic group such as phenyl and benzyl, and a halogen-containing group such as fluoroethyl and p-fluorobenzyl). R ₂ is preferably a 2-, 3- or 4-pyridyl group, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl group, more preferably a 3- or 4-pyridyl group. . In these groups, the nitrogen atom may be substituted with an N oxide group. R ₂ is most preferably a 3-pyridyl group or a 3-pyridyl group in which a nitrogen atom is substituted with an N oxide group.

［式中、Ｒ_３及びＲ_４は、互いに独立に、水素、メチル又はエチルである（ただしＲ_３とＲ_４が同時に水素である場合は除く）］
で表される化合物又は該化合物のピリジル基上の窒素原子がＮオキシド基により置換された化合物である。とりわけ、Ｒ_３とＲ_４がともにメチルである場合が好ましい。 Of the compounds represented by the formula (I), the most preferred compound as a probe for amyloid imaging is represented by the formula (II):

[Wherein R ₃ and R ₄ are independently of each other hydrogen, methyl or ethyl (except when R ₃ and R ₄ are simultaneously hydrogen)]
Or a compound in which the nitrogen atom on the pyridyl group of the compound is substituted with an N oxide group. In particular, it is preferable that both R ₃ and R ₄ are methyl.

  Among the compounds represented by the formula (I), various compounds other than the compound represented by the formula (II) can be suitably used as the probe for amyloid imaging. Table 1 shows an example of a compound (including a compound represented by the formula (II)) that can be suitably used as a probe for amyloid imaging. “Compound number” in Table 1 is a number given by the present inventors for the sake of convenience. In this specification, a compound may be specified by this compound number.

  Among the compounds shown in Table 1, compound numbers 239-5, 239-6, 239-19, 239-25, 240-7, 240-11, 240-13, 240-24 and 240-26 are amyloids. Is particularly high and can be suitably used in the present invention.

  The compound used in the present invention may be used in the form of a pharmaceutically acceptable salt or solvate. When the compound used in the present invention has a basic group, the pharmaceutically acceptable salt includes a salt with an organic acid or an inorganic acid, for example, hydrochloride, hydrobromide, sulfate, heavy salt. Sulfate, phosphate, acid phosphate, acetate, oxalate, maleate, fumarate, succinate, lactate, tartrate, benzoate, citrate, gluconate, cyclohexyl Examples thereof include sulfamate, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate and the like. When the compound used in the present invention has an acidic group, pharmaceutically acceptable salts include salts with organic bases or inorganic bases, such as alkali metal salts such as sodium salts and potassium salts; calcium salts; Examples include alkaline earth metal salts such as magnesium salts; ammonium salts; organic amine salts such as triethylamine salts, ethanolamine salts, amino acid salts (lysine salts, arginine salts, etc.), and the like. Examples of pharmaceutically acceptable solvates include hydrates.

  The probe for amyloid imaging according to the present invention can be used in the following manner. The amyloid imaging probe according to the present invention is labeled with a labeling substance, the labeled probe is administered to a living body in vivo (for example, intravenously administered), and then the elderly in the brain using an image measuring device such as PET or SPECT. The accumulated amount and distribution of plaques can be measured, and early diagnosis or onset prediction of diseases in which amyloid accumulates such as Alzheimer's disease can be performed. Examples of labeling substances include, but are not limited to, radionuclides. Radionuclides include γ-ray emitting nuclides such as 51Cr, 59Fe, 57Co, 67Ga, 75Se, 81mKr, 99mTc, 111In, 123I, 131I, 133Xe, 201Tl, 11C, 13N, 15O, 18F, 35mCl, 76Br, 45Ti, 48V , 60Cu, 61Cu, 62Cu, 66Ga, 89Zr, 94mTc, 124I, and the like, but not limited thereto. As is obvious to those skilled in the art, “m” represents a nuclear isomer.

  Furthermore, since the compound of the present invention specifically binds to senile plaques and emits strong fluorescence, it is useful as a staining agent for pathological diagnosis after biopsy or death of Alzheimer's disease patients. Staining of brain sections with the compound of the present invention can be carried out by the usual method as shown in “Screening of candidate compounds”. In this case, the concentration of the compound is 1 μM, and incubation for 5 minutes is sufficient. (Fig. 4)

  The probe for amyloid imaging according to the present invention is provided as a composition (that is, a composition for amyloid imaging) for use in image diagnosis of a disease in which amyloid accumulates, such as Alzheimer's disease, in combination with a pharmaceutically acceptable carrier. May be. Pharmaceutically acceptable carriers include, but are not limited to, solubilizers, pH adjusters, and stabilizers. Specific examples of the carrier include, but are not limited to, polysorbate 80, sodium hydrogen carbonate, and ethylenediaminetetraacetic acid.

The manufacturing method of the said compound is not specifically limited. For example, the dienone compound of the present invention (R ₁ CH═CH—CH═CH—C (═O) R ₂ ) is composed of α, β-unsaturated aldehyde (R ₁ CH═CH—CH═O), acetylpyridine, acetyl An isolated compound with an acetyl group such as pyridine oxide (CH ₃ C (═O) R ₂ ) can be obtained in an isolated yield of 60 to 90% by heating in methanol in the presence of an amine catalyst. In addition, the amine catalyst gives a similar result even with hydrochloride or acetate as its salt. As the amine catalyst, pyrrolidine or its hydrochloride is particularly preferred. See the Examples for more specific examples of production methods.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to the examples.

