KR101291037B1 - Resveratrol derivatives and styryl five-membered aromatic compounds and their use of binding and diagnostic imaging agents for beta-amyloid plaques - Google Patents

Abstract

The present invention relates to the use of resveratrol derivatives and styryl-pentagonal aromatic compounds and binders and diagnostic imaging agents for beta-amyloid plaques thereof. Beta-amyloid plaques and neurofibrillary tangles are widely known as the etiology of Alzheimer's disease, and thus, novel styryltriazole derivatives (( E ) -1- (2- [ ¹⁸ F) labeled with radioisotopes among the derivatives of the present invention. ] Fluoroethyl) -4- (4- N , N -dimethylaminostyryl) -1 H -1,2,3-triazole) is a beta-amyloid plaque because it has excellent brain permeability and brain pharmacokinetics in normal mice. In the case of Alzheimer's disease, which is highly accumulated, it may be used for the treatment of Alzheimer's disease by binding to beta-amyloid plaques, and the derivative of the present invention labeled with radioisotopes may be used for diagnosis of Alzheimer's disease.

Description

RESVERATROL DERIVATIVES AND STYRYL FIVE-MEMBERED AROMATIC COMPOUNDS AND THEIR USE OF BINDING AND DIAGNOSTIC IMAGING AGENTS FOR BETA-AMYLOID PLAID

The present invention relates to the use of resveratrol derivatives and styryl-pentagonal aromatic compounds and binders and diagnostic imaging agents for beta-amyloid plaques thereof.

As the population ages, the prevalence of dementia is also increasing rapidly. The current dementia population is estimated at 36 million people, doubling every 20 years (Prince M, Jackson J. World Alzheimer Report. London, England: Alzheimer's Disease International; 2009), and in the United States, new dementia every 70 seconds. The patient is occurring.

About 70% of people with dementia are Alzheimer's disease, and the cause of the dementia is unknown, but after analysis of their brain tissue, amyloid plaques formed by accumulation of beta-amyloid peptides between neurons. And the presence of neurofibrillary tangles formed by hyperphosphorylated tau protein filaments in neurons (Ginsberg SD, Schmidt ML, Crino PB, Eberwine JH, Lee VMY, Trojanowski JQ. Molecular pathology of Alzheimer's disease and Cerebral cortex: neurodegenerative and age-related changes in structure and function of cerebral cortex; Kluwer Academic / Plenum: New York, 1999: pp 603-654; Lee VM, Trojanowski JQ. Neurodegenerative tauopathies: human disease and transgenic mouse models Neuron 1999; 24: 507-510; Selkoe DJ. The origins of Alzheimer disease: a is for amyloid. JAMA 2000; 283: 1615-1617). Among the beta-amyloid peptides, amyloid precursor protein is cut by beta and gamma-secretase, mainly 42 (beta-amyloid (1-42)) or 40 amino acids (beta-amyloid (1-40). It consists of)). Accumulation of these beta-amyloid peptides is an early etiology prior to brain damage and the development of lumps of nerve fibers (Naslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. JAMA 2000; 283: 1571-1577). Recently, methods for inhibiting or eliminating beta-amyloid production have been studied for the treatment of Alzheimer's disease. In addition, methods for diagnosing beta-amyloid plaques in the brain of Alzheimer's disease patients using ligands that bind to beta-amyloid plaques are being studied because early diagnosis of Alzheimer's disease may affect the prognosis of the disease. Ligands that specifically bind to beta-amyloid plaques are based on staining agents used to stain beta-amyloid plaques and neurofibrillary masses in brain tissues after Alzheimer's disease, such as Congo red, chrysamine-G, and thioflavin-T. Was developed. Congo red and chrysamine-G were studied labeled with radioactive iodine or technetium-99m, but did not cross the blood brain barrier well (Mathis CA, et al. Synthesis of a lipophilic, radioiodinated ligand with high affinity to amyloid protein in Alzheimer's disease brain tissue.J. Labeled.Compd.Radiopharm. 1997; 40: 94-95; Dezutter NA, et al. Preparation of ^{99 m} Tc-N ₂ S ₂ conjugates of Chrysamine G, potential probes for the β-amyloid protein of Alzheimer's disease.J. Label.Compd.Radiopharm. 1999; 42: 309-324; Dezutter NA, et al. ^{99 m} Tc-MAMA-Chrysamine G, a probe for β-amyloid protein of Alzheimer's disease.Eur. J. Nucl Med. 1999; 26: 1392-1399).

FDDNP was developed by introducing fluoromethyl groups into DDNP, a lipophilic and neutral dye. [ ¹⁸ F] FDDNP penetrates the blood brain barrier well due to its high lipophilic properties (log P = 3.92), but it is nonspecific binding in the brain. This is known to be high. This radioligand has been reported to reflect both beta-amyloid plaques and nerve fiber masses in PET images of patients with Alzheimer's disease (Agdeppa ED, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthaylethylidene derivatives as positron emission tomography imaging probes of β-amyloid plaques in Alzheimer's disease.J. Neurosci. 2001; 21: RC189; Barrio JR, et al. PET imaging of tangles and plaques in Alzheimer disease with a highly hydrophobic probe.J. Label.Compd. Radiopharm. 1999 42: S194-195).

Thioflavin-T was transformed into a neutral structure to better penetrate the blood brain barrier. Representative ligand [ ¹¹ C] 6-OH-BTA-1 ([ ¹¹ C] PIB, K _i = 0.87 nM) is a benzothiazole derivative, which is the frontal cortex, temporal parietal cortex, whole and posterior cortex in Alzheimer's disease brain. , High intake in the striatum, consistent with a known distribution pattern of beta-amyloid plaques in the Alzheimer's disease brain (Mathis CA, et al. Synthesis and evaluation of ¹¹ C-labeled 6-substituted 2-arybenzothiazoles as amyloid imaging agents.J. Med. Chem. 2003; 46: 2740-2754; Engler H, et al. First human study with a benzothiazole amyloid-imaging agent in Alzheimer's disease and control subjects. Neurobiol.Aging 2002; 23: S429; Klunk WE , et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann. Neurol. 2004; 55: 306-319). However, the short half-life (20 minutes) of ¹¹ C limits the clinical use.

