WO2012017891A1 - Pyridyl benzofuran derivative - Google Patents

Abstract

The present invention relates to: a pyridyl benzofuran derivative; and a composition for diagnosing amyloid-related diseases, which contains the derivative.

Description

Pyridylbenzofuran derivative

The present invention relates to a pyridylbenzofuran derivative and a composition for diagnosing amyloid-related diseases comprising the derivative.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, irreversible memory loss, disorientation, and language impairment. The presence of β-amyloid (Aβ) aggregates in the brain is generally recognized as a prominent feature of AD (Non-patent Documents 1 and 2). Since the definitive diagnosis of AD is only by pathological examination of autopsy brain tissue, development of a technique that enables imaging of β-amyloid plaques in vivo is strongly desired (Non-patent Documents 3-5). ).

Preliminary studies in positron emission tomography (PET) include [ ¹¹ C] 4-N-methylamino-4′-hydroxystilbene (SB-13) (Non-Patent Documents 6 and 7), [ ¹¹ C] 2- (4 ′-(methylaminophenyl) -6-hydroxybenzothiazole (PIB) (Non-Patent Documents 8 and 9), [ ¹¹ C] 2- (2- [2-dimethylaminothiazol-5-yl] ethenyl)- 6- (2- [fluoro] ethoxy) benzoxazole (BF-227) (Non-patent Document 10), and [ ¹¹ C] -2- [6- (methylamino) pyridin-3-yl] -1,3- It has been suggested that the uptake and retention of benzothiazol-6-ol (AZD2184) (Non-Patent Document 11) (FIG. 1) in the brain differs between AD patients and controls. The successful imaging of brain β-amyloid plaques using ¹¹ C-labeled tracers at 1 and 10 was a major impetus for further improvements in this technique, however, ¹¹ C has a short half-life (t _{1 / 2} : 20 min), limiting its potential as a diagnostic tool because ¹⁸ F, an isotope with a longer half-life (t _1/2 : 110 min), is more useful for this purpose, recent development of similar drug labeled with ¹⁸ F have been attempted ^{intensively. [18 F] -2- (1-} (2- (N- (2- fluoroethyl) -N- methylamino) naphthalene A preliminary study with -6-yl) ethylidene) malononitrile (FDDNP) (12, 13) showed for the first time that uptake and retention in the brain of AD patients is different. The stilbene derivative (E) -4- (N-methylamino) -4 ′-(2- (2- (2- [ ¹⁸ F] -fluoroethoxy) ethoxy) ethoxy) -stilbene (BAY94-9172) (Non-Patent Documents 14 and 15), (E) -4- (2- (6- (2- (2- (2-([ ¹⁸ F] -fluoroethoxy) ethoxy) ethoxy) pyridine-3) of a styrylpyridine derivative. -Ilvinyl) -N-methylbenzenamine (AV-45) (Non-Patent Document 16-18), and the PIB analog 2- (3- [ ¹⁸ F] -fluoro-4-methylamino-phenyl) benzothiazole-6 All (GE-067) (Non-Patent Document 19) (FIG. 1) has been shown to be useful for imaging β-amyloid plaques in living brain tissue in phase 2 and phase 3 clinical trials. (Non-Patent Document 20).

The inventors evaluated a series of fluorinated benzofuran derivatives as candidates for ¹⁸ F-labeled tracers for imaging β-amyloid plaques with PET (Non-patent Document 21). These derivatives showed excellent affinity for Aβ aggregates both in vitro and in vivo. In particular, brain tissue by 4- (5- (2- (2- (2-fluoroethoxy) ethoxy) ethoxy) benzofuran-2-yl) -N, N-dimethylbenzenamine (FPHBF-1) (FIG. 2) Permeability was promising. However, this probe was not suitable for in vivo imaging because of slow drainage from normal mouse brain. Therefore, there is a clinical need to finely regulate the kinetics of uptake and excretion of benzofuran derivatives. In the previous results regarding brain uptake and clearance from the brain, high lipophilicity is pointed out as one of the reasons for the slow discharge from the brain (Non-Patent Documents 8, 22-24).

Recently, a fluoropyridylbenzofuran derivative, 2- (2-fluoro-6- (methylamino) pyridin-3-yl) benzofuran-5-ol (AZD4694) (FIG. 2), has been used as a cortical β-amyloid in living brain tissue. It was reported that it was promising for imaging plaque (Non-patent Document 26). However, in this document, the in vivo properties of ¹⁸ F labeling and [ ¹⁸ F] AZD4694 are not reported.

An object of the present invention is to provide a pyridylbenzofuran derivative suitable for in vivo β-amyloid plaque imaging.

The present inventors tried to develop a novel fluorinated pyridylbenzofuran derivative having low lipophilicity by replacing the phenyl group of phenylbenzofuran with a pyridyl group. A new approach called core structure fluoro-PEGylation (FPEG) for labeling derivatives with ¹⁸ F has been developed by Kung et al. Since this approach provides a simple and convenient way to incorporate ¹⁸ F into the target without significantly increasing lipophilicity, we chose FPEG for labeling of pyridylbenzofuran derivatives. The present inventors have developed a novel fluorinated ligand having a fluoropolyethyleneglycol side chain and a dimethylaminopyridyl group, 5- (5- (2- (2- (2-fluoroethoxy) ethoxy) ethoxy) benzofuran-2- Yl) -N, N-dimethylpyridin-2-amine (FPYBF-1) (FIG. 2) and several pyridylbenzofuran derivatives were synthesized. The first successful radiolabelling of pyridylbenzofuran derivatives was evaluated for in vivo imaging of β-amyloid plaques, completing the present invention.

That is, the present invention
Formula (I)

[Where,
R ₁ is a hydroxy group, a C _1-10 alkoxy group and a formula: — (CH ₂ CH ₂ O) _n —X (wherein _n represents an integer of 1 to 10 and X represents a halogen atom). Selected from the group
R ₂ is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents either a hydrogen atom or a C _1-3 alkyl group).
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently a group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a C _1-4 alkyl group, and a C _1-4 alkoxy group. Selected from)
Or a pharmaceutically acceptable salt thereof.

The present invention also provides
Formula (II)

[Wherein R ₁ represents a hydroxy group, a C _1-10 alkoxy group and a formula: — (CH ₂ CH ₂ O) _n —X (wherein _n represents an integer of 1 to 10, X represents a halogen atom Selected from the group consisting of:
R ₂ is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents a hydrogen atom or a C _1-3 alkyl group)]
Or a pharmaceutically acceptable salt thereof.

The present invention also provides any of the aforementioned compounds or a pharmaceutically acceptable salt thereof, which is labeled with a radionuclide.

The present invention also provides a composition for diagnosing amyloid-related diseases, comprising any one of the aforementioned compounds labeled with a radionuclide or a pharmaceutically acceptable salt thereof.

The present invention also provides an imaging agent for amyloid plaques, comprising any one of the above compounds labeled with a radionuclide or a pharmaceutically acceptable salt thereof.

The present invention also includes:
a. Introducing into the mammal a detectable amount of any of the aforementioned compounds labeled with a radionuclide or a pharmaceutically acceptable salt thereof;
b. Leaving the compound for a time sufficient to bind to the amyloid plaque; and c. Detecting a compound bound to one or more amyloid plaques, a method for imaging amyloid plaques is provided.

The present invention makes it possible to image amyloid plaques in brain tissue and to diagnose diseases characterized by the presence of amyloid protein aggregates such as Alzheimer's disease.

Chemical structure of PET imaging agent targeting β-amyloid plaques in AD patients. Chemical structure of benzofuran derivatives FPHBF-1, FPYBF-1, and AZD4694. FPYBF-1 vs. [ ¹²⁵ I] IMPY competition curve. In vitro autoradiography of [ ¹⁸ F] FPYBF-1. (A) Brain tissue from AD patient. (B) Brain tissue of a control subject. Ex vivo autoradiography of [ ¹⁸ F] FPYBF-1. (A) Tg2576 transgenic mouse. (B) Wild type mouse. (C) Staining of the same brain section as (A) with thioflavin-S. Competition curve for FPYBF-2 vs. [ ¹²⁵ I] IMPY. In vitro autoradiography of [ ¹⁸ F] FPYBF-2. (A) Brain tissue from AD patient. (B) Brain tissue of a control subject. [ ¹⁸ F] FPYBF-2 ex vivo autoradiography. (A) Tg2576 transgenic mouse. (B) Wild type mouse. (C) Staining of the same brain section as (A) with thioflavin-S. Purification of Re-BAT-Bp by HPLC. Re-BAT-Bp vs. [ ¹²⁵ I] IMPY competition curve. In vitro autoradiography of [ ^99m Tc] BAT-Bp. Right: Labeled with [ ^99m Tc] BAT-Bp. Left: Staining of the same section with thioflavin-S. Purification of Re-BAT-Bp-5 by HPLC. In vitro autoradiography of [ ^99m Tc] BAT-Bp-5. Right: Labeled with [ ^99m Tc] BAT-Bp-5. Left: Staining of the same section with thioflavin-S.