Candidate compound screening
About 1100 compounds of SIGMA-ALDRICH Library of Rare Chemicals, Alzheimer's disease (AD) brain sections were screened for the affinity of the compounds for senile plaques. AD brain fixed in formalin, preserved with phosphate-buffered saline (PBS), soaked in 10, 20, 30% sucrose, frozen and embedded in OCT Compound in dry ice-acetone, diluted to 30 mm with cryostat Cut AD brain sections were prepared.

  AD brain sections were suspended in a solution obtained by diluting the compound with distilled water to a concentration of 1, 10, 100 μM and incubated for 1 hour. The section was washed three times with distilled water, mounted on a slide glass, and examined with a fluorescence microscope. An example of a fluorescence microscope image is shown in FIG. Eleven of the 1100 compounds have affinity for senile plaques, and six of them have a structure not conventionally known as a compound having affinity for senile plaques. FIG. 1 shows senile plaques (arrows) visualized by the binding of compounds Nos. 239 and 240 among the above 6 compounds.

Compounds 239 and 240 have the following structure:

  Using the above two compounds 239 and 240 as lead compounds, various derivatives (each compound shown in Table 1) with further enhanced binding affinity and specificity to amyloid β (Aβ) protein were synthesized.

Synthesis Examples of Compounds 239-22 and 240-24 Compounds 239-22 ( 9 in the scheme) and 240-24 ( 10 in the scheme) can be synthesized by the following scheme.

  Each step will be described below.

Synthesis of (2)

To a 50 mL eggplant-shaped flask, 2.00 g (9.13 mmol) of 4-iodo-phenylamine ( 1 ) was added and purged with nitrogen. Thereto were added anhydrous CH ₂ Cl ₂ 9 mL, anhydrous DMF 6 mL, and Et ₃ N 2.4 mL (18.3 mmol), and the mixture was cooled to 0 ° C. in an ice bath. Thereto was added dropwise 2.18 g (10.0 mmol) of di-tert-butyl dicarbonate dissolved in 3 mL of anhydrous CH ₂ Cl ₂ and the temperature was raised to room temperature. The mixture was stirred at room temperature for 13 hours. A white solid (1,3-bis- (4-iodo-phenyl) -urea) then formed. After confirming the completion of the reaction by TLC, the white solid (1,3-bis- (4-iodo-phenyl) -urea) was suction filtered and washed with Et ₂ O. 15 mL of distilled water was added to the filtrate, and the aqueous layer was extracted 3 times with 20 mL of Et ₂ O. The organic layer was dried over Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: ethyl acetate = 20: 1), and the obtained white solid was washed with 10 mL of hexane three times to obtain 766.1 mg (yield 26%) of 2 . TLC (hexane: ethyl acetate = 5: 1) 1 : R _f = 0.19, 2 : R _f = 0.44, 2 : ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.58 (2H, d, J = 8.8 Hz) , 7.15 (2H, d, J = 8.8 Hz), 6.43 (1H, br s), 1.51 (9H, s).

Synthesis of (3)

NaH 105.6 mg (60%, 2.64 mmol) was placed in a 50 mL eggplant-shaped flask, washed with hexane, and dried by blowing nitrogen. Thereto, 2.5 mL of anhydrous THF was added, and the mixture was cooled to 0 ° C. with an ice bath. 2 766.1 mg (2.40 mmol) dissolved in anhydrous THF 2.5 mL was slowly added dropwise thereto. At this time, it foamed vigorously. Thereafter, the mixture was stirred at 0 ° C. for 15 minutes and at room temperature for 1 hour, and disappearance of 2 was confirmed by crude NMR. The reaction was cooled in an ice bath, quenched by dropwise addition of saturated NH ₄ Cl aq, 5 mL of distilled water was added, and the aqueous layer was extracted 3 times with 20 mL of Et ₂ O. The organic layer was dried over Na ₂ SO ₄ and the solvent was distilled off under reduced pressure to obtain 3 845.4 mg. TLC (Hexane: Ethyl acetate = 5: 1) 2 : R _f = 0.44, 3 : R _f = 0.44, 3 : ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.63 (2H, d, J = 8.8 Hz) , 7.00 (2H, d, J = 8.8 Hz), 3.23 (3H, s), 1.45 (9H, s).

Synthesis of (4)

50 mL 3 1.54 g of crude eggplant type flask (4.62 mmol), anhydrous _{K 2 CO 3 3.19 g (23.1} mmol), and, placed _{Pd (PPh 3) 4 133.5 mg} (0.116 mmol), purged with argon. Thereto were added anhydrous DMF 10 mL and ethyl acrylate 1.0 mL (9.24 mmol), and degassing and argon substitution were repeated three times. The reaction mixture was stirred at 80 ° C. for 13 hours. At this time, the inside of the system changed to black. After confirming the completion of the reaction by TLC, the reaction mixture was cooled to room temperature, and the solid was filtered through Celite under reduced pressure. Distilled water (20 mL) was added to the filtrate, and the aqueous layer was extracted three times with 20 mL of Et ₂ O. The organic layer was dried over Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: Et ₂ O = 5: 1) to obtain 1.26 g (yield 89%) of 4 . TLC (hexane: ethyl acetate = 5: 1) 3 : R _f = 0.44, 4 : R _f = 0.27, 4 : ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.65 (1H, d, J = 16 Hz) , 7.48 (2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 6.38 (1H, d, J = 16 Hz), 4.26 (2H, q, J = 7.2 Hz), 3.28 (3H, s), 1.57 (9H, s), 1.34 (3H, q, J = 7.2 Hz).