Recently, compounds with ¹⁸ F (110 minutes) with a half-life longer than ¹¹ C have been developed. PIB derivative 3 '-[ ¹⁸ F] F-PIB ([ ¹⁸ F] GE067, 3'-F-PIB: K _i = 0.74 nM) and styryl derivative [ ¹⁸ F] AV-1 ([ ¹⁸ F] BAY94-9172, AV-1: K _i = 2.22 nM) and [ ¹⁸ F] AV-45 (AV-45: K _i = 2.87 nM) are useful for imaging beta-amyloid plaques using PET in Alzheimer's disease patients (Koole M, et al. Whole-body biodistribution and radiation dosimetry of ¹⁸ F-GE067: a radioligand for in vivo brain amyloid imaging. J. Nucl. Med. 2009; 50: 818-822; Rowe CC, et al. Imaging of amyloid β in Alzheimer's disease with ¹⁸ F-BAY94-9172, a novel PET tracer: proof of mechanism.Lancet Neurol. 2008; 7: 129-135; Zhang W, et al. ¹⁸ F-Labeld styrylpyridines as PET agents for amyloid plaque imaging.Nucl. Med. Biol. 2007; 34: 89-97).

Resveratrol ((E) -5- (4- hydroxystyryl) benzene-1,3-diol; (E) -5- (4- hydroxy-styryl) benzene-1,3-diol) is a poly contained in grapes As a phenol, it is known to promote beta-amyloid intracellular degradation and to have a neuroprotective effect on the cytotoxicity of beta-amyloid (Han YS, et al. Neuroprotective effects of resveratrol against β-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br. J. Pharmacol. 2004; 141: 997-1005; Marambaud P, et al. Resveratrol promotes clearance of Alzheimer's disease amyloid-β peptides.J. Biol. Chem. 2005; 280: 37377-37382).

Styryl compounds are known to specifically bind to beta-amyloid plaques but only styrylbenzene and styrylpyridine derivatives have been reported. Therefore, the styryltriazole compound synthesized using the click reaction is expected to have high utility as a binder or a diagnostic agent for beta-amyloid plaques. Click reactions are widely used to synthesize triazole compounds from terminal alkyne and azide compounds, and are used in many fields such as drug development because they often use efficient and mild conditions and often do not require protecting groups or purification processes (Kolb, HC, et al, Click chemistry: diverse chemical function from a few good reactions.Angew. Chem. Int. Ed. 2001; 40: 2004-2021). In addition, pentagonal aromatic compounds pyrrole, imidazole, pyrazole, tetrazole, furan, isoxazole, oxazole, thiophene, thiazole, isothiazole and the like may be used instead of triazole.

Therefore, resveratrol derivatives and styryl-pentagonal aromatic compounds that specifically bind to beta-amyloid plaques and diagnostic imaging agents using them may be useful for the early diagnosis of Alzheimer's disease patients. It may be useful to predict the therapeutic effect.

The present invention provides a novel compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition as a binder and a diagnostic imaging agent for beta-amyloid plaques comprising the same, and the present invention also provides a beta- for preventing, treating and diagnosing Alzheimer's disease. Amyloid plaques provide the use of binders and diagnostic imaging agents.

The present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

Where

R ₁ To R ₁₀ are each independently,

H, OH, halo, alkyl, haloalkyl, alkyloxy, haloalkyloxy, amino, monoalkylamino, dialkylamino, halopolyethyleneoxy, [ ¹¹ C] monoalkylamino, [ ¹²³ I] iodoalkyloxy, [ ¹²⁴ I] iodoalkyloxy, [ ¹²⁵ I] iodoalkyloxy, [ ¹³¹ I] iodoalkyloxy, [ ¹²³ I] iodopolyethyleneoxy, [ ¹²⁴ I] iodopolyethyleneoxy, [ ¹²⁵ I] iodo Polyethyleneoxy, [ ¹³¹ I] iodopolyethyleneoxy, [ ⁷⁶ Br] bromoalkyloxy, [ ⁷⁶ Br] bromopolyethyleneoxy, [ ⁷⁷ Br] bromoalkyloxy, [ ⁷⁷ Br] bromopolyethyleneoxy, [ ¹⁸ F] fluoroalkyloxy or [ ¹⁸ F] fluoropolyethyleneoxy;

Here, only one substituent of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R _{6 ,} R ₇ , R ₈ , R _9, and R ₁₀ may be a substituent containing a radioisotope.

In the present invention, haloalkyl in the compound of Formula 1 is fluoroalkyl, chloroalkyl, bromoalkyl or iodoalkyl, wherein the halo is fluoro, chloro, bromo, or iodo; Said alkyl is C ₁ -C ₈ alkyl; The halopolyethyleneoxy provides a compound or a pharmaceutically acceptable salt thereof characterized in that n = 1-8 halo (ethoxy) n-.

Furthermore, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula 1 is any one selected from the group consisting of the following compounds:

,

,

R=F, ¹⁸F

,

,

R = F, ¹⁸ F

The present invention provides a compound of formula 2 or a pharmaceutically acceptable salt thereof.

[Formula 2]

Where

W, X and Z are each independently C or N, Y is each independently N, O or S, and the pentagonal ring is pyrrole, imidazole, pyrazole, tetrazole, furan, isoxazole, oxazole, thiophene , Thiazole, isothiazole;

R ₁ to R ₉ are each independently H, OH, alkyl, haloalkyl, alkyloxy, haloalkyloxy, amino, monoalkylamino, dialkylamino, halopolyethyleneoxy, [ ¹¹ C] monoalkylamino, [ ¹²³ I ] Iodoalkyloxy, [ ¹²⁴ I] iodoalkyloxy, [ ¹²⁵ I] iodoalkyloxy, [ ¹³¹ I] iodoalkyloxy, [ ¹²³ I] iodopolyethyleneoxy, [ ¹²⁴ I] iodopolyethyleneoxy , [ ¹²⁵ I] iodopolyethyleneoxy, [ ¹³¹ I] iodopolyethyleneoxy, [ ⁷⁶ Br] bromoalkyloxy, [ ⁷⁶ Br] bromopolyethyleneoxy, [ ⁷⁷ Br] bromoalkyloxy, [ ⁷⁷ Br] Bromopolyethyleneoxy, [ ¹⁸ F] fluoroalkyloxy or [ ¹⁸ F] fluoropolyethyleneoxy;

R ₆ , R ₇ , R ₈ and R ₉ may be each independently free of substituents,

When R ₈ is free of substituents Y may be O or S, the pentagonal ring may be furan, isoxazole, oxazole, thiophene, thiazole, isothiazole and the like,

Here, only one substituent of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ R ₆ , R ₇ , R _8, and R ₉ may be a substituent containing a radioisotope.

In the present invention, haloalkyl in the compound of Formula 2 is fluoroalkyl, chloroalkyl, bromoalkyl, or iodoalkyl, wherein the halo is fluoro, chloro, bromo, or iodo; Said alkyl is C ₁ -C ₈ alkyl; The halopolyethyleneoxy provides a compound or a pharmaceutically acceptable salt thereof characterized in that n = 1-8 halo (ethoxy) n-.