The compounds of the present invention
Formula (I)

[Where,
R ₁ is a hydroxy group, a C _1-10 alkoxy group and a formula: — (CH ₂ CH ₂ O) _n —X (wherein _n represents an integer of 1 to 10 and X represents a halogen atom). Selected from the group
R ₂ is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents either a hydrogen atom or a C _1-3 alkyl group).
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently a group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a C _1-4 alkyl group, and a C _1-4 alkoxy group. Selected from)
It is represented by

In a preferred embodiment, the compounds of the invention have the general formula (II)

[Wherein R ₁ represents a hydroxy group, a C _1-10 alkoxy group and a formula: — (CH ₂ CH ₂ O) _n —X (wherein _n represents an integer of 1 to 10, X represents a halogen atom Selected from the group consisting of:
R ₂ is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents a hydrogen atom or a C _1-3 alkyl group)]
It is.

Examples of the C _1-10 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, and a pentyl group.

Examples of the C _1-4 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.

Examples of halogen atoms include F, Cl, Br, and I. In a preferred embodiment, X is F.

In preferred embodiments, —NRaRb is —NH ₂ , —NHCH ₃ or —N (CH ₃ ) ₂ .

In one embodiment, R ₁ is — (CH ₂ CH ₂ O) _n —X (wherein _n represents an integer of 1 to 10 and X represents a halogen atom). n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In a preferred embodiment, n represents an integer of 1 to 3, 1 to 4, or 1 to 5.

A preferred compound of the present invention is FPYBF-1 or FPYBF-2 represented by the following formula.

FPYBF-1

FPYBF-2

In another embodiment, R ₁ is a C _1-10 alkoxy group, preferably a C _1-5 alkoxy group. In another aspect of this embodiment, R ₁ is a C _1-3 alkoxy group.

The compounds of the present invention are described in the following examples, or in Cheng et al., Bioorg Med Chem Lett, 20, 6141-44, 2010 and Ono et al., J Med Chem, 54, 2971-2979, 2011 Can be synthesized according to

In the present invention, a compound is “labeled with a radionuclide” when one or more atoms in the compound have the same atomic number but are substituted with radioactive isotopes having different mass numbers, or the compound is radioactive. It means that the nuclide is bound. As radioactive isotopes of atoms in the compound, H, C, N, O, F, Cl, Br, and the radioisotopes of I, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹⁵ O, ¹⁸ F, ³⁶ Cl, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, and ¹¹ C and ¹⁸ F are preferred. Examples of the radionuclide bonded to the compound of the present invention include ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga, or ^99m Tc, and ^99m Tc is particularly preferable. These radionuclides can be substituted for the atoms in the compound of the present invention and bonded to the compound of the present invention by a method generally used for each radionuclide.

^99m Tc is usually bound to the unlabeled compound in the form of a complex. Complexes containing ^99m Tc include complexes containing 2-hydrazinopyridine (Liu S et al, Bioconjug Chem. 1996 Jan-Feb; 7 (1): 63-71), N- (2-mercaptoethyl) -2 Complexes containing — [(2-mercaptoethyl) amino] -acetamide (Zhen W et al, J Med Chem. 1999 Jul 29; 42 (15): 2805-15), 2,2 ′-(1,2-ethane Complex containing diyldiimino) bisethanethiol (Oya S et al, Nucl Med Biol. 1998 Feb; 25 (2): 135-40), tricarbonyl complex (Schibli R et al, Bioconjug Chem. 2000 May-Jun; 11 (3): 345-51) and the like (these documents are incorporated herein by reference).

Preferred labeling compounds of the present invention are as follows.
[ ¹⁸ F] FPYBF-1

[ ¹⁸ F] FPYBF-2

[ ^99m Tc] BAT-Bp

[ ^99m Tc] BAT-Bp-5

Examples of the “pharmaceutically acceptable salt” include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, sulfate, hydrochloride, nitrate, phosphate and the like. For example, but not limited to.

The present invention also relates to a composition for diagnosing amyloid-related diseases, comprising the compound of the present invention labeled with a radionuclide or a pharmaceutically acceptable salt thereof.

The “amyloid-related disease” in the present invention means a disease in which the presence of amyloid protein aggregates is observed. Since the compound of the present invention binds to a protein having a β-sheet structure, the “amyloid-related diseases” in the present invention include amyloid proteins having a β-sheet structure such as tau, α-synuclein and prion in addition to β-amyloid. Diseases in which the presence of aggregates are observed. Specifically, the “amyloid-related disease” in the present invention includes Alzheimer's disease, Mediterranean fever, Maccle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloidosis Hereditary cerebral hemorrhage (including hereditary cerebral hemorrhage with Dutch or Icelandic amyloidosis), Down syndrome, scrapie, Kreuzfeld-Jakob disease, Kuru, Gerstmann-Stroisler-Scheinker syndrome, medullary carcinoma of the thyroid, isolated These include atrial amyloid, β ₂ -microglobulin amyloid in dialysis patients, inclusion body myositis, β ₂ -amyloid deposition in muscle wasting disease, and Langerhans type II diabetes insulinoma. Among these, the diagnostic composition of the present invention is particularly suitable for diseases in which the presence of β-amyloid (Aβ) aggregates is observed, such as Alzheimer's disease, hereditary cerebral hemorrhage with Dutch amyloidosis, and Down's syndrome. In addition, precursor symptoms of diseases that are generally not recognized as “diseases” are also included in “amyloid-related diseases” in the present invention. Examples of prodromal symptoms of such diseases include mild cognitive impairment (MCI) seen before the onset of Alzheimer's disease.

Diagnosis of amyloid-related diseases using the composition of the present invention is usually performed by administering the composition of the present invention to a subject to be diagnosed or a laboratory animal, and then taking a brain image, and the state of the compound of the present invention ( Quantity, distribution, etc.). The composition of the present invention may contain a compound labeled with a γ-emitting nuclide such as ¹²³ I, ⁶⁷ Ga, or ^99m Tc when diagnosing by computer tomography (SPECT). When a diagnosis is performed by an imaging method (PET), a compound labeled with a positron emitting nuclide such as ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁶² Cu, ⁶⁸ Ga, or ⁷⁶ Br may be included.

The method of administration of the composition of the present invention is not particularly limited, and is appropriately determined according to the type of compound and radionuclide and the condition of the subject, but is usually intradermal, intraperitoneal, vein, artery, or spinal fluid. Administered by injection or infusion. The dose of the composition of the present invention is also appropriately determined according to the kind of the compound and radionuclide and the condition of the subject. For example, in the case of an adult, the dose of the compound of the present invention is 10 ⁻¹⁰ to 10 ⁻³ per day. mg, preferably 10 ⁻⁸ to 10 ⁻⁵ mg may be administered.

Since the composition of the present invention is usually administered by injection or infusion, the composition of the present invention may contain, in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof, components usually contained in injection solutions or infusion solutions. . Such components include liquid carriers (for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol), antibacterial agents, Examples include a local anesthetic (eg, procaine hydrochloride, dibucaine hydrochloride), a buffer (eg, Tris-HCl buffer, Hepes buffer), and an osmotic pressure regulator (eg, glucose, sorbitol, sodium chloride).

The present invention also relates to an amyloid plaque imaging agent comprising the compound of the present invention or a pharmaceutically acceptable salt thereof labeled with a radionuclide. “Amyloid plaques” are formed by aggregation of amyloid proteins having a β-sheet structure. Examples of amyloid protein include β-amyloid, tau, α-synuclein, and prion. The imaging agent of the present invention is particularly suitable for imaging amyloid plaques formed by β-amyloid. The amyloid plaque imaging agent of the present invention can be prepared and used in the same manner as the composition for diagnosing amyloid-related diseases.

The present invention also provides
a. Introducing a detectable amount of a compound of the present invention or a pharmaceutically acceptable salt thereof labeled with a radionuclide into a mammal;
b. Leaving the compound for a time sufficient to bind to the amyloid plaque; and c. Detecting a compound bound to one or more amyloid plaques;
A method for imaging amyloid plaques.

“Mammals” include, but are not limited to, humans, mice, rats, rabbits, dogs, monkeys. Preferably, the “mammal” is a human.