Synthesis of (5)

LiAlH ₄ 156.7 mg (4.13 mmol) was placed in a 50 mL eggplant-type two-necked flask and purged with nitrogen. Thereto was added anhydrous Et ₂ O 10 mL, and the mixture was cooled to 0 ° C. in an ice bath. 4 1.26 g (4.13 mmol) dissolved in 4 mL of anhydrous Et ₂ O was slowly added dropwise and stirred for 20 minutes in an ice bath. After confirming the completion of the reaction by TLC, distilled water was added dropwise to quench the reaction. Thereto was repeated 3 times that 10 mL of Et ₂ O was added and the supernatant was collected. The aqueous layer was added with 30 mL of distilled water, extracted three times with 30 mL of Et ₂ O, and added to the collected supernatant. The organic layer was dried over Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: Et ₂ O = 1: 1 to 1: 2) to obtain 874.3 mg of 5 (yield 80%). TLC (hexane: ethyl acetate = 5: 1) 4 : R _f = 0.27, 5 : R _f = 0.01, 5 : ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.34 (2H, d, J = 8.2 Hz) , 7.19 (2H, d, J = 8.2 Hz), 6.59 (1H, d, J = 15.7 Hz), 6.33 (1H, dd, J = 5.5, 16 Hz), 4.32 (2H, br d, J = 5.5 Hz) ), 3.25 (3H, s), 1.45 (9H, s).

Synthesis of (6)

765 mg of MS4A was placed in a 20 mL eggplant-shaped flask, and MS4A was activated for 15 minutes while heating under vacuum. Then, argon substitution was carried out, 5 874.3 mg (3.32 mmol), N-methylmorpholine (NMO) 583.4 mg (4.98 mmol) and anhydrous CH ₂ Cl ₂ 7 mL were added, and the mixture was cooled to 0 ° C. in an ice bath. Thereafter, 63.3 mg (0.166 mmol) of tetra-n-propylammonium perruthenate (TPAP) was added all at once. Then, it heated up to room temperature and stirred for 1 hour. Completion of the reaction was confirmed by TLC, the reaction mixture was directly purified by flash column chromatography (CH ₂ Cl ₂ alone, from _{CH 2 Cl 2: MeOH = 100} : to 1) to give 6 a 694.0 mg (yield: 80 %)Obtained. TLC (Hexane: Ethyl acetate = 5: 1) 5 : R _f = 0.01, 6 : R _f = 0.14, 6 : ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.69 (1H, d, J = 7.7 Hz) , 7.53 (2H, d, J = 8.5 Hz), 7.44 (1H, d, J = 16 Hz), 7.34 (1H, d, J = 8.5 Hz), 6.68 (2H, dd, J = 16, 7.7 Hz) , 3.30 (3H, s), 1.48 (9H, s).

Synthesis of (7)

3-acetylpyridine 80.5 mg (0.664 mmol), 6 347.0 mg (1.33 mmol), and MeOH 2 mL were placed in a 10 mL eggplant-shaped flask, and the atmosphere was replaced with nitrogen. Thereto was added 17 μL (0.199 mmol) of pyrrolidine, and the mixture was stirred at 60 ° C. for 5 hours. After the completion of the reaction was confirmed by crude NMR, MeOH was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: ethyl acetate = 2.5: 1 to 1.5: 1) to obtain 182.6 mg of 7 (yield 75%). TLC (hexane: ethyl acetate = 1: 1), 7 : ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.18 (1H, dd, J = 2.2, 0.8Hz), 8.79 (1H, dd, J = 4.9, 0.9 Hz), 8.28 (1H, dt, J = 8.0, 2.2 Hz), 7.64 (1H, ddd, J = 15, 8.8, 1.3 Hz), 7.44-7.45 (3H, m), 7.22-7.30 (2H, m ), 6.99-7.06 (3H, m), 3.28 (3H, s), 1.47 (9H, s).

Synthesis of (8)

3-acetylpyridine N-oxide 80.5 mg (0.664 mmol), 6 347.0 mg (1.33 mmol), and MeOH 2 mL were placed in a 10 mL eggplant-shaped flask and purged with nitrogen. Thereto was added 17 μL (0.199 mmol) of pyrrolidine, and the mixture was stirred at 60 ° C. for 5 hours. After the completion of the reaction was confirmed by crude NMR, MeOH was distilled off under reduced pressure. The residue was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 60: 1 to 45: 1) to obtain 165.3 mg (65% yield) of 8 . TLC (CH ₂ Cl ₂ : MeOH = 10: 1) 3-acetylpyridine N-oxide: R _f = 0.29, 6 : R _f = 0.84, 8 : R _f = 0.29, 8 : ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.75 (1H, s), 8.37 (1H, d, J = 6.1 Hz), 7.81 (1H, d, J = 7.4 Hz), 7.67 (1H, dd, J = 15, 11 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.43 (1H, dd, J = 7.4, 6.1 Hz), 7.28 (2H, d, J = 8.5 Hz), 6.99 (1H, d, J = 15 Hz), 6.96 (1H, d, J = 15, 11 Hz), 6.89 (1H, dd, J = 15, 15 Hz), 3.29 (3H, s), 1.48 (9H, s).