Furthermore, the present invention provides a compound, or a pharmaceutically acceptable compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 2 is any one selected from the group consisting of the following compounds:

,

R=F, ¹⁸F

,

R = F, ¹⁸ F

The present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition binds to beta-amyloid plaque, wherein the pharmaceutical composition prevents Alzheimer's disease. , Treatment and diagnosis, and are formulated as injections, tablets, capsules or skin patches.

The present invention also provides a pharmaceutical composition as a diagnostic imaging agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition prevents, treats and diagnoses Alzheimer's disease, Formulated in tablets, capsules or skin patches.

The resveratrol derivatives and styryl-pentagonal aromatic compounds of the present invention are derived from in vitro binding affinity to beta-amyloid (1-42) aggregates, lipophilic properties, brain uptake in normal mice and pharmacokinetics in the brain. Useful as a binder and diagnostic imaging agent in plaques.

In particular, resveratrol derivatives and styryl-pentagonal aromatic compounds labeled with radioisotopes are intended for use in Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT). It can be used for diagnosis of Alzheimer's disease.

1 shows ( E ) -1- (2- [ ¹⁸ F] fluoroethyl) -4- (4- N, N -dimethylaminostyryl) -1 H -1,2,3-triazole in normal mice After the tail vein injection shows the brain intake of radioactivity measured over time.
Figure 2 is (E) -1- (2- fluoro-ethyl) -4-concentration of the (4- N, N-dimethylamino-styryl) -1 H -1,2,3- triazol against beta-amyloid ( 1-42) shows specific binding curves for aggregates.

Resveratrol (( E ) -5- (4-hydroxystyryl) benzene-1,3-diol) is a polyphenol in grapes that promotes the intracellular degradation of beta-amyloid and affects the cytotoxicity of beta-amyloid. It is known to have a neuroprotective effect. Stilbene and styrylpyridine compounds have also been developed for the use of diagnostic imaging agents for beta-amyloid plaques. In the present invention, a compound having a pentagonal aromatic ring bonded to a resveratrol derivative and a styryl structure was developed as a binder and a diagnostic imaging agent for beta-amyloid plaque for diagnosis, treatment and prevention of dementia. Compounds in which a pentagonal aromatic ring is bonded to a styryl structure are new compounds that have not been reported.

In the present invention, a resveratrol derivative and a styryl-triazole compound were synthesized to measure binding affinity for beta-amyloid (1-42) aggregates, and showed a binding affinity of 0.49 nM to 39.70 nM. Among them, the styryl-triazole compound (Example 6), which is a compound having excellent binding affinity, was labeled with ¹⁸ F to measure lipophilic properties, and showed appropriate blood brain barrier permeability (log P _{O / W} = 1.74). In addition, when the body distribution was measured in normal mice, brain uptake was 5.38% ID / g 2 minutes after injection, 0.68% ID / g after 30 minutes, and 0.52% ID / g after 60 minutes. In addition, the brain intake ratio of 2 minutes and 30 minutes was 7.9, and the brain intake ratio of 2 minutes and 60 minutes was 10.3. Since the brains of normal mice do not have beta-amyloid plaque accumulation, the pharmacokinetics of good radioligands should show high initial brain uptake and fast discharge over time. Although three radiopharmaceuticals are currently in clinical trials in the United States, the brain intake ratio of 2 and 60 minutes in normal mice is 3.9-4.82, which is not superior to the pharmacokinetics developed in the present invention (2 minutes / 60 minutes brain intake ratio). = 10.3). Therefore, it is important to obtain intellectual property rights because the present invention has better body properties than these radiopharmaceuticals.

The derivative of the present invention has high binding affinity for beta-amyloid (1-42) aggregates, high initial brain uptake and good pharmacokinetics in normal mice, and thus can be used for the prevention and treatment of dementia, and radioisotopes. Derivatives of the invention labeled with may be used for diagnostic dementia.

The compositions comprising the substances according to the invention can be used, respectively, formulated into injections, tablets, capsules, or skin patches, according to conventional methods, and used in powders, granules, tablets, capsules, suspensions, emulsions, syrups, Oral formulations such as aerosols, external preparations, suppositories, or in the form of sterile injectable solutions can be used. More specifically, when formulating the composition, it can be prepared using a diluent or an excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ), Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. in addition to commonly used diluents such as water and liquid paraffin . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.

The extract of the present invention may vary depending on the age, sex, and weight of the patient, but in general, an amount of 0.01 to 500 mg / kg, preferably 0.1 to 100 mg / kg, may be administered once or several times a day. Can be. When labeled with radioisotopes and used for diagnostic purposes, it may be administered in an amount less than 0.7 μg / kg. In addition, the dosage of the extract can be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Example

Example  One. ( E ) -5- (4- Fluorostyryl ) Benzene-1,3- Diol  synthesis

( E ) -1- (4-fluorostyryl) -3,5-dimethoxybenzene (100 mg, 0.38 mmol) dissolved in dichloromethane (1.6 mL) and then dissolved in dichloromethane 1 M BBr ₃ (2.32 mL) ) Was added slowly at 0 ° C. After the reaction solution was stirred at room temperature for 20 hours, the reaction was stopped with a saturated sodium bicarbonate solution and extracted with dichloromethane. Purification using flash column chromatography gave a product (white solid, 50 mg, 56%).

¹ H NMR (CD ₃ OD) δ 6.21 (t, J = 2.0 Hz, 1H), 6.49 (d, J = 2.5 Hz, 2H), 6.94 (d, J = 16.0 Hz, 1H), 7.03 (d, J = 16.5 Hz, 1H), 7.07 (t, J = 8.5 Hz, 2H), 7.52-7.55 (m, 2H); MS (EI) m / z 302 (M ⁺ ); HRMS calcd (C ₁₄ H ₁₁ O ₂ F), 230.0745; Found, 230.0743.

Example  2. ( E ) -1- (4- Fluorostyryl ) -3,5- Of dimethoxybenzene  synthesis

Example  2-1. Diethyl  3,5- Of dimethoxybenzylphosphonate  synthesis

3,5-dimethoxybenzyl bromide (1 g, 4.32 mmol) was dissolved in triethylphosphite (750 μL) and stirred at 160 ° C. for 4 hours. After distilling off the solvent of the reaction solution under reduced pressure, the product was purified by flash column chromatography to obtain a product (yellow liquid, 1.23 g, 98.9%).