The labeling with the radionuclide and the detection of the labeled compound may be performed as described above. That is, SPECT and PET can be used for detection, and the radionuclide may be selected according to the detection method. Moreover, introduction into mammals may be performed as described for the composition for diagnosing amyloid-related diseases.

“A detectable amount of a compound of the invention or a pharmaceutically acceptable salt thereof labeled with a radionuclide” and “a sufficient amount of time for the compound to bind to amyloid plaques” And a person skilled in the art can appropriately determine depending on the compound used and the detection method. For example, the amount and time of these can be determined by introducing various concentrations of the labeled compound into the mammal of interest, and detecting this labeled compound with the selected detection method at various times after introduction. .

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

[Example 1]
FPYBF-1

1. Synthesis of FPYBF-1 The synthesis of FPYBF-1 is shown in Scheme 1.

Scheme 1

Reagents and conditions: (a) Pd (Ph ₃ P) ₄ , Na ₂ CO ₃ (aq) / dioxane, reflux; (b) paraformaldehyde, sodium cyanoborohydride, acetic acid, room temperature; (c) BBr ₃ , CH ₂ Cl ₂ , room temperature; (d) 2- [2- (2-chloroethoxy) ethoxy] ethoxy, K ₂ CO ₃ , DMF, 100 ° C; (e) DAST, DME, 0 ° C; (f) Tosyl chloride, Pyridine, room temperature.

5- (5-Methoxybenzofuran-2-yl) pyridin-2-amine (1)

5-methoxybenzofuran-2-boronic acid (576 mg, 3.0 mmol), 2-amino-5-iodopyridine (660 mg, 3.0 mmol), and Pd (Ph ₃ ) ₄ (366 mg, 0.3 mmol) (2 M A solution of Na ₂ CO ₃ (aq) / dioxane (150 mL, 1: 1) was stirred at reflux overnight. The mixture was cooled to room temperature and 1 M NaOH (20 mL) was added. After extraction with ethyl acetate, the organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give 374 mg of compound 1 (52.1%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.85 (s, 3H), 4.67 (s, 2H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd, 1H , J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz). MS: m / z 241 (M ⁺ + H).

5- (5-Methoxybenzofuran-2-yl) -N, N-dimethylpyridin-2-amine (2)

A mixture of Compound 1 (360 mg, 1.5 mmol), paraformaldehyde (450 mg, 15 mmol), and sodium cyanoborohydride (284 mg, 4.5 mmol) in acetic acid (20 mL) was stirred overnight at room temperature. And then poured into 100 mL of water. Sodium bicarbonate was added to adjust the pH to 8-9. After extraction with ethyl acetate, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give 249 mg of compound 2 (62.0%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.15 (s, 6H), 3.85 (s, 3H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd, 1H , J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz). MS: m / z 269 (M ⁺ + H).

2- (6- (Dimethylamino) pyridin-3-yl) benzofuran-5-ol (3)

BBr ₃ (4.8 mL, 1 M solution in CH ₂ Cl ₂ ) was added dropwise to a solution of compound 2 (248 mg, 0.93 mmol) in CH ₂ Cl ₂ (20 mL) in an ice bath. The mixture was warmed to room temperature and stirred for 1 hour. Water (20 mL) was added while the reaction mixture was cooled in an ice bath. After extraction with ethyl acetate, the organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give 234 mg of compound 3 (98.9%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.15 (s, 6H), 4.89 (s, 1H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd, 1H , J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz). MS: m / z 255 (M ⁺ + H).

2- (2- (2- (2- (6- (dimethylamino) pyridin-3-yl) benzofuran-5-yloxy) ethoxy) ethoxy) ethanol (4)

To a solution of compound 3 (233 mg, 0.92 mmol) and 2- [2- (2-chloroethoxy) ethoxy] ethanol (180 μL, 1.20 mmol) in DMF (5 mL) was added anhydrous K ₂ CO ₃ (414 mg , 3.0 mmol) was added. The reaction mixture was stirred for 18 hours at 100 ° C. and poured into water. After extraction with chloroform, the organic layers were combined and dried over Na ₂ SO ₄ . The solvent was evaporated to give a residue which was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give 204 mg of compound 4 (57.2%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.15 (s, 6H), 3.60-3.64 (m, 2H), 3.69-3.72 (m, 6H), 3.85-3.89 (m, 2H), 4.16-4.19 ( m, 2H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz). MS: m / z 387 (M ⁺ + H).

5- (5- (2- (2- (2-Fluoroethoxy) ethoxy) ethoxy) benzofuran-2-yl) -N, N-dimethylpyridin-2-amine (5)

To a solution of compound 4 (136 mg, 0.35 mmol) in 1,2-dimethoxyethane (DME) (5 mL) was added DAST (100 μL, 0.70 mmol) in a dry ice-acetone bath. The reaction mixture was stirred for 1 h at room temperature and poured into saturated NaHSO ₃ solution. After extraction with chloroform, the organic layer was separated, dried over Na ₂ SO ₄ and filtered. The residue was purified by preliminary TLC (hexane: ethyl acetate = 1: 6) to give 62 mg of compound 5 (45.6%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.15 (s, 6H), 3.69-3.72 (m, 6H), 3.85-3.89 (m, 2H), 4.16-4.20 (m, 2H), 4.49-4.52 ( m, 1H), 4.60-4.63 (m, 1H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz ), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H HRJ (EI): m / z calcd for C ₂₁ H ₂₅ FN ₂ O ₄ (M ⁺ ) 388.1798, found 387.1790.

2- (2- (2- (2- (2- (6- (dimethylamino) pyridin-3-yl) benzofuran-5-yloxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate (6)

Tosyl chloride (233 mg, 1.22 mmol) was added to a solution of compound 4 (203 mg, 0.53 mmol) in pyridine (5 mL). The reaction mixture was stirred for 3 hours at room temperature. After extraction with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ . The solvent was evaporated to give a residue that was purified by preparative TLC (hexane: ethyl acetate = 1: 1) to give 233 mg of compound 6 (81.4%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.41 (s, 3H), 3.15 (s, 6H), 3.71 (m, 6H), 3.85-3.89 (m, 2H), 4.16-4.20 (m, 4H) , 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz) , 7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz) .HRMS (EI): m / z calcd for C ₂₈ H ₃₂ N ₂ O ₇ S (M ⁺ ) 540.1930, found 540.1927.

2. In vitro binding test for Aβ aggregates In order to evaluate the affinity of FPYBF-1 for Aβ aggregates, it was bound in solution using [ ¹²⁵ I] IMPY as a ligand according to a conventional method (Non-patent Documents 29 and 30). A test was conducted. Aβ (1-42) was purchased from Peptide Institute, Inc. (Osaka, Japan). The peptide was aggregated by gentle dissolution in a buffer (pH 7.4) containing 10 mM sodium phosphate and 1 mM EDTA. This solution was incubated at 37 ° C. for 42 hours with gentle and continuous shaking. 50 μL FPYBF-1 (0.008 pM-400 μM in 10% EtOH), 50 μL 0.02 nM [ ¹²⁵ I] IMPY, 50 μL Aβ (1-42) aggregates, and 850 μL 10% EtOH The mixture containing was incubated at room temperature for 3 hours. The mixture was then filtered through Whatman GF / B filter paper using a Brandel M-24 cell harvester and the radioactivity of the filter paper containing bound ¹²⁵ I ligand was measured with a γ counter. The value of 50% inhibitory concentration (IC ₅₀ ) was determined using GraphPad Prism 5.0 from the displacement curves of three independent experiments and the value of the inhibition constant (K _i ) was determined using the Cheng-Prusoff equation: K _i = IC ₅₀ / (1 + [L] / K _d ) where [L] is the concentration of [ ¹²⁵ I] IMPY used in the test and K _d is the dissociation constant of IMPY (4.2 nM). FPYBF-1 inhibited [ ¹²⁵ I] IMPY binding in a dose-dependent manner with a K _i value of 0.9 nM (FIG. 3). This suggests that FPYBF-1 has excellent affinity for Aβ (1-42) aggregates.

K _i values of FPYBF-1 is similar to the K _i values reported previously phenyl benzofuran derivative (K _i = 2.0 nM) (Non-Patent Document 21), the affinity phenyl against Aβ aggregates pyridyl benzofuran derivatives Even when substituted with a pyridyl group, it was still high. This result also shows that the benzofuran skeleton can withstand a high degree of structural modification (Non-Patent Documents 21, 22, and 31).

3. ¹⁸ Production of F-labeled FPYBF-1

Reagents and conditions: (a) Kryptofix 222, K ₂ CO ₃ , acetonitrile, 120 ° C.