Synthesis of (9)

7 165.3 mg (0.434 mmol) was placed in a 10 mL eggplant-shaped flask and purged with nitrogen. Thereto, 1 mL of anhydrous CH ₂ Cl ₂ was added, and after cooling to 0 ° C. with an ice bath, 1 mL of trifluoroacetic acid was added dropwise. Then, it heated up to room temperature and stirred for 30 minutes. After confirming the completion of the reaction by TLC, the reaction mixture was quenched by dropwise addition of saturated K ₂ CO ₃ aq in an ice bath. The reaction mixture was extracted with CH ₂ Cl ₂ until no stick colors in CH ₂ Cl _2, dried over Na ₂ SO _4. Then, the solvent was distilled off under reduced pressure to obtain 129.4 mg (yield 98%) of 9 . TLC (hexane: ethyl acetate = 1: 1) 7 : R _f = 0.33, 9 : R _f = 0.30, 9 : ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.16 (1H, d, J = 5.1 Hz) , 8.76 (1H, dt, J = 5.1, 1.7Hz), 8.25 (1H, dt, J = 7.9, 1.7Hz), 7.66 (1H, dd, J = 15, 11 Hz), 7.43 (1H, ddd, J = 7.9, 5.1, 0.8 Hz), 7.38 (2H, d, J = 9.2 Hz), 6.99 (1H, d, J = 15 Hz), 6.95 (1H, d, J = 15 Hz), 6.85 (1H, dd , J = 15, 11 Hz), 6.58 (2H, d, J = 8.8 Hz), 2.89 (3H, s).

Synthesis of (10)

8 165.3 mg (0.434 mmol) was placed in a 10 mL eggplant-shaped flask and purged with nitrogen. Thereto, 1 mL of anhydrous CH ₂ Cl ₂ was added, and after cooling to 0 ° C. with an ice bath, 1 mL of trifluoroacetic acid was added dropwise. Then, it heated up to room temperature and stirred for 30 minutes. After confirming the completion of the reaction by TLC, the reaction mixture was quenched by dropwise addition of saturated K ₂ CO ₃ aq in an ice bath. The reaction mixture was extracted with CH ₂ Cl ₂ until no stick colors in CH ₂ Cl _2, dried over Na ₂ SO _4. Thereafter, the solvent was distilled off under reduced pressure to obtain 122.6 mg of 10 (yield> 99%). TLC (CH ₂ Cl ₂ : MeOH = 10: 1 double expansion) 8 : R _f = 0.41, 10 : R _f = 0.38, 10 : ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.72 (1H, t, J = 1.4 Hz), 8.32 (1H, dt, J = 6.3, 0.9 Hz), 7.78 (1H, dt, J = 11, 6.3 Hz), 7.68 (1H, dd, J = 14.5, 11 Hz), 7.23- 7.42 (3H, m), 7.03 (1H, d, J = 15 Hz), 6.82 (1H, dd, J = 15, 1.1 Hz), 6.77 (1H, d, J = 15 Hz), 6.58 (2H, d , J = 8.8 Hz), 2.90 (3H, s).

Synthesis of Compounds 239-6 and 240-13 Compounds 239-6 and 240-13 are methylation reactions of 9 (Compound 239-22) and 10 (Compound 240-24), respectively, which are the final compounds of the above synthesis examples. Methyl chloride, K ₂ CO ₃ , in DMF solvent).

Also, commercially available (CH ₃ ) ₂ NC ₆ H ₄ —CH═CH—CH═O and 3-acetylpyridine were heated in methanol at 40 ° C. in the presence of a pyrrolidine catalyst to give compound 239-6. Could be obtained in 99% yield. Compound 240-13 was obtained in 90% yield by the same method except that 3-acetylpyridine oxide was used in place of 3-acetylpyridine.
Compound 239-6: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.16 (1H, br.s), 8.77 (1H, t, J = 5.0 Hz), 8.24 (1H, dt, J = 1.9, 8.0 Hz), 7.66 (1H, dd, J = 11, 15 Hz), 7.45 (1H, dd, J = 5.0, 8.0 Hz), 7.42 (2H, d, J = 9.0 Hz), 7.01 (1H, d, J = 15 Hz), 6.93 (1H, d, J = 15 Hz), 6.86 (1H, dd, J = 11, 15 Hz), 6.71 (2H, d, J = 9.0 Hz), 3.03 (6H, s).
Compound 240-13: ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.71-8.78 (1H, m), 8.31-8.35 (1H, m), 7.85 (1H, d, J = 15 Hz), 7.76- 7.85 (1H, m), 7.69 (1H, dd, J = 11, 15 Hz), 7.54 (2H, d, J = 8.8 z), 7.36-7.44 (1H, m), 7.12 (1H, d, J = 15 Hz), 7.04 (1H, d, J = 15 Hz), 6.84 (1H, dd, J = 11, 15 Hz), 6.68-6.80 (2H, m), 3.04 (6H, s).