¹ H NMR (CDCl ₃ ) δ 1.26 (t, J = 7.0 Hz, 6H), 3.07 (s, 1H), 3.11 (s, 1H), 3.78 (s, 6H), 4.02-4.05 (m, 4H), 6.35 (d, J = 2.0 Hz, 1H), 6.46 (t, J = 2.5 Hz, 2H); MS (EI) m / z 288 (M ⁺ ); HRMS (C ₁₃ H ₂₁ 0 ₅ P) calc. 288.1122; Found, 288.1127.

Example  2-2. ( E ) -1- (4- Fluorostyryl ) -3,5- Of dimethoxybenzene  synthesis

Diethyl 3,5-dimethoxybenzylphosphonate (300 mg, 1.04 mmol) and 4-fluorobenzaldehyde (129 mg, 1.04 mmol) were dissolved in DMF (5 mL) and potassium t-butoxide at 0 ° C. ( 233 mg, 2.08 mmol) was added and reacted at room temperature for 1 hour. The reaction solution was treated with ethyl acetate and water and purified using flash column chromatography to obtain a product (white solid, 196 mg, 74%).

¹ H NMR (CDCl ₃ ) δ 3.83 (s, 6H), 6.40 (t, J = 2.0 Hz, 1H), 6.65 (d, J = 2.5 Hz, 2H), 6.94 (d, J = 16.0 Hz, 1H) , 7.04 (d, J = 16.5 Hz, 1H), 7.05 (t, J = 11.0 Hz, 2H), 7.45-7.48 (m, 2H); MS (EI) m / z 258 (M ⁺ ); HRMS (C ₁₆ H ₁₅ 0 ₂ F) calc. 258.1075; Found, 258.1056.

Example  3. ( E ) -1- (4- (2- Fluoroethoxy ) Stiryl ) -3,5- Of dimethoxybenzene  synthesis

Example  3-1. 4- (2- Fluoroethoxy ) Benzaldehyde  synthesis

To a solution of acetonitrile (17 mL) dissolved 4-hydroxybenzaldehyde (100 mg, 0.82 mmol) and potassium carbonate (212 mg, 0.98 mmol) was added 2-fluoroethyl para-toluenebenzenesulfonate (0.97 mmol). Then stirred at 70 ° C. for 17 h. The reaction solution was treated with ethyl acetate and water, and then purified using flash column chromatography to obtain a product (white solid, 129 mg, 95%).

¹ H NMR (CDCl ₃ ) δ 4.31 (dt, J = 28.5 and 4.5 Hz, 2H), 4.79 (dt, J = 47.5 and 4 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 7.85 (d, J = 6.5 Hz, 2H), 9.90 (s, 1H); MS (EI) m / z 168 (M ⁺ ); HRMS (C ₉ H ₉ 0 ₂ F) calc. 168.0594; Found, 168.0587.

Example  3-2. ( E ) -1- (4- (2- Fluoroethoxy ) Stiryl ) -3,5- Of dimethoxybenzene synthesis

Diethyl 3,5-dimethoxybenzylphosphonate (160 mg, 0.59 mmol) and 4- (2-fluoroethoxy) benzaldehyde (99.2 mg, 0.59 mmol) were dissolved in DMF (3 mL) and then at 0 ° C. Potassium t-butoxide (133 mg, 1.18 mmol) was added thereto and reacted at room temperature for 1 hour. The reaction solution was treated with ethyl acetate and water and purified using flash column chromatography to obtain a product (white solid, 100 mg, 56%).

¹ H NMR (CDCl ₃ ) δ 3.83 (s, 6H), 4.24 (dt, J = 28.0 and 4.0 Hz, 2H), 4.76 (dt, J = 47.5 and 4.0 Hz, 2H), 6.38 (t, J = 2.5 Hz, 1H), 6.64 (d, J = 2.5 Hz, 2H), 6.91 (d, J = 17.0 Hz, 1H), 6.91 (t, J = 8.5 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 7.45 (d, J = 4.5, 2H); MS (EI) m / z 302 (M ⁺ ); HRMS (C ₁₈ H ₁₉ O ₃ F) calc'd, 302.1308; Found, 302.1318.

Example  4. ( E ) -1- (4- (3- Fluoropropoxy ) Stiryl ) -3,5- Of dimethoxybenzene synthesis

Example  4-1. 4- (3- Fluoropropoxy ) Benzaldehyde  synthesis

To a solution of acetonitrile (17 mL) dissolved 4-hydroxybenzaldehyde (100 mg, 0.82 mmol) and potassium carbonate (212 mg, 0.98 mmol) was added 3-fluoropropyl para-toluenebenzenesulfonate (0.97 mmol). Then stirred at 70 ° C. for 17 h. The reaction solution was treated with ethyl acetate and water, and then purified using flash column chromatography to obtain a product (white solid, 155 mg, 95%).

¹ H NMR (CDCl ₃ ) δ 2.21 (dt, J = 26.0 and 6.0 Hz, 2H), 4.19 (t, J = 6.5 Hz, 2H), 4.66 (dt, J = 47.0 and 6.0 Hz, 2H), 7.01 ( d, J = 7.0 Hz, 2H), 7.84 (d, J = 9.0 Hz, 2H), 9.89 (s, 1H); MS (EI) m / z 182 (M ⁺ ); HRMS (C ₁₀ H ₁₁ 0 ₂ F) calc. 182.0752; Found, 182.0743.

Example  4-2. ( E ) -1- (4- (3- Fluoropropoxy ) Stiryl ) -3,5- Of dimethoxybenzene synthesis castle

Potassium t- in a solution of DMF (3 mL) dissolved in diethyl 3,5-dimethoxybenzylphosphonate (170 mg, 0.59 mmol) and 4- (3-fluoropropoxy) benzaldehyde (107.4 mg, 0.59 mmol). Butoxide (133 mg, 1.18 mmol) was added thereto, followed by reaction at room temperature for 1 hour. The reaction solution was treated with ethyl acetate and water and purified using flash column chromatography to obtain a product (white solid, 117.5 mg, 63%).

¹ H NMR (CDCl ₃ ) δ 2.18 (dt, J = 26.0 and 6.0 Hz, 2H), 3,82 (s, 6H), 4.12 (t, J = 6.0 Hz, 2H), 4.65 (dt, J = 47.0 And 6.0 Hz, 2H), 6.37 (t, J = 2.5 Hz, 1H), 6.64 (d, J = 2.5 Hz, 2H), 6.90 (d, J = 16 Hz, 1H), 6.90 (t, J = 8.0 Hz, 2H), 7.03 (d, J = 16.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H); MS (EI) m / z 316 (M ⁺ ); HRMS (C ₁₉ H ₂₁ O ₃ F) calc. 316.1467; Found, 316.1475.