[ ¹⁸ F] Fluoride is produced by Cyclotron (CYPRIS HM-18, Sumitomo Heavy Industries, Ltd., Tokyo) via the ¹⁸ O (p, n) ¹⁸ F reaction, and as an aqueous solution in water rich in ¹⁸ O. -Passed through Pak Light QMA cartridge (Waters). The cartridge was dried with N ₂ and ¹⁸ F activity was adjusted to 1.0 mL Kryptofix 222 / K ₂ CO ₃ solution (9.5 mg Kryptofix 222 and 1.7 mg K ₂ CO ₃ in acetonitrile / water (96/4). Elution). The solvent was removed at 120 ° C. under a stream of argon gas. The residue was dried twice under nitrogen gas flow at 120 ° C. azeotropically with 1 mL anhydrous acetonitrile. A solution of tosyl precursor 6 (1.0 mg) in acetonitrile (200 μL) was added to the reaction vessel containing ¹⁸ F activity. The mixture was heated at 120 ° C. for 10 minutes. Water (5 mL) was added and the mixture was passed through a conditioned Oasis HLB cartridge (3 cm ³ ) (Waters). The cartridge was washed with 10 mL water and the labeled compound was eluted with 2 mL acetonitrile. The eluted compound was purified by preparative HPLC [YMC-Pack Pro C18 column (20 mm × 150 mm), acetonitrile / water (60/40), flow rate 3.0 mL / min]. The retention time of the desired ¹⁸ F labeled product is 10.0 minutes. The radiochemical purity and specific activity, analytical HPLC [YMC-Pack Pro C18 column (4.6 mm × 0.99 mm), acetonitrile / water (60/40), flow rate 1.0 mL / min] measured by, ^[18 F FPYBF-1 was obtained with a radiochemical purity> 99% and a specific activity of 242 GBq / μmol. Specific activity was assessed by comparing the UV peak intensity of the purified ¹⁸ F labeled compound with a known concentration of a reference non-radioactive compound.

4). Biodistribution in normal mice In order to evaluate the uptake of [ ¹⁸ F] FPYBF-1 in the brain, biodistribution experiments were performed in normal mice. Animal experiments were conducted in accordance with the facility guidelines and were approved by the Kyoto University Animal Experiment Committee. Under anesthesia with isoflurane, 100 μL of [ ¹⁸ F] FPYBF-1 (185-370 kBq) containing 0.1% BSA solution was injected directly into the tail vein of ddY mice (22-25 g, male). These mice (n = 5 for each time point) were killed at 2, 10, 30, and 60 minutes after injection. The organs of interest were removed, weighed, and radioactivity was measured with an automatic gamma counter (COBRAII, Packard). The sample dose (%) / g was calculated by comparing the sample count to the diluted initial dose. The results are shown in Table 1.

[ ¹⁸ F] FPYBF-1 showed sufficiently high uptake (5.16% ID / g) in PET 2 minutes after injection, and radioactivity in the brain disappeared over time (2.44% ID / 60 at 60 minutes after injection). g). Since normal brain tissue does not have β-amyloid plaques that trap [ ¹⁸ F] FPYBF-1, radioactivity should be excreted very quickly. Thus, the rapid clearance of [ ¹⁸ F] FPYBF-1 from normal brain indicates that FPYBF-1 is suitable for detection of β-amyloid plaques in AD brain.

One way of selecting ligands having in vivo an appropriate kinetics is to use _{2 min} / brain _{60 min} ratios brain for the comparison of the discharge rate _{(brain 2 min / brain 60 min} ratio) as an indicator (Non Patent Document 32). The ratio of [ ¹⁸ F] FPYBF-1 to the brain _{2 min} / _{60 min} brain (2.1) is [ ¹⁸ F] BAY94-9172 (4.8) (Non-Patent Document 14) and [ ¹⁸ F] AV-45 (3.8) (Non- Although lower than that of Patent Document 16), it was improved compared with the previously reported value of [ ¹⁸ F] FPHBF-1 (1.0) (Non-Patent Document 21). The ^[18 F] Preferred in vivo pharmacokinetic FPYBF-1 was achieved by changing the pyridyl group a ^[18 F] FPHBF-1 of the phenyl group. In HPLC analysis, the retention times of [ ¹⁸ F] FPYBF-1 and [ ¹⁸ F] FPHBF-1 are 14.8 minutes and 36.5 minutes, respectively, indicating that the lipophilicity of [ ¹⁸ F] FPYBF-1 is [ ¹⁸ F] FPHBF-1 Suggests lower than -1. Lipophilicity is only one of the factors affecting the brain's uptake of compounds (Non-patent Document 4), but may explain the preferable pharmacokinetics of [ ¹⁸ F] FPYBF-1 in the brain. Bone uptake at 60 minutes has decreased (1.42% ID / g), indicating that there is little in vivo defluorination and relatively little interference with imaging. Suggest.

5. In vitro autoradiography Next, specific binding of [ ¹⁸ F] FPYBF-1 to β-amyloid plaques was confirmed using brain tissue sections from AD and control subjects. Postmortem brain sections (5 μm, temporal lobe) of AD patients and control subjects were incubated with [ ¹⁸ F] FPYBF-1 (444 kBq / 50 μL) for 1 hour at room temperature. The sections are then immersed in saturated Li ₂ CO ₃ (in 40% EtOH) (2 x 2 minute washes), washed with 40% EtOH (1 x 2 min washes), and rinsed with water for 30 seconds. It is. After drying, ¹⁸ F-labeled sections were exposed to BAS imaging plates (Fuji Photo Film Co., Tokyo, Japan) overnight. Autoradiographic images were obtained with a BAS5000 scanner system (Fuji Photo Film Co., Ltd.). The results are shown in FIG.

Autoradiographic images showed that β-amyloid plaques were extensively labeled in the AD brain (FIG. 4A) but not in the control brain (FIG. 4B). This result suggests that [ ¹⁸ F] FPYBF-1 shows affinity for β-amyloid plaques in addition to synthetic Aβ aggregates.

6). ^[18 F] To further clarify the ^[18 F] potential FPYBF-1 as probes for imaging of β- amyloid plaques in vivo plaque labeling biological brain tissue by FPYBF-1, Tg2576 mice (36 months of age , Male) and wild type mice (36 months old, male) as age-matched controls were ex vivo autoradiographed. Tg2576 transgenic mice show significant Aβ deposition in the cingulate cortex, dentate gyrus, hippocampal CA1 by 11-13 months of age (Non-patent Document 33), and in vitro to evaluate the specific binding of β-amyloid plaques And frequently used in in vivo experiments (Non-Patent Documents 28, 34, 35). Tg2576 transgenic mice (36 months old, male) and wild type mice (36 months old, male) were used as Alzheimer's disease model and age-matched controls, respectively. After anesthesia with 1% isoflurane, 11.1 MBq [ ¹⁸ F] FPYBF-1 (in 200 μL of 0.1% BSA solution) was injected via the tail vein. The animals were allowed to recover for 30 minutes and then killed by decapitation. The brain was immediately removed and frozen in a dry ice / hexane bath. 20 μm sections were cut and exposed overnight to BAS imaging plates (Fuji Photo Film Co., Tokyo, Japan). In this way, an ex vivo film autoradiogram was obtained. After autoradiography experiments, the same sections were stained with thioflavin-S to confirm the presence of β-amyloid plaques. For staining of thioflavin-S, sections were immersed in 0.125% thioflavin-S solution (containing 50% EtOH) for 3 minutes and washed in 50% EtOH. After drying, the sections were then examined with a microscope (Nikon, Eclipse 80i) equipped with a B-2A filter set (excitation, 450-490 nm; diachronic mirror, 505 nm; long pass filter, 520 nm). The results are shown in FIG.

By autoradiography, clear labeling of β-amyloid plaques was seen in the brain of Tg2576 mice (FIG. 5A). Such labeling was not observed in the brains of wild type mice (FIG. 5B). The presence of β-amyloid plaques was confirmed by co-staining the sections with thioflavin-S, a pathological dye commonly used for staining β-amyloid plaques (FIG. 5C). This result is consistent with the in vitro results and indicates that [ ¹⁸ F] FPYBF-1 is very selective in binding to β-amyloid in the brain.

As described above, FPYBF-1 showed high affinity for in vitro Aβ aggregates and β-amyloid plaques in sections of autopsy AD brain. FPYBF-1 also showed good uptake in the brain (5.16% ID / g at 2 minutes after injection) and excellent binding to β-amyloid plaques ex vivo in transgenic mice.