  Other dienone compounds (239-19, 239-25, 240-7, 240-13, 240-24, 240-26) shown in Table 1 could also be synthesized by the same scheme as above.

Synthesis of Compound 239-19
In a 10 mL eggplant-shaped flask, add 3-acetylpyridine (43.4 mg, 0.358 mmol), (E) -3- (4- (diethylamino) phenyl) acrylaldehyde (80.0 mg, 0.394 mmol) and MeOH (1 mL). Replaced with nitrogen. Furthermore, pyrrolidine (9 μL, 0.107 mmol) was added, and the mixture was stirred at 60 ° C. for 2.5 hours. After confirming the completion of the reaction by NMR, MeOH was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: EtOAc = 3: 1 to 2: 1) to give 239-19 (96.6 mg, yield 88%). ¹ H-NMR (300 MHz, d ⁶ -acetone): δ9.16 (1H, dd, J = 0.8, 2.2 Hz), 8.75 (1H, dd, J = 1.7, 5.0 Hz), 8.30 (1H, ddd, J = 1.6, 2.2, 8.0 Hz), 7.61 (1H, dd, J = 11, 15 Hz), 7.53 (1H, ddd, J = 0.8, 4.7, 7.7 Hz), 7.45 (2H, d, J = 8.8 Hz ), 7.15 (1H, d, J = 15 Hz), 7.10 (1H, d, J = 15 Hz), 6.98 (1H, ddd, J = 0.8, 11, 15 Hz), 6.73 (2H, d, J = 8.8 Hz), 3.45 (4H, q, J = 7.1 Hz), 1.16 (6H, t, J = 7.1 Hz).

Synthesis of Compound 239-25

NaH (1.45 g, 36.3 mmol) was placed in a 50 ml two-necked eggplant type flask, washed three times with hexane (10 mL), and dried by blowing nitrogen. Anhydrous THF (15 mL) was added, and the mixture was cooled to 0 ° C. with an ice bath, and a solution of methyl diethylphosphonoacetate (7.28 g, 34.7 mmol) dissolved in anhydrous THF (5 mL) was slowly added dropwise. Then, it stirred for 1 hour with 0 degreeC. At this time, the reaction mixture became colorless and transparent simultaneously with violent foaming. Further, indole-3-carbaldehyde (2.00 g, 16.5 mmol) dissolved in anhydrous THF (5 mL) was slowly added dropwise at 0 ° C., and the mixture was stirred at room temperature for 21 hours. Then half. Sat. NH ₄ Cl (4 mL) was added at 0 ° C. Distilled water (20 mL) was further added, and the mixture was extracted 3 times with Et ₂ O (25 mL). The organic layer was separated and dried over Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: Et ₂ O = 1: 1) to give 239-25a (1.17 g, yield 80%). 239-25a: ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.44 (1H, br.s), 7.93 (1H, d, J = 16 Hz), 7.89-7.95 (1H, m), 7.51 (1H , d, J = 2.7 Hz), 7.39-7.45 (1H, m), 7.26-7.33 (1H, m), 6.48 (1H, d, J = 16 Hz), 3.82 (3H, s).

To a 50 mL eggplant-shaped flask, 239-25a (2.64 g, 13.1 mmol), anhydrous CH ₂ Cl ₂ (15 mL), anhydrous DMF (10 mL) and Et ₃ N (3.7 mL, 26.2 mmol) were added, and the atmosphere was replaced with nitrogen. Then, it was cooled to 0 ° C. with an ice bath. Thereto was added dropwise di-tert-butyl dicarbonate (3.67 g, 19.7 mmol) dissolved in anhydrous CH ₂ Cl ₂ (5 mL), and the mixture was stirred at room temperature for 19 hours. After confirming the completion of the reaction by TLC, distilled water (15 mL) was added, and the aqueous layer was extracted three times with Et ₂ O (20 mL). The organic layer was dried over Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: Et ₂ O = 10: 1) to obtain 239-25b (3.84 g, yield 97%). 239-25b: ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.19 (1H, d, J = 7.7 Hz), 7.86 (1H, s), 7.80-7.86 (2H, m), 7.39 (1H, td , J = 1.4, 7.6 Hz), 7.33 (1H, td, J = 1.4, 7.6 Hz), 6.54 (1H, d, J = 16 Hz), 3.82 (3H, s), 1.68 (9H, s).