Example  5. ( E ) -1- (2- Fluoroethyl ) -4- (4- N - Methylaminostyryl )-One H -1,2,3- tree Synthesis of azoles

Example  5-1. 2- Azidoethanol  synthesis

2-bromoethanol (2.26 mL, 32.1 mmol) was dissolved in water (12 mL), and sodium azide (3.15 g, 48.1 mmol) was added thereto and stirred at 85 ° C. for 16 hours. The reaction solution was treated with water and diethyl ether, and the organic layer was distilled under reduced pressure to remove the solvent to obtain a product (1.97 g, 70%).

¹ H NMR (CDCl ₃ ) δ 3.47 (t, J = 5.0 Hz, 2H), 3.80 (t, J = 5.0 Hz, 2H); MS (CI) m / z 88 (M ⁺ + H); HRMS (C ₂ H ₆ N ₃ O) calc. 88.0511; Found, 88.0513.

Example  5-2. 4-( Diethoxymethyl ) -1- (2- Hydroxyethyl )-One H -1,2,3- Triazole synthesis castle

3,3-diethoxy-1-propene (736 μL, 5.16 mmol) and 2-azidoethanol (450 mg, 5.16 mmol) were dissolved in 1: 1 t-butanol and water (19 mL), followed by sodium Ascorbate (409 mg, 2.06 mmol) and CuSO ₄ (258 mg, 1.03 mmol) were added and stirred at room temperature for 4 hours. The reaction solution was treated with dichloromethane and water and purified using flash column chromatography to obtain a product (colorless liquid, 840 mg, 76%).

¹ H NMR (CDCl ₃ ) δ 1.24 (t, J = 7.0 Hz, 6H), 3.72 (q, J = 7.0 Hz, 4H), 4.11 (t, J = 5.0 Hz, 2H), 4.58 (t, J = 4.0 Hz, 2H), 8.26 (s, 1 H), 10.15 (s, 1 H); MS (CI) m / z 216 (M ⁺ + H); HRMS (C ₉ H ₁₈ N ₃ O ₃ ) calc. 216.1348; Found, 216.1346.

Example  5-3. 4-( Diethoxymethyl ) -1- (2- Methylsulfonyloxyethyl )-One H -1,2,3- Triazole Synthesis of

4- (diethoxymethyl) -1- (2-hydroxyethyl) -1 H -1,2,3-triazole (1 g, 4.65 mmol) was dissolved in dichloromethane (58 mL) and then at 0 ° C. Triethylamine (3.8 mL, 27.87 mmol) was added slowly, then methanesulfonyl chloride (720 μL, 9.30 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was treated with dichloromethane and water and purified using flash column chromatography to give the product (yellow solid, 1.3 g, 95%).

¹ H NMR (CDCl ₃ ) δ 1.24 (t, J = 7.0 Hz, 6H), 2.44 (s, 3H), 3.72 (q, J = 7.0 Hz, 4H), 4.64 (t, J = 5.0 Hz, 2H) , 4.71 (t, J = 4.0 Hz, 2H), 8.24 (s, 1 H), 10.13 (s, 1 H); MS (CI) m / z 294 (M + + H); HRMS (C ₁₀ H ₂₀ N ₃ 0 ₅ S) calc. 294.1047; Found, 294.1046.

Example  5-4. 4-( Diethoxymethyl ) -1- (2- Fluoroethyl )-One H -1,2,3- Triazole synthesis castle

4- (diethoxymethyl) -1- (2-methylsulfonyloxyethyl) -1 H -1,2,3-triazole (1.3 g, 4.43 mmol) was dissolved in acetonitrile (34 mL), followed by CsF ( 1.5 g, 9.87 mmol) was added thereto and stirred at 100 ° C. for 10 hours. The reaction solution was treated with dichloromethane and water, and then purified using flash column chromatography to give a product (yellow liquid, 762 mg, 79%).

¹ H NMR (CDCl ₃ ) δ 1.24 (t, J = 7.0 Hz, 6H), 3.70 (q, J = 7.0 Hz, 4H), 4.74 (dt, J = 27.0 and 4.5 Hz, 2H), 4.83 (dt, J = 47.0 and 4.5 Hz, 2H), 8.22 (s, 1H), 10.17 (s, 1H); MS (EI) m / z 217 (M ⁺ ); HRMS (C ₉ H ₁₆ FN ₃ O ₂ ) calc. 217.1227; Found, 217.1229.

Example  5-5. 4-( Formyl ) -1- (2- Fluoroethyl )-One H -1,2,3- Triazole  synthesis

4- (diethoxymethyl) -1- (2-fluoroethyl) -1 H -1,2,3-triazole (500 mg, 2.3 mmol) was dissolved in chloroform (13.5 mL) and then 50% at 0 ° C. Trifluoroacetic acid (4.8 mL, 31.15 mmol) was added slowly and stirred for 1 hour. The reaction solution was treated with chloroform and water, and then purified using flash column chromatography to obtain a product (white solid, 141 mg, 43%).

¹ H NMR (CDCl ₃ ) δ 4.75 (dt, J = 27.0 and 4.5 Hz, 2H), 4.85 (dt, J = 47.0 and 4.5 Hz, 2H), 8.24 (s, 1H), 10.18 (s, 1H); MS (EI) m / z 143 (M ⁺ ); HRMS (C ₅ H ₆ FN ₃ O) calc. 143.0496; Found, 143.0493.

Example  5-6. Diethyl  4- Of nitrobenzylphosphonate  synthesis

4-nitrobenzyl bromide (1 g, 4.62 mmol) was dissolved in triethylphosphite (801 μL, 4.66 mmol) and stirred at 160 ° C. for 3 hours. After distilling off the solvent of the reaction solution under reduced pressure, the product was purified using flash column chromatography to obtain a product (pale yellow oil, 1.08 g, 86%).

¹ H NMR (CDCl ₃ ) δ 1.27 (t, J = 7.0 Hz, 6H), 3.24 (d, J = 22.5 Hz, 2H), 4.02-4.08 (m, 4H), 7.47 (d, J = 11.0 Hz, 2H), 8.18 (d, J = 8.0 Hz, 2H); MS (EI) m / z 273 (M ⁺ ); HRMS (C ₁₁ H ₁₆ NO ₅ P) calc. 273.0766; Found, 273.0765.