[Example 2]
FPYBF-2

1. Synthesis of FPYBF-2 The synthesis of FPYBF-2 is shown in Scheme 2.

Scheme 2

^a Reagent: (a) Pd (Ph ₃ P) ₄ , 2 M Na ₂ CO ₃ (aq) / dioxane; (b) 1) NaOMe, MeOH, (CHO) _n ; 2) NaBH ₄ ; (c) BBr ₃ , CH ₂ Cl ₂ ;
(d)

, K ₂ CO ₃ , DMF; (e) TBDMSCI, Imidazole, DCM; (f) TBAF (1M), THF; (g) (BOC) ₂ O, THF; (h) MsCI, Et ₃ N, DCM; ( i) TBAF (1M), THF; (j) TFA, DCM.

5- (5-Methoxybenzofuran-2-yl) pyridin-2-amine (1)

5-methoxybenzofuran-2-ylboronic acid (576 mg, 3.0 mmol), 5-iodopyridin-2-amine (660 mg, 3.0 mmol), and Pd (Ph ₃ ) ₄ (366 mg, 0.3 mmol) (2M Na _A solution of ₂ CO ₃ (aq) / dioxane (150 mL, 1: 1) was stirred at reflux overnight. After the mixture was cooled to room temperature, 1 M NaOH (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give 374 mg of compound 1 (52.1%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.85 (s, 3H), 4.67 (s, 2H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (d, d , 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (d, d, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz). MS: m / z 241 (M ⁺ + H).

5- (5-Methoxybenzofuran-2-yl) -N-methylpyridin-2-amine (2)

Sodium methoxide (275 mg, 5.0 mmol) was added to compound 1 (240 mg, 1.0 mmol) in methanol (15 mL) followed by paraformaldehyde (101 mg, 4.0 mmol). The solution was heated to reflux for 2 hours and cooled to 0 ° C. with an ice bath. Sodium borohydride (128 mg, 4.0 mmol) was added. The mixture was again refluxed for 1 hour and poured onto crushed ice. After extraction with ethyl acetate, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give 234 mg of compound 1 (92.1%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.98 (d, 3H, J = 5.2 Hz), 3.84 (s, 3H), 4.78 (s, 1H), 6.47 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.84 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 4.4 Hz), 7.00 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.87 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.59 (d, 1H, J = 2.8 Hz). MS: m / z 255 (M ⁺ + H).

2- (6- (Methylamino) pyridin-3-yl) benzofuran-5-ol (3)

BBr ₃ (4.8 mL, 1 M solution in CH ₂ Cl ₂ ) was added dropwise in an ice bath to a solution of compound 2 (234 mg, 0.92 mmol) (in CH ₂ Cl ₂ (20 mL)). The mixture was warmed to room temperature and stirred for 1 hour. Water (20 mL) was added while the reaction mixture was cooled in an ice bath. The mixture was extracted with ethyl acetate and the organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give 218 mg of compound 3 (99.0%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.98 (d, 3H, J = 5.2 Hz), 4.78 (s, 1H), 6.47 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.84 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 4.4 Hz), 7.00 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.87 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.59 (d, 1H, J = 2.8 Hz). MS: m / z 241 (M ⁺ + H).

2- (2- (6- (methylamino) pyridin-3-yl) benzofuran-5-yloxy) ethanol (4)

To a solution of compound 3 (197 mg, 0.82 mmol) and 2- [2- (2-chloroethoxy) ethoxy] ethanol (180 μL, 1.20 mmol) in DMF (5 mL) was added anhydrous K ₂ CO ₃ (414 mg , 3.0 mmol) was added. The reaction mixture was stirred for 18 hours at 100 ° C., poured into water and extracted with chloroform. The organic layers were combined and dried over Na ₂ SO ₄ . The solvent was evaporated to give a residue, which was purified by silica gel chromatography (hexane: ethyl acetate = 1: 6) to give 224.3 mg of compound 4 (60.3%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.98 (d, 3H, J = 5.2 Hz), 3.62 (d, 2H, J = 4.4 Hz), 3.70-3.74 (m, 6H), 3.84 (s, 2H ), 4.11 (s, 2H), 5.18 (s, 1H), 6.47 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.84 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 4.4 Hz), 7.00 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.87 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.59 (d , 1H, J = 2.8 Hz) .MS: m / z 373 (M ⁺ + H).

5- (5- (2- (tert-butyldimethylsilyloxy) ethoxy) benzofuran-2-yl) -N-methylpyridin-2-amine (5)

Compound 4 (61.2 mg, 0.17 mmol) and TBDMSCl (41 mg, 0.27 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of imidazole (24 mg, 0.34 mmol). The solution was stirred at room temperature for 2 hours. After extraction with ethyl acetate, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 6) to obtain 72.5 mg of compound 5 (87.6%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.08 (s, 6H), 0.90 (s, 9H), 2.98 (d, 3H, J = 5.2 Hz), 3.62 (d, 2H, J = 4.4 Hz), 3.70-3.74 (m, 6H), 3.84 (s, 2H), 4.11 (s, 2H), 5.18 (s, 1H), 6.47 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.84 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 4.4 Hz), 7.00 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.87 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.59 (d, 1H, J = 2.8 Hz). MS: m / z 487 (M ⁺ + H).

tert-butyl 5- (5- (2- (2- (2- (tert-butyldimethylsilyloxy) ethoxy) ethoxy) ethoxy) benzofuran-2-yl) pyridin-2-yl (methyl) carbamate (6)

Compound 5 (72.5 mg, 0.15 mmol) was dissolved in anhydrous THF (5.0 mL), followed by addition of Boc anhydride (66 mg, 0.30 mmol). The solution was refluxed overnight. After extraction with ethyl acetate, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain 37.4 mg of compound 6 (46.7%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.03 (s, 6H), 0.86 (s, 9H), 1.50 (s, 9H), 3.37 (s, 3H), 3.62-3.68 (m, 6H), 3.82 -3.88 (m, 2H), 4.09-4.12 (m, 2H), 6.86 (d, 1H, J = 4.4 Hz), 6.88 (s, 1H), 6.98 (d, 1H, J = 2.4 Hz), 7.33 ( d, 1H, J = 8.8 Hz), 7.76 (d, 1H, J = 10 Hz), 7.95 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.75 (d, 1H, J = 1.6 Hz ) MS:. m / z 587 (M + + H).

tert-Butyl 5- (5- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzofuran-2-yl) pyridin-2-yl (methyl) carbamate (7)

TBAF (1 M in THF), 0.30 mL) was added via syringe to a solution of compound 6 (37.4 mg, 0.07 mL) in THF (5 mL). The solution was stirred at room temperature for 5 hours. After extraction with ethyl acetate, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain 30.5 mg of compound 7 (93.0%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.57 (s, 9H), 3.45 (s, 3H), 3.62-3.65 (m, 2H), 3.70-3.78 (m, 6H), 3.83-3.93 (m, 2H), 4.07-4.18 (m, 2H), 6.87 (d, 1H, J = 6.8 Hz), 6.94 (s, 1H), 7.06 (d, 1H, J = 2.4 Hz), 7.40 (d, 1H, J = 9.2 Hz), 7.82 (d, 1H, J = 8.8 Hz), 8.02 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2 Hz), 8.83 (d, 1H, J = 2.8 Hz). MS: ^{m / z 473 (M + +} H).

2- (2- (2- (2- (6- (tert-butoxycarbonyl) pyridin-3-yl) benzofuran-5-yloxy) ethoxy) ethoxy) ethyl methanesulfonate (8)

Compound 7 (30.5 mg, 0.065 mmol) was dissolved in dichloromethane (5 mL), followed by addition of triethylamine (35 mg, 0.35 mmol). Methanesulfonyl chloride (25 mg, 0.21 mmol) was then added via syringe. The solution was stirred at room temperature for 3 hours. After extraction with ethyl acetate, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 6) to obtain 24.6 mg of compound 8 (74.5%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.54 (s, 9H), 3.06 (s, 3H), 3.44 (s, 3H), 3.69-3.72 (m, 6H), 3.79-3.88 (m, 2H) , 4.11-4.17 (m, 2H), 4.37-4.39 (m, 2H), 6.90 (dd, 1H, J ₁ = 9.2 Hz, J ₂ = 2.8 Hz), 6.95 (s, 1H), 7.05 (d, 1H , J = 2.4 Hz), 7.40 (d, 1H, J = 8.8 Hz), 7.83 (d, 1H, J = 8.0 Hz), 8.02 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.83 (d, 1H, J = 0.8 Hz) .HRMS (EI: m / z calcd for C ₂₆ H ₃₄ N ₂ O ₉ S (M ⁺ ) 550.1985, found 550.1989.

tert-Butyl 5- (5- (2- (2- (2-fluoroethoxy) ethoxy) ethoxy) benzofuran-2-yl) pyridin-2-yl (methyl) carbamate (9)

TBAF (1 M in THF), 0.20 mL) was added to a solution of compound 8 (27 mg, 0.05 mmol) in anhydrous THF (10 mL). The mixture was refluxed for 4 hours. After cooling to room temperature, it was subjected to ethyl acetate extraction, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain 22.3 mg of compound 9 (94.0%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.57 (s, 9H), 3.44 (s, 3H), 3.71-3.83 (m, 6H), 3.88-3.91 (m, 2H), 4.22-4.51 (m, 1H), 4.61-4.63 (m, 1H), 6.91 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 6.94 (s, 1H), 7.05 (d, 1H, J = 6.0 Hz), 7.38 (d, 1H, J = 8.8 Hz), 7.81 (d, 1H, J = 8.8 Hz), 8.02 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.82 (d, 1H, J = 2.4 Hz) .MS: m / z 475 (M ⁺ + H).