LiAlH ₄ (50.5 mg, 1.33 mmol) was placed in a 50 mL eggplant-type two-necked flask, purged with nitrogen, added anhydrous Et ₂ O (4 mL), and cooled to 0 ° C. in an ice bath. 239-25b (400.0 mg, 1.33 mmol) dissolved in anhydrous Et ₂ O (3 mL) was slowly added dropwise and stirred for 20 minutes in an ice bath. After confirming the completion of the reaction by TLC, distilled water was added dropwise to quench the reaction. Further, Et ₂ O (3 mL) was added and the supernatant was collected three times. The aqueous layer was added with 10 mL of distilled water, extracted three times with 20 mL of Et ₂ O, and added to the collected supernatant. The organic layer was dried over Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: EtOAc = 4: 1 to 2: 1) to give 220.4 mg (61% yield) of 239-25c. 239-25c: ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.16 (1H, d, J = 8.2 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.63 (1H, s), 7.27- 7.37 (2H, m), 6.73 (1H, d, J = 16 Hz), 6.46 (1H, dt, J = 5.8, 16 Hz), 4.36 (3H, dd, J = 1.4, 5.8 Hz), 1.67 (9H , s).

MS4A (420 mg) was placed in a 10 mL eggplant-shaped flask and activated while heating under reduced pressure. Then, it was replaced with argon, 239-25c (227.1 mg, 0.831 mmol), N-methylmorpholine oxide (146.0 mg, 1.25 mmol) and anhydrous CH ₂ Cl ₂ ( 2 mL), cooled to 0 ° C. in an ice bath, and tetra-n-propylammonium perruthenate (TPAP) (14.6 mg, 0.0416 mmol) was added in one portion. Then, it stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the reaction mixture was directly purified by flash column chromatography (CH ₂ Cl ₂ ) to obtain 239-25d (177.3 mg, yield 79%). 239-25d: ¹ H-NMR (300 MHz, CDCl ₃ ) δ9.68 (1H, d, J = 7.7 Hz), 8.21 (1H, d, J = 7.7 Hz), 7.96 (1H, s), 7.82- 7.86 (1H, m), 7.63 (1H, d, J = 16 Hz), 7.42 (1H, td, J = 1.1, 7.1 Hz), 7.36 (1H, td, J = 1.1, 7.1 Hz), 6.85 (1H , dd, J = 7.7, 16 Hz), 1.70 (9H, s).

3-acetylpyridine 51.9 mg (0.428 mmol), 239-25d, 174.2 mg (0.642 mmol) and 1 mL of MeOH were placed in a 10 mL eggplant-shaped flask and purged with nitrogen. Thereto was added pyrrolidine 10 μL (0.199 mmol), and the mixture was stirred at 60 ° C. for 5 hours. After the completion of the reaction was confirmed by crude NMR, MeOH was distilled off under reduced pressure. The residue was purified by flash column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1.5) to obtain 60.8 mg (38% yield) of 239-25e. Further, 239-25, 25.3 mg (yield 22%) in which the Boc group of 239-25e was deprotected was obtained. Boc group deprotection was treated with TFA, and 239-25 was obtained in 45%. 239-25e: ¹ H-NMR (300 MHz, CDCl ₃ ) δ9.26 (1H, d, J = 1.9 Hz), 8.84 (1H, dd, J = 1.7, 5.2 Hz), 8.80 (1H, d, J = 8.2 Hz), 8.20 (1H, d, J = 7.4 Hz), 8.14 (1H, s), 7.86-7.89 (2H, m), 7.70-7.79 (2H, m), 7.34-7.43 (3H, m) , 7.17-7.29 (2H, m), 7.60 (1H, d, J = 15 Hz), 1.70 (9H, s).
239-25: ¹ H-NMR (300 MHz, d ⁶ -acetone) δ10.8 (1H, br.s), 9.20-9.21 (1H, m), 8.35 (1H, dt, J = 1.9, 8.0 Hz) , 8.20-8.07 (1H, m), 7.65-7.79 (2H, m), 7.45-7.59 (3H, m), 7.23-7.32 (4H, m).

Synthesis of Compound 240-26

3-acetylpyridine (51.9 mg, 0.428 mmol), 239-25d (174.2 mg, 0.642 mmol) and MeOH (1 mL) were placed in a 10 mL eggplant-shaped flask, and the atmosphere was replaced with nitrogen. Further pyrrolidine (10 μL, 0.199 mmol) was added, and the mixture was stirred at 60 ° C. for 5 hours. After confirming the completion of the reaction by NMR, MeOH was distilled off under reduced pressure. The residue was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 60: 1 to 20: 1) to give 240-26a (60.8 mg, 38% yield). At the same time, 240-26 (25.3 mg, yield 22%) in which the Boc group was deprotected was obtained. The Boc group was deprotected by treatment with TFA to obtain 239-25 in 43%. 240-26a: ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.75-8.79 (1H, m), 8.36-8.41 (1H, m), 8.04-8.22 (2H, m), 7.57-7.89 (3H, m), 7.06-7.59 (5H, m), 6.87-6.99 (1H, m), 1.70 (9H, s). 240-26: ¹ H-NMR (300 MHz, d ⁶ -acetone) δ10.9 (1H, br.s), 8.92 (1H, s), 8.60-8.63 (1H, m), 8.20-8.17 (1H, m), 8.01-8.04 (1H, m), 7.72-7.83 (3H, m), 7.31-7.58 (2H, m), 7.19-7.31 (4H, m).

Synthesis of Enone Compounds Representative examples of enone synthesis methods are shown below. Other enone compounds shown in Table 1 can be synthesized in the same manner.