Example  5-7. ( E ) -1- (2- Fluoroethyl ) -4- (4- Nitrostyryl )-One H -1,2,3- Triazole Synthesis of

4- (formyl) -1- (2-fluoroethyl) -1 H -1,2,3-triazole (208 mg, 0.76 mmol) with diethyl 4-nitrobenzylphosphonate (110 mg, 0.54 mmol) was dissolved in methanol (1.2 mL), and 0.5 M sodium methoxide (109 mg, 1.19 mmol) was added thereto and stirred at 75 ° C. for 1 hour. The precipitate in the reaction solution was washed with cold methanol and filtered under reduced pressure to give the product (yellow solid, 154 mg, 77%).

¹ H NMR (CD ₃ OD) δ 4.76 (dt, J = 27.0 and 4.6 Hz, 2H), 4.83 (dt, J = 47.0 and 4.6 Hz, 2H), 7.35-7.44 (m, 2H), 7.77 (d, J = 8.0, 2H), 8.22-8.24 (m, 3H).

Example  5-8. ( E ) -1- (2- Fluoroethyl ) -4- (4- Aminostyryl )-One H -1,2,3- Triazole Synthesis of

( E ) -1- (2-fluoroethyl) -4- (4-nitrostyryl) -1 H -1,2,3-triazole (140 mg, 0.53 mmol) in ethanol (10 mL) Then, SnCl ₂ · 2H ₂ O (494 mg, 2.19 mmol) and c-HCl (0.5 mL) were added and stirred at 80 ° C for 2 hours. The reaction solution was neutralized with a saturated NaHCO ₃ solution, treated with ethyl acetate and water, and purified using flash column chromatography to obtain a product (yellow solid, 79 mg, 64%).

¹ H NMR (CD ₃ OD) δ 4.70 (dt, J = 25.5 and 4.6 Hz, 2H), 4.81 (dt, J = 45.5 and 4.9 Hz, 2H), 6.68 (d, J = 8.5, 2H), 6.84 ( d, J = 16.5, 1H), 7.16 (d, J = 16.5, 1H), 7.28 (d, J = 8.5, 2H), 8.01 (s, 1H).

Example  5-9. ( E ) -1- (2- Fluoroethyl ) -4- (4- N - Methylaminostyryl )-One H -1,2,3- The Synthesis of Riazoles

( E ) -1- (2-fluoroethyl) -4- (4-aminostyryl) -1 H -1,2,3-triazole was dissolved in methanol (22 mL), and 0.5 M dissolved in methanol. Sodium methoxide (2.14 mL, 1.07 mmol) and paraformaldehyde (32.3 mg, 1.07 mmol) were added thereto and stirred at 65 ° C. for 2 hours. After cooling the reaction solution to 0 ℃ sodium borohydride was added and stirred at 65 ℃ for 1 hour. The reaction solution was treated with ethyl acetate and water and purified using flash column chromatography to give a product (brown solid, 20 mg, 37%).

¹ H NMR (CDCl ₃ ) δ 2.86 (s, 3H), 4.67 (dt, J = 25.0 and 5.0 Hz, 2H), 4.80 (dt, J = 45.0 and 5.0 Hz, 2H), 6.59 (d, J = 8.5 , 2H), 6.88 (d, J = 16.5, 1H), 7.21 (d, J = 16.5, 1H), 7.35 (d, J = 8.5, 2H), 7.64 (s, 1H); MS (EI) m / z 246 (M ⁺ ); HRMS (C ₁₃ H ₁₅ FN ₄ ) calc. 246.1283; Found, 246.1281.

Example  6. ( E ) -1- (2- Fluoroethyl ) -4- (4- N , N - Dimethylaminostyryl )-One H Synthesis of -1,2,3-triazole

Example  6-1. 4-( Formyl ) -1- (2- Hydroxyethyl )-One H -1,2,3- Triazole  synthesis

4- (diethoxymethyl) -1- (2-hydroxyethyl) -1 H -1,2,3-triazole (503 mg, 2.34 mmol) synthesized in Example 5-2 was diluted with chloroform (13 mL). After dissolving in, 50% TFA (4.4 mL, aqueous solution) was added and stirred at 0 ° C. for 2 hours. The reaction solution was neutralized with 1 N sodium hydroxide, treated with ethyl acetate and water, and concentrated to give a product (white solid, 300 mg, 91%).

¹ H NMR (CDCl ₃ ) δ 4.12 (t, J = 5.0 Hz, 2H), 4.59 (t, J = 5.0 Hz, 2H), 8.27 (s, 1H), 10.14 (s, 1H); MS (EI) m / z 141 (M ⁺ ); HRMS (C ₅ H ₇ N ₃ 0 ₂ ) calc. 141.0538; Found, 141.0539.

Example  6-2. 4-( Formyl ) -1- (2- ( Methoxymethoxy ) Ethyl) -1 H -1,2,3- Triazole synthesis castle

4- (formyl) -1- (2-hydroxyethyl) -1 H -1,2,3-triazole (300 mg, 2.12 mmol) was dissolved in THF (15 mL), followed by diisopropylethylamine ( DIPEA, 741 μL, 4.25 mmol) and chloromethylmethyl ether (323 μL, 4.25 mmol) were added thereto, and the mixture was stirred under reflux for 16 hours. The reaction solution was treated with ethyl acetate and water and purified using flash column chromatography to give a product (colorless liquid, 230 mg, 58%).

¹ H NMR (CDCl ₃ ) δ 3.27 (s, 3H), 3.94 (t, J = 5.0 Hz, 2H), 4.61 (s, 2H), 4.64 (t, J = 5.0 Hz, 2H), 8.25 (s, 1H), 10.15 (s, 1 H); MS (CI) m / z 186 (M ⁺ + H); HRMS (C ₇ H ₁₂ N ₃ O ₃ ) calc., 186.0879; Found, 186.0874.

Example  6-3. Diethyl  4- Of nitrobenzylphosphonate  synthesis

4-nitrobenzyl bromide (1 g, 4.62 mmol) was dissolved in triethylphosphite (801 μL, 4.66 mmol) and stirred at 160 ° C. for 3 hours. The solvent of the reaction solution was removed by distillation under reduced pressure, and then purified using flash column chromatography to obtain a product (pale yellow oil, 1.08 mg, 85%).

¹ H NMR (CDCl ₃ ) δ 1.27 (t, J = 7.0 Hz, 6H), 3.24 (d, J = 22.5 Hz, 2H), 4.02-4.08 (m, 4H), 7.47 (d, J = 11.0 Hz, 2H), 8.18 (d, J = 8.0 Hz, 2H); MS (EI) m / z 273 (M ⁺ ); HRMS (C ₁₁ H ₁₆ NO ₅ P) calc. 273.0766; Found, 273.0765.