5- (5- (2- (2- (2-fluoroethoxy) ethoxy) ethoxy) benzofuran-2-yl) -N-methylpyridin-2-amine (10)

Trifluoroacetic acid (1.27 mL) was slowly added to a solution of compound 9 (22.3 mg, 0.047 mmol) in dichloromethane (2 mL). The mixture was then stirred at room temperature for 1 hour. After extraction with ethyl acetate, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain 8.9 mg of compound 10 (50.6%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.98 (d, 3H, J = 5.2 Hz), 3.71-3.80 (m, 6H), 3.79-3.88 (m, 2H), 4.11- 4.18 (m, 2H) , 4.49-4.51 (m, 1H), 4.61-4.63 (m, 1H), 4.80 (s, 1H), 6.45 (d, 1H, J = 8.8 Hz), 6.75 (s, 1H), 6.85 (dd, 1H , J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.01 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 9.2 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.59 (d, 1H, J = 2 Hz). HRMS (EI: m / z calcd for C ₂₀ H ₂₃ FN ₂ O ₄ (M ⁺ ) 374.1642, found 374.1650.

2. In vitro binding test for Aβ aggregates As described in Example 1, the affinity of FPYBF-2 for Aβ aggregates was evaluated. The results are shown in FIG. The inhibition constant of FPYBY-2 was Ki = 2.41 ± 0.11 nM.

3. ¹⁸ Production of F-labeled FPYBF-2

Reagents and conditions: (a) Kryptofix 222 / K ₂ CO ₃ , ¹⁸ F, MeCN, 120 ° C. for 5 minutes; (b) 10% HCl (aq), 120 ° C. for 5 minutes.

[ ¹⁸ F] Fluoride is produced by Cyclotron (CYPRIS HM-18, Sumitomo Heavy Industries, Ltd., Tokyo) via the ¹⁸ O (p, n) ¹⁸ F reaction, and as an aqueous solution in water rich in ¹⁸ O. -Passed through Pak Light QMA cartridge (Waters). The cartridge was dried with N ₂ and ¹⁸ F activity was adjusted to 1.0 mL Kryptofix 222 / K ₂ CO ₃ solution (9.5 mg Kryptofix 222 and 1.7 mg K ₂ CO ₃ in acetonitrile / water (96/4). Elution). The solvent was removed at 120 ° C. under a stream of argon gas. The residue was dried twice under nitrogen gas flow at 120 ° C. azeotropically with 1 mL anhydrous acetonitrile. A solution of mesylate precursor 8 (1.0 mg) in acetonitrile (200 μL) was added to the reaction vessel containing ¹⁸ F activity. The mixture was heated at 120 ° C. for 5 minutes and cooled for 1 minute. HCl (10% aqueous solution, 450 μL) was then added and the mixture was again heated at 120 ° C. for 5 minutes. Aqueous NaOH was added to adjust the pH to basic (pH 8-9). The mixture was extracted with ethyl acetate (1 mL × 2), and the solvent was removed under nitrogen gas. The residue was purified by preparative HPLC [YMC-Pack Pro C18 column (20 mm × 150 mm), acetonitrile / water (70/30), flow rate 4.0 mL / min]. The retention time of the desired ¹⁸ F labeled product is 13.3 minutes. The radiochemical purity and specific activity, analytical HPLC [YMC-Pack Pro C18 column (4.6 mm × 0.99 mm), acetonitrile / water (50/50), flow rate 1.0 mL / min] measured by, ^[18 F ] FPYBF-2 was obtained with a radiochemical purity> 99% and a specific activity of 242 GBq / μmol. Specific activity was assessed by comparing the UV peak intensity of the purified ¹⁸ F labeled compound with a known concentration of a reference non-radioactive compound.

4). Biodistribution in normal mice As described in Example 1, the biodistribution of [ ¹⁸ F] FPYBF-2 was evaluated. For the stomach and intestine, the proportion of radiation dose in each organ was calculated by comparing the tissue count to an appropriately diluted aliquot of injectable material. The results are shown in Table 2.

5. In Vitro Autoradiography As described in Example 1, specific binding of [ ¹⁸ F] FPYBF-2 to β-amyloid plaques was confirmed. The results are shown in FIG.

6). In vivo plaque labeling with [ ¹⁸ F] FPYBF-2 As described in Example 1, binding of [ ¹⁸ F] FPYBF-2 to β-amyloid plaques was confirmed in Tg2576 transgenic mice. The results are shown in FIG.

[Example 3]
^99m Tc / Re-BAT-Bp

M: ^99m Tc / Re

1. Synthesis of Re-BAT-Bp The synthesis of Re-BAT-Bp is shown in Scheme 3.

Scheme 3

Reagents: (a) Pd (Ph ₃ P) ₄ , 2 M Na ₂ CO ₃ (aq) / dioxane; (b) paraformaldehyde, sodium cyanoborohydride, acetic acid; (c) BBr ₃ , CH ₂ Cl ₂ ; (d) 1,3-Dibromopropane, CH ₃ CN, K ₂ CO ₃ ; (e) Tr-Boc-BAT, CH ₃ CN, DIPEA; (f) Triethylsilane, TFA; (g) (Ph ₃ P) ₂ ReOCl ₃ , AcONa, CH ₂ Cl ₂ / MeOH.

5- (5-Methoxybenzofuran-2-yl) pyridin-2-amine (1)

5-methoxybenzofuran-2-boronic acid (576 mg, 3.0 mmol), 2-amino-5-iodopyridine (660 mg, 3.0 mmol), and Pd (Ph ₃ ) ₄ (366 mg, 0.3 mmol) (2 M A solution of Na ₂ CO ₃ (aq) / dioxane (150 mL, 1: 1) was stirred at reflux overnight. The mixture was cooled to room temperature and 1 M NaOH (20 mL) was added. After extraction with ethyl acetate, the organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give 374 mg of compound 1 (52.1%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.85 (s, 3H), 4.67 (s, 2H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd, 1H , J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz). MS: m / z 241 (M ⁺ + H).

5- (5-Methoxybenzofuran-2-yl) -N, N-dimethylpyridin-2-amine (2)

A mixture of Compound 1 (360 mg, 1.5 mmol), paraformaldehyde (450 mg, 15 mmol), and sodium cyanoborohydride (284 mg, 4.5 mmol) in acetic acid (20 mL) was stirred overnight at room temperature. And then poured into 100 mL of water. Sodium carbonate was added to adjust the pH to 8-9. After extraction with ethyl acetate, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give 249 mg of compound 2 (62.0%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.15 (s, 6H), 3.85 (s, 3H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd, 1H , J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz). MS: m / z 269 (M ⁺ + H).

2- (6- (Dimethylamino) pyridin-3-yl) benzofuran-5-ol (3)

BBr ₃ (4.8 mL, 1 M solution in CH ₂ Cl ₂ ) was added dropwise in a ice bath to a solution of compound 2 (248 mg, 0.93 mmol) in CH ₂ Cl ₂ (20 mL). The mixture was warmed to room temperature and stirred for 1 hour. Water (20 mL) was added while the reaction mixture was cooled in an ice bath. After extraction with ethyl acetate, the organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give 234 mg of compound 3 (98.9%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.15 (s, 6H), 4.89 (s, 1H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd, 1H , J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz). MS: m / z 255 (M ⁺ + H).