Synthesis of Compound 239-5

3-acetylpyrrolidine (60.6 mg, 0.500 mmol), 4- (dimethylamino) -benzaldehyde (74.6 mg, 0.500 mmol) and MeOH (0.7 mL) were placed in a 10 mL eggplant-shaped flask and purged with nitrogen. Further, pyrrolidine (5 μL (0.101 mmol) was added and stirred for 4 hours at 60 ° C. After the completion of the reaction was confirmed by NMR, MeOH was distilled off under reduced pressure, and the residue was subjected to flash column chromatography (hexane: EtOAc = 3: 1 to 1: 1) to give 239-5 (102.6 mg, 81% yield) 239-5: ¹ H-NMR (300 MHz, CDCl ₃ ) δ9.23 (1H, d, J = 1.4 Hz), 8.79 (1H, dd, J = 1.4, 5.0 Hz), 8.45 (1H, dt, J = 1.7, 7.9 Hz), 7.86 (1H, d, J = 15 Hz), 7.59 (1H, t, J = 7.2 Hz), 7.56 (2H, d, J = 9.2 Hz), 7.27 (1H, d, J = 15 Hz), 6.72 (2H, d, J = 9.1 Hz), 3.08 (6H, s) .

Synthesis of Compound 240-7

A 10 mL eggplant-shaped flask was charged with 137.1 mg (1.00 mmol) of 3-acetylpyridine N-oxide, 290.3 mg (2.00 mmol) of indole-3-carbaldehyde and 2 mL of i-PrOH, and purged with nitrogen. Thereto were added pyrrolidine 25 μL (0.300 mmol) and acetic acid 17 μL (0.300 mmol), and the mixture was stirred at 85 ° C. for 21 hours. After the completion of the reaction was confirmed by crude NMR, the reaction was quenched with NaHCO 3 aq and extracted three times with 30 ml of CH ₂ Cl ₂ . Thereafter, the organic layer was dried over Na ₂ SO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 80: 1 to 25: 1) to give 250.9 mg (95% yield) of 240-7. 240-7: ¹ H-NMR (300 MHz, d ⁶ -DMSO) δ12.0 (1H, br.s), 8.81 (1H, t, J = 1.6 Hz), 8.20 (1H, s), 8.12-8.17 (1H, m), 8.12 (1H, d, J = 15 Hz), 7.99 (1H, ddd, J = 1.1, 1.6, 7.7 Hz), 7.58 (1H, ddd, J = 0.6, 6.3, 8.0 Hz), 7.53 (1H, d, J = 15 Hz), 7.46-7.51 (1H, m), 7.19-7.28 (2H, m).

Binding of Amyloid Fibrils to Candidate Compounds The binding ability of each candidate compound to amyloid fibrils prepared from amyloid β protein was confirmed.
Amyloid β40 (Aβ40) and amyloid β42 (Aβ42) (both Peptide Laboratories, Inc.) were each dissolved in DMSO so as to have a concentration of 10 mM. Amyloid fibrils were prepared by diluting Aβ40 or Aβ42 stock solutions to 200 μM in PBS and incubating at 37 ° C. for 24 hours.

  1 μM compounds 239-6 and 240-13 were added to 2 μM Aβ40 or Aβ42 fibril solution in a 24-well plate, and examined with a fluorescence microscope. A fluorescence microscope image is shown in FIG. Compounds 239-6 and 240-13 were both shown to have the ability to bind amyloid fibrils. Similar experiments were conducted for 239-19, 239-25, 240-24, and 240-26, and binding to amyloid fibrils was confirmed.

Experiment on inhibition of binding between compound amyloid fibril and thioflavin T Thioflavin T is known to bind to amyloid β protein constituting senile plaques. It can be said that a compound that competitively inhibits the binding of amyloid fibrils prepared from amyloid β protein and thioflavin T is useful as a compound for amyloid imaging. Then, the binding inhibition experiment of amyloid fibril and thioflavin T of each candidate compound was conducted.

  Aβ40 fibril solution was prepared in the same manner as described above. Candidate compounds are added at a concentration of 1-20 μM to 4 μM Aβ40 fibril solution containing 6 μM Thioflavin T, incubated for 30 minutes, and then fluorescence intensity (excitation wavelength: 440 nm, fluorescence wavelength: 480 mm) Was measured.

  As a positive control sample, Congo Red, which is well known as a compound that binds to amyloid β protein, was used.

  The results are shown in Figure 3. It is clear that any of the compounds 239-5, 239-6, 240-7, 240-11, 240-13 can inhibit the binding of amyloid fibrils to thioflavin T as potently as Congo Red or more. became. Compounds 239-6 and 240-13 particularly strongly inhibited the binding of amyloid fibrils to thioflavin T.