Example  6-4. ( E ) -1- (2- ( Methoxymethoxy ) Ethyl) -4- (4- Nitrostyryl )-One H -1,2,3- The Synthesis of Riazoles

4- (formyl) -1- (2- (methoxymethoxy) ethyl) -1 H -1,2,3-triazole (100 mg, 0.54 mmol) and diethyl 4-nitrobenzylphosphonate ( 150 mg, 0.54 mmol) was dissolved in DMF (2.75 mL), and potassium t-butoxide (134 mg, 1.19 mmol) was added thereto and stirred at room temperature for 1 hour. The reaction solution was treated with ethyl acetate and water, and then purified using flash column chromatography to obtain a product (yellow solid, 106 mg, 65%).

¹ H NMR (CDCl ₃ ) δ 3.29 (s, 6H), 3.95 (t, J = 5.0 Hz, 2H), 4.61 (t, J = 5.0 Hz, 2H), 4.62 (s, 2H), 7.24 (d, J = 17.5 Hz, 1H), 7.41 (d, J = 16.5 Hz, 1H), 7.62 (d, J = 5.0 Hz, 2H), 7.79 (s, 1H), 8.22 (d, J = 9.0 Hz, 2H) ; MS (EI) m / z 304 (M ⁺ ); HRMS (C ₁₄ H ₁₆ N ₄ O ₄ ) calculated, 304.1168; Found, 304.1171.

Example  6-5. ( E ) -4- (4- Aminostyryl ) -1- (2- Hydroxyethyl )-One H -1,2,3- Triazole Synthesis of

( E ) -1- (2- (methoxymethoxy) ethyl) -4- (4-nitrostyryl) -1 H -1,2,3-triazole (100 mg, 0.328 mmol) in ethanol (6.2 mL), SnCl ₂ (303 mg, 1.35 mmol) was added thereto, and stirred at 80 ° C. for 2 hours. The reaction solution was treated with ethyl acetate and water, and then the organic layer was concentrated to give a product (yellow solid, 50 mg, 76%).

¹ H NMR (acetone, d ₆ ) δ 3.99 (t, J = 5.0 Hz, 2H), 4.51 (t, J = 5.0 Hz, 2H), 6.90 (d, J = 16.5 Hz, 1H), 7.12 (d, J = 16.0 Hz, 1H), 7.30 (d, J = 6.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 8.05 (s, 1H); MS (EI) m / z 230 (M ⁺ ); HRMS (C ₁₂ H ₁₄ N ₄ O) calc'd, 230.1170; Found, 230.1167.

Example  6-6. ( E ) -1- (2- Hydroxyethyl ) -4- (4- N , N - Dimethylaminostyryl )-One H -1,2,3-t Lee Synthesis of azoles

( E ) -4- (4-aminostyryl) -1- (2-hydroxyethyl) -1 H -1,2,3-triazole (45 mg, 0.19 mmol) and paraformaldehyde (58.6 mg, 1.95 mmol) was dissolved in acetic acid (9 mL), and sodium cyanoborohydride (36.8 mg, 0.58 mmol) was added thereto, followed by stirring at room temperature for 20 hours. The reaction solution was diluted with NaHCO ₃ After neutralization with saturated solution and treatment with ethyl acetate and water, the organic layer was concentrated to give the product (yellow solid, 35 mg, 69%).

¹ H NMR (CD ₃ OD) δ 2.97 (s, 6H), 3.96 (t, J = 5.0 Hz, 2H), 4.49 (t, J = 5.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H ), 6.88 (d, J = 16.5 Hz, 1H), 7.19 (d, J = 16.5 Hz, 1H), 7.40 (d, J = 9.0 Hz, 2H), 8.02 (s, 1H); MS (EI) m / z 258 (M ⁺ ); HRMS calcd (C ₁₄ H ₁₈ N ₄ O), 258.1480; Found, 258.1480.

Example  6-7. ( E ) -1- (2- Methanesulfonyloxyethyl ) -4- (4- N , N - Dimethylaminostyryl )-One H Synthesis of -1,2,3-triazole

( E ) -1- (2-hydroxyethyl) -4- (4- N , N -dimethylaminostyryl) -1 H -1,2,3-triazole (50 mg, 0.19 mmol) was converted to dichloromethane. After dissolving in (1.5 mL), triethylamine (161.9 μL, 1.16 mmol) was added thereto, and stirred at room temperature for 1 hour. The reaction solution was treated with ethyl acetate and water, and then purified using flash column chromatography to obtain a product (yellow solid, 46.2 mg, 71%).

¹ H NMR (CDCl ₃ ) δ 2.95 (s, 6H), 2.99 (s, 3H), 4.70 (t, J = 5.0 Hz, 2H), 4.75 (t, J = 5.0 Hz, 2H), 6.69 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 16 Hz, 1H), 7.24 (d, J = 15.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 8.10 (s, 1H) ; MS (EI) m / z 336 (M ⁺ ); HRMS (C ₁₅ H ₂₀ N ₄ 0 ₃ S) calc. 336.1256; Found, 336.1260.

Example  6-8. ( E ) -1- (2- Fluoroethyl ) -4- (4- N , N - Dimethylaminostyryl )-One H -1,2,3-t Lee Synthesis of azoles

(E) -1- (2- methanesulfonyloxy-ethyl) -4- (4- N, N - dimethyl amino styryl) -1 H -1,2,3- triazole (20 mg, 0.06 mmol) to After dissolving in acetonitrile (1 mL) was added CsF (27 mg, 0.18 mmol) and stirred at 100 ℃ for 10 hours. The reaction solution was treated with ethyl acetate and water, and then purified using flash column chromatography to obtain a product (yellow solid, 7.2 mg, 47%).

¹ H NMR (CDCl ₃ ) δ 2.98 (s, 6H), 4.67 (dt, J = 27.0 and 4.5 Hz, 2H), 4.80 (dt, J = 47.0 and 4.5 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 16.5 Hz, 1H), 7.24 (d, J = 16.5 Hz, 1H), 7.39 (d, J = 9.0 Hz, 2H), 8.19 (s, 1H); MS (EI) m / z 260 (M ⁺ ); HRMS (C ₁₄ H ₁₇ FN ₄ ) calc. 260.1437; Found, 260.1440.