5- (5- (3-Bromopropoxy) benzofuran-2-yl) -N, N-dimethylpyridin-2-amine (4)

To a solution of compound 3 (324.9 mg, 1.27 mmol) in CH ₃ CN (20 mL) was added K ₂ CO ₃ (216 mg, 1.57 mmol) and 1,3-dibromopropane (0.65 mL, 6.4 mmol). . The mixture was heated to reflux for 18 hours, cooled to room temperature and then evaporated to dryness. The residue was dissolved in CHCl ₃ and washed with brine. The organic layer was dried over Na ₂ SO ₄ and evaporated to dryness. The crude product was subjected to silica gel chromatography (ethyl acetate: hexane = 3: 7) to obtain 275 mg of compound 4 (yield 73.2%).
¹ H NMR (400 MHz, CDCl ₃ ): δ2.09 (t, 2H, J = 6.4 Hz), 3.09 (s, 6H), 3.60 (t, 2H, J = 6.4 Hz), 4.08 (t, 2H, J = 5.8 Hz), 6.48 (s, 1H), 6.68 (s, 1H), 6.80 (d, 1H, J = 6.4 Hz), 6.96 (s, 1H), 7.33 (d, 1H, J = 8.8 Hz) , 7.79 (d, 1H, J = 9.2 Hz), 8.64 (s, 1H). MS: m / z 375 (M ⁺ + H).

tert-Butyl 2-((3- (2- (6- (dimethylamino) pyridin-3-yl) benzofuran-6-yloxy) propyl) (2- (tritylthio) ethyl) amino) ethyl (2- (tritylthio) Ethyl) carbamate (5)

Compound 4 (272 mg, 0.72 mmol) and tert-butyl 2- (tritylthio) ethyl (2- (2- (tritylthio) ethylamino) ethyl) carbamate (TRT-Boc-BAT) (550 mg, 0.72 mmol) (acetonitrile (In 30 mL) was added DIPEA (225 μL, 1.45 mmol). The reaction mixture was heated to reflux for 12 hours. When the solvent was evaporated, a saturated NaCl solution was added, extracted with CHCl ₃ , the organic layers were combined, dried over Na ₂ SO ₄ and evaporated to dryness. The crude product was subjected to silica gel chromatography (ethyl acetate: hexane = 3: 7) to obtain 343.6 mg of compound 5 (yield 45.0%).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.26 (s, 9H), 1.61 (s, 2H), 2.16-2.30 (m, 10H), 2.77-2.87 (m, 4H), 2.97 (s, 6H ), 3.81 (s, 2H), 6.40 (d, 1H, J = 9.2 Hz), 6.55 (s, 1H), 6.66 (d, 1H, J = 6.4 Hz), 6.84 (s, 1H), 7.03-7.20 (m, 19H), 7.21-7.31 (m, 12H), 7.71 (d, 1H, J = 9.2 Hz), 8.55 (s, 1H) .HRMS (FAB +): m / z calcd for C ₆₇ H ₇₁ N ₄ O ₄ S ₂ (MH ⁺ ) 1059.4917, found 1059.4910.

Re-BAT-Bp (6)
To a solution of compound 5 (137.6 mg, 0.13 mmol) in TFA (6 mL) was added triethylsilane (0.29 mL) and stirred for 10 minutes, then the solvent was removed under a stream of nitrogen gas. The residue was dissolved in 10 mL CH ₂ Cl ₂ and (Ph ₃ P) ₂ ReOCl ₃ (217 mg, 0.26 mmol) and 1 M sodium acetate (in methanol (7 mL)) were added. The reaction mixture was heated to reflux for 4 hours and then cooled to room temperature. Ethyl acetate (60 mL) was added and the mixture was filtered. The solvent was evaporated to give a residue, which was purified by silica gel chromatography (CHCl ₃ : CH ₃ OH = 10: 1) to give 29 mg of compound 6 (33% yield).
¹ H NMR (400 MHz, CDCl ₃ ): δ2.27-2.34 (m, 2H), 2.98-3.06 (m, 2H), 3.16 (s, 6H), 3.28-3.47 (m, 2H), 3.78-3.93 (m, 2H), 4.07-4.33 (m, 6H), 6.56 (d, 1H, J = 8.8 Hz), 6.75 (s, 1H), 6.80 (d, 1H, J = 6.4 Hz), 6.98 (s, 1H), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (d, 1H, J = 9.2 Hz), 8.65 (s, 1H) .HRMS (FAB +): m / z calcd for C ₂₄ H ₃₂ N ₄ O ₃ ReS ₂ (MH ⁺ ) 675.1471, found 675.1469.

2. Purification of Re-BAT-Bp The results of HPLC are shown in FIG.

3. Binding test to Aβ aggregates in vitro As described in Example 1, binding tests were performed using 50 μL Re-BAT-Bp (0.008 pM-400 μM in 10% EtOH). The results are shown in FIG. The IC ₅₀ of Re-BAT-Bp was 13.6 ± 0.30 (nM).

4). Analysis by ^99m T labeling reaction and RP-HPLC

1) TFA, Et ₃ SiH; 2) CH ₃ CN, 0.1 N HCl, ^99m Tc-GH.

To a solution of sodium heptanoate dihydrate (2 g, 7.04 mmol) (in nanopure water (25 mL)), add 0.75 mL of SnCl ₂ · 2H ₂ O solution [12 mg of Tin (II) chloride dihydrate ( 53.2 mmol) dissolved in 15 mL 0.1 M HCl] was added. The pH of this solution was adjusted to pH 8.5-9.0 with a small amount of 0.1 M NaOH and then lyophilized to obtain Sn glucoheptonic acid (SnGH). SnGH (1 mg) was added to Na ^99m TcO ₄ solution (200 μL) and reacted at room temperature for 10 minutes to obtain a ^99m TcGH solution. Triethylsilane (10 μL) was mixed with a solution of compound 5 (0.5 mg) (in TFA (200 μL)), and then the solvent was removed under a stream of nitrogen gas. The residue was dissolved in acetonitrile (200 μL) and 0.1 M HCl (15 μL) and ^99m TcGH solution (200 μL) were added. The reaction mixture was heated to 80-90 ° C. for 10 minutes. After cooling to room temperature, the mixture was purified by RP-HPLC to give [ ^99m Tc] BAT-Bp. [ ^99m Tc] BAT-Bp was analyzed by RP-HPLC for analysis using a Cosmosil C ₁₈ column and the solvent was H ₂ O / acetonitrile (0:00 (start) 3/2 → 30:00 3/7). And analyzed at a flow rate of 1.0 mL / min. Absorption of the complex was measured at 254 nm and ^99m Tc-labeled radioactivity was recorded for 60 minutes.

5. Biodistribution in normal mice As described in Example 1, 100 μL of [ ^99m Tc] BAT-Bp (4 μCi) -containing physiological saline was injected into the tail vein of ddY mice (22-25 g, male). . The results are shown in Table 3.

6). In Vitro Autoradiography Tg2576 and control wild-type mouse brain sections (10 μm) were incubated with [ ^99m Tc] BAT-Bp (93 kBq / 200 μL) for 1 hour at room temperature. The sections were then washed with 50% EtOH (twice for 2 minutes) and rinsed with water for 30 seconds. After drying, ^99m Tc-labeled sections were exposed to BAS imaging plates (Fuji Photo Film Co., Tokyo, Japan) overnight. Autoradiographic images were obtained with a BAS5000 scanner system (Fuji Photo Film Co., Ltd.). The results are shown in FIG. [ ^99m Tc] BAT-Bp labeled β-amyloid plaques in Tg2576 mouse brain sections, but not wild-type mouse brain sections.

[Example 4]
^99m Tc / Re-BAT-Bp-5

M: ^99m Tc / Re

1. Synthesis of Re-BAT-Bp-5 The synthesis of Re-BAT-Bp-5 is shown in Scheme 4.

Scheme 4

Reagents: (a) Pd (Ph ₃ P) ₄ , 2 M Na ₂ CO ₃ (aq) / dioxane; (b) paraformaldehyde, sodium cyanoborohydride, acetic acid; (c) BBr ₃ , CH ₂ Cl ₂ ; (d) 1,5-Dibromopropane, CH ₃ CN, K ₂ CO ₃ ; (e) Tr-Boc-BAT, CH ₃ CN, DIPEA; (f) Triethylsilane, TFA; (g) (Ph ₃ P) ₂ ReOCl ₃ , AcONa, CH ₂ Cl ₂ / MeOH.