Using a method similar to that for screening for binding of compounds 239-6 and 240-13 to senile plaques in AD brain tissue (compound concentration is 1 μM, incubation time is 1 minute), AD brains of compounds 239-6 and 240-13 are used. Tissue binding to senile plaques was confirmed.
For comparison, immunostaining of senile plaques in AD brain tissue was performed. After confirming the binding of compounds 239-6 and 240-13 to senile plaques in AD brain tissue by the above procedure, the same AD brain section was washed with PBS, treated with 70% formic acid for 15 minutes, and 0.3% H Incubate with methanol containing ₂ O ₂ for 30 minutes to block endogenous peroxidase, then block in PBS containing 5% normal horse serum (VECTOR) and 0.4% TritonX-100 for 1 hour, and diluted 1000-fold. Incubated with Aβ monoclonal antibody (4G8, SIGNET) (4 ° C, overnight). After washing with PBS, it was incubated with biotinylated anti-mouse IgG antibody (1: 500) (VECTOR) for 1 hour, and color development was performed using VECTASTAIN ABC kit (VECTOR) and DAB substrate kit (VECTOR). The results are shown in the lower part of FIG.

  From the photograph of FIG. 4, it can be seen that compounds 239-6 and 240-13 can visualize senile plaques in AD brain tissue with the same clarity as immunostaining.

Administration of Compound 239-6 to Transgenic Mice Compound 239-6 was saturated in a cationic liposome solution for DNA transfection (Lipofectamine 2000, Invitrogen).
The above saturated solution was administered to 12-month-old transgenic mice (APP swTg2576) from the tail vein, 4 hours later, the brain was removed and frozen and embedded in OCT Compound (Tissue-Tek) to prepare 10-μm sections. Speculum.

  In addition, as a control experiment, the same treatment was performed on the non-administered mice using the same transgenic mice.

  The results are shown in FIG. The upper and lower photographs for each treatment zone are microscopic images with different magnifications for the same sample.

It is a photograph which shows an example of the fluorescence microscope image in the screening about the affinity of the library compound with respect to the senile plaque using the Alzheimer's disease (AD) brain section. It is a photograph which shows the fluorescence-microscope image which shows the binding ability of the compounds 239-6 and 240-13 of this invention with respect to an amyloid fibril. It is a figure which shows the inhibitory ability of the coupling | bonding of the amyloid beta fibril and thioflavin T by the compound of this invention. It is a photograph which shows the senile plaque of AD brain visualized by use of the compound of this invention, or immunostaining. It is a photograph which shows the fluorescence microscope image of the brain which administered the compound 239-6 from the tail vein to the 12-month-old transgenic mouse, and was extracted 4 hours afterward.

Claims (12)

Formula (I):

[Wherein n is an integer of 1 or 2,
-CH = CH- may be E-form or Z-form,
R ₁ may be substituted by a substituent, and may have 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur as ring atoms, monocyclic or bicyclic An aromatic group of formula
R ₂ is a monocyclic or bicyclic nitrogen-containing aromatic group in which the nitrogen atom may be substituted with an N oxide group, and is selected from the group consisting of oxygen, nitrogen and sulfur as a ring atom The nitrogen-containing aromatic group which may further have ˜3 heteroatoms and may be substituted by a further substituent]
Or a pharmaceutically acceptable salt or solvate of the compound. R ₁ may have 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur as ring atoms, substituted by an electron donating group, monocyclic or bicyclic The probe for amyloid imaging according to claim 1, which is an aromatic group of The probe for amyloid imaging according to claim 1 or 2, wherein R ₂ is a 3- or 4-pyridyl group in which a nitrogen atom may be substituted with an N oxide group.   The probe for amyloid imaging according to any one of claims 1 to 3, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt or solvate of the compound is labeled.   The probe for amyloid imaging according to claim 4, wherein the label is a radionuclide.   The probe for amyloid imaging according to claim 5, wherein the radionuclide is a γ-ray emitting nuclide.   The probe for amyloid imaging according to claim 6, wherein the γ-ray emitting nuclide is selected from the group consisting of 51Cr, 59Fe, 57Co, 67Ga, 75Se, 81mKr, 99mTc, 111In, 123I, 131I, 133Xe, and 201Tl.   The probe for amyloid imaging according to claim 4, wherein the label is derived from a positron emitting nuclide.   The positron emitting nuclide is selected from the group consisting of 11C, 13N, 15O, 18F, 35mCl, 76Br, 45Ti, 48V, 60Cu, 61Cu, 62Cu, 66Ga, 89Zr, 94mTc, and 124I. Probe for amyloid imaging.   A composition for amyloid imaging, comprising the probe for amyloid imaging according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier. Formula (I):

[Wherein n is an integer of 1 or 2,
-CH = CH- may be E-form or Z-form,
R ₁ may be substituted by a substituent, and may have 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur as ring atoms, monocyclic or bicyclic An aromatic group of formula
R ₂ is a monocyclic or bicyclic nitrogen-containing aromatic group in which the nitrogen atom may be substituted with an N oxide group, and is selected from the group consisting of oxygen, nitrogen and sulfur as a ring atom The nitrogen-containing aromatic group which may further have ˜3 heteroatoms and may be substituted by a further substituent]
A compound represented by (however,

Or a pharmaceutically acceptable salt or solvate of the compound. Formula (II):

[Wherein R ₃ and R ₄ are independently of each other hydrogen, methyl or ethyl (except when R ₃ and R ₄ are simultaneously hydrogen)]
Or a compound in which the nitrogen atom on the pyridyl group of the compound is substituted with an N oxide group, or a pharmaceutically acceptable salt or solvate of these compounds.

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