5- (5- (5-Bromopentoxy) benzofuran-2-yl) -N, N-dimethylpyridin-2-amine (4)

Compounds 1 to 3 were synthesized as described in Example 3. To a solution of compound 3 (154.7 mg, 0.61 mmol) in CH ₃ CN (20 mL) was added K ₂ CO ₃ (216 mg, 1.57 mmol) and 1,3-dibromopropane and 1,5-dibromopentane (139 mg , 0.61 mmol) was added. The mixture was heated to reflux for 18 hours, cooled to room temperature and then evaporated to dryness. The residue was dissolved in CHCl ₃ and washed with brine. The organic layer was dried over Na ₂ SO ₄ and evaporated to dryness. The crude product was subjected to silica gel chromatography (ethyl acetate: hexane = 3: 7) to obtain 275 mg of compound 4 (yield 50.2%).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.48-1.56 (m, 2H), 1.67-1.72 (m, 2H), 1.79-1.86 (m, 2H), 3.01 (s, 6H), 3.30-3.34 (m, 2H), 3.84-3.87 (m, 2H), 6.40 (d, 1H, J = 8.8 Hz), 6,61 (s, 1H), 6.70 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 6.85 (d, 1H, J = 2.8 Hz), 7.24 (d, 1H, J = 8.8 Hz), 7.71 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.54 ( d, 1H, J = 2.0 Hz ) MS:. m / z 404 (M + + H).

tert-Butyl 2-((5- (2- (6- (dimethylamino) pyridin-3-yl) benzofuran-5-yloxy) pentyl) (2- (tritylthio) ethyl) amino) ethyl (2- (tritylthio) Ethyl) carbamate (5)

Compound 4 (124.4 mg, 0.31 mmol) and tert-butyl 2- (tritylthio) ethyl (2- (2- (tritylthio) ethylamino) ethyl) carbamate (TRT-Boc-BAT) (237.2 mg, 0.31 mmol) (acetonitrile (In 20 mL) was added DIPEA (96.2 μL, 0.62 mmol). The reaction mixture was heated to reflux for 12 hours. When the solvent was evaporated, a saturated NaCl solution was added, extracted with CHCl ₃ , the organic layers were combined, dried over Na ₂ SO ₄ and evaporated to dryness. The crude product was subjected to silica gel chromatography (ethyl acetate: hexane = 3: 7) to obtain 343.6 mg of compound 5 (yield 45.0%).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.28 (s, 13H), 1.65 (m, 2H), 2.17 (m, 10H), 2.88 (m, 4H), 3.03 (s, 6H), 3.85 ( m, 2H), 6.45 (d, 1H, J = 9.2 Hz), 6.62 (s, 1H), 6.72 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 6.88 (d, 1H, J = 2.4 Hz), 7.10 (m, 19H), 7.15 (m, 12H), 7.75 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.56 (d, 1H, J = 2.4 Hz). HRMS (FAB +): m / z calcd for C ₆₉ H ₇₄ N ₄ O ₄ S ₂ (MH ⁺ ) 1087.5230, found 1087.5238.

Re-BAT-Bp-5 (6)
To a solution of compound 5 (86.2 mg, 0.079 mmol) in TFA (3 mL) was added triethylsilane (0.29 mL) and stirred for 10 minutes, then the solvent was removed under a stream of nitrogen gas. The residue was dissolved in 10 mL CH ₂ Cl ₂ and (Ph ₃ P) ₂ ReOCl ₃ (135 mg, 0.15 mmol) and 1 M sodium acetate (in methanol (5 mL)) were added. The reaction mixture was heated to reflux for 4 hours and then cooled to room temperature. Ethyl acetate (60 mL) was added and the mixture was filtered. The solvent was evaporated to give a residue, which was purified by silica gel chromatography (CHCl ₃ : CH ₃ OH = 10: 1) to give 17 mg of compound 6 (yield 30%).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.56-1.63 (m, 6H), 1.75-1.94 (m, 4H), 2.96-3.03 (m, 2H), 3.16 (s, 6H), 3.22-3.39 (m, 4H), 3.76-3.86 (m, 2H), 4.01-4.04 (m, 2H), 4.09-4.15 (m, 2H), 6.58 (d, 1H, J = 9.2 Hz), 6.75 (s, 1H ), 6.82 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 6.99 (d, 1H, J = 2.8 Hz), 7.36 (d, 1H, J = 8.8 Hz), 6.99 (d, 1H , J = 2.8 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.88 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 8.65 (d, 1H, J = 2.4 Hz). HRMS (FAB +): m / z calcd for C ₂₆ H ₃₅ N ₄ O ₃ ReS ₂ (MH ⁺ ) 703.1784, found.703.1781.

2. Purification of Re-BAT-Bp-5 The results of HPLC are shown in FIG.

3. Analysis by ^99m T labeling reaction and RP-HPLC

1) TFA, Et ₃ SiH; 2) CH ₃ CN, 0.1 N HCl, ^99m Tc-GH.

[ ^99m Tc] BAT-Bp-5 was obtained as described in Example 3 and analyzed by RP-HPLC.

4). Biodistribution in normal mice As described in Example 1, 100 μL of [ ^99m Tc] BAT-Bp-5 (4 μCi) -containing physiological saline was added to the tail vein of ddY mice (22-25 g, male). Injected. The results are shown in Table 4.

5. In vitro autoradiography [ ^99m Tc] BAT-Bp-5 was confirmed to bind to β-amyloid plaques of Tg2567 transgenic mice as described in Example 3 (FIG. 13).

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Claims (22)

1. Formula (I)
   

   

   [Where,
   R ₁ is a hydroxy group, a C _1-10 alkoxy group and a formula: — (CH ₂ CH ₂ O) _n —X (wherein _n represents an integer of 1 to 10 and X represents a halogen atom). Selected from the group
   R ₂ is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents either a hydrogen atom or a C _1-3 alkyl group).
   R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently a group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a C _1-4 alkyl group, and a C _1-4 alkoxy group. Selected from)
   Or a pharmaceutically acceptable salt thereof.
2. Formula (II)
   

   

   [Wherein R ₁ represents a hydroxy group, a C _1-10 alkoxy group and a formula: — (CH ₂ CH ₂ O) _n —X (wherein _n represents an integer of 1 to 10, X represents a halogen atom Selected from the group consisting of:
   R ₂ is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents a hydrogen atom or a C _1-3 alkyl group)]
   The compound of Claim 1 represented by these, or its pharmaceutically acceptable salt.
3. R ₁ is a hydroxy group, a C _1-3 alkoxy group and a formula: — (CH ₂ CH ₂ O) _n —X (wherein _n represents an integer of 1 to 10, and X represents a halogen atom)
   The compound according to claim 2 or a pharmaceutically acceptable salt thereof selected from the group consisting of:
4. The compound according to claim 1 or 2, wherein R ₁ is-(CH ₂ CH ₂ O) _n -X (wherein _n represents an integer of 1 to 10 and X represents a halogen atom) or a compound thereof A pharmaceutically acceptable salt.
5. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein n is an integer of 1 to 5.
6. The compound according to claim 4, wherein X is F, or a pharmaceutically acceptable salt thereof.
7. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
   

   
8. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
   

   
9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₁ is a C _1-10 alkoxy group.
10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₁ is a C _1-3 alkoxy group.
11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is labeled with a radionuclide.
12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the radionuclide is ¹¹ C, ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga, or ^99m Tc.
13. 13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is labeled with ¹⁸ F.
14. 14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof represented by the following formula:
    

    
15. 14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof represented by the following formula:
    

    
16. 13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is labeled with ^99m Tc.
17. The compound according to claim 16, which is represented by the following formula, or a pharmaceutically acceptable salt thereof.
    

    
18. The compound according to claim 16, which is represented by the following formula, or a pharmaceutically acceptable salt thereof.
    

    
19. A composition for diagnosing amyloid-related diseases, comprising the compound according to any one of claims 11 to 18 or a pharmaceutically acceptable salt thereof.
20. Amyloid-related diseases include Alzheimer's disease, Mediterranean fever, Maccle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, scrapie, Kreuz Feld-Jakob disease, Kourou, Gerstmann-Stroisler-Scheinker syndrome, medullary thyroid cancer, isolated atrial amyloid, β ₂ -microglobulin amyloid in dialysis patients, inclusion body myositis, β ₂ -amyloid deposition in muscle wasting disease 20. The composition of claim 19, wherein the composition is selected from the group consisting of: and Langerhans type II diabetes insulinoma.
21. An amyloid plaque imaging agent comprising the compound according to any one of claims 11 to 18 or a pharmaceutically acceptable salt thereof.
22. Less than:
    a. Introducing a detectable amount of a compound according to any of claims 11 to 18 or a pharmaceutically acceptable salt thereof into a mammal;
    b. Leaving the compound for a time sufficient to bind to the amyloid plaque; and c. Detecting a compound bound to one or more amyloid plaques, the method for imaging amyloid plaques.

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