Example  7. ( E ) -1- (4- (3- [ ¹⁸ F] Fluoropropoxy ) Stiryl ) -3,5- Of dimethoxybenzene  synthesis

NBu ₄ NHCO ₃ to ¹⁸ F (40% aqueous solution) was added thereto, and then the water was removed using CH ₃ CN and nitrogen gas at 90 ° C. nBu ₄ NHCO ₃ may be used instead of the nBu ₄ NOH or _{K 2 CO 3 / Kryprofix 2,} 2,2. The resulting nBu ₄ N [ ¹⁸ F] F was converted to the precursor ( E ) -1- (4- (3- (toluenesulfonyl) propoxy) styryl) -3, using CH ₃ CN (200 μL). After transferring to a vial containing 5-dimethoxybenzene (2 mg, 4.25 μmol), and reacted at 110 ℃ for 10 minutes. The temperature of the reaction solution was lowered to room temperature, treated with water and ethyl acetate, followed by extraction to remove the solvent and purified using HPLC. HPLC solvents were mixed with a 0.1% TFA aqueous solution and acetonitrile 40:60 mixture and flowed out at a rate of 4 mL per minute, and the release of radioligand was released in 29 to 30 minutes using a UV detector (254 nm) and a radiation detector simultaneously. Confirmed.

Example  8. ( E ) -1- (2- [ ¹⁸ F] Fluoroethyl ) -4- (4- N , N - Dimethylaminostyryl )-One H -1,2,3-t Lee Synthesis of azoles

^After nBu ₄ NHCO ₃ (40% aqueous solution) was added to an appropriate amount of ¹⁸ F, water was removed using CH ₃ CN and nitrogen gas at 90 ° C. nBu ₄ NHCO ₃ may be used instead of the nBu ₄ NOH or _{K 2 CO 3 / Kryprofix 2,} 2,2. The resulting nBu ₄ N [ ¹⁸ F] F was converted to the precursor ( E ) -1- (2-methanesulfonyloxyethyl) -4- (4- N , N -dimethyl using CH ₃ CN (200 μL). After transfer to a vial containing aminostyryl) -1 H -1,2,3-triazole (2 mg, 5.94 μmol), and reacted at 90 ℃ for 10 minutes. The temperature of the reaction solution was lowered to room temperature, treated with water and ethyl acetate, followed by extraction to remove the solvent and purified using HPLC. HPLC solvent was mixed with 10 mM ammonium formate solution and acetonitrile 60:40 solution and flowed out at a rate of 4 mL per minute, using a UV detector (254 nm) and a radiation detector simultaneously for 18 to 19 minutes. The outflow was confirmed.

Experimental Example  1. Beta-amyloid (1-42) aggregates Resveratrol  And Styryl In Vitro Binding Affinity of Riazole Derivatives

The resveratrol or styryltriazole derivatives were stirred well with beta-amyloid (1-42) aggregates at room temperature for 15 minutes, followed by radioligand 2- [4 '-(dimethylamino) phenyl] -6- [ ¹²⁵ I] Iodobenzothiazole ([ ¹²⁵ I] TZDM) was added and stirred at room temperature for 3 hours. After passing the reaction solution through a GF / B (whatman, 90 × 125 mm) filter paper, the filter paper was washed twice with 3 mL of 10% ethanol and the radioactivity adsorbed on the filter paper was counted. Nonspecific binding was measured using thioflavin-T instead of resveratrol derivatives. K _i values were obtained using PRISM software. The novel resveratrol derivative ( E ) -1- (4- (3-fluoropropoxy) styryl) -3,5-dimethoxybenzene had the best binding affinity (K _i = 0.49 nM) and styryl Triazole derivative ( E ) -1- (2- [ ¹⁸ F] fluoroethyl) -4- (4- N , N -dimethylaminostyryl) -1 H -1,2,3-triazole also beta The binding affinity for amyloid aggregates (K _i = 12.80 nM) was good. Generally, when K _i value is about 10 nM, it is evaluated as an excellent compound. The binding affinity for the beta-amyloid (1-42) aggregates of representative resveratrol and styryltriazole derivatives is shown in Table 1.

compound K _i (nM) TZDM 2.01 Example 1 ( E ) -5- (4-fluorostyryl) benzene-1,3-diol 39.70 Example 2 ( E ) -1- (4-fluorostyryl) -3,5-dimethoxybenzene 4.95 Example 3 ( E ) -1- (4- (2-fluoroethoxy) styryl) -3,5-dimethoxybenzene 0.74 Example 4 ( E ) -1- (4- (3-fluoropropoxy) styryl) -3,5-dimethoxybenzene 0.49 Example 5 ( E ) -1- (2-fluoroethyl) -4- (4- N -methylaminostyryl) -1 H -1,2,3-triazole - Example 6 ( E ) -1- (2-fluoroethyl) -4- (4- N, N -dimethylaminostyryl) -1 H -1,2,3-triazole 12.80

Experimental Example  2. New Styryltriazole  Derivative Lipophilic  Measure

( E ) -1- (2- [ ¹⁸ F] fluoroethyl) -4- (4- N , N -dimethylaminostyryl) -1 H -1,2,3-triazole labeled with radioisotopes Was mixed with 1-octanol and water mixture, and the degree of distribution in the 1-octanol layer and the water layer was measured, respectively. As a result, ( E ) -1- (2-fluoroethyl) -4- (4- N , N- The log P of dimethylaminostyryl) -1 H -1,2,3-triazole was 1.74. This suggests excellent blood brain barrier permeability of the novel styryltriazole derivatives of the present invention.

(E) -1- (4- (3- [18 F] Fluoro-propoxy) styryl) -3,5-dimethoxybenzene was a log P of is 2.84.

Experimental Example  3. Normal In mice New Styryltriazole  Brain uptake and pharmacokinetic studies of derivatives

Novel styryltriazole derivatives labeled with radioisotopes of Example 6 (( E ) -1- (2- [ ¹⁸ F] fluoroethyl) -4- (4- N , N -dimethylaminostyryl) -1 H -1,2,3-triazole) was injected intravenously into the tail of a normal mouse, and then the main body tissues including the brain were weighed and weighed, and then the radioactivity was counted to inject (%) / tissue (g). ) (% ID / g). The measured brain uptake was 5.38% ID / g at 2 minutes after injection and rapidly decreased with time to 0.68% ID / at 30 minutes (2/30 minutes = 7.9, 2/60 minutes = 10.3). This suggests that the novel styryltriazole derivatives of the present invention have the appropriate pharmacokinetics for imaging beta-amyloid plaques.

While the present invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. You will know. In addition, many modifications may be made to adapt a particular situation and material to the teachings of the invention without departing from the essential scope thereof. Accordingly, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention be construed as including all embodiments falling within the scope of the appended claims.

Claims (12)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In this formula,
R ₁ , R ₃ , R ₅ , R ₆ , R ₇ , R ₉ , and R ₁₀ are each independently H,
R ₂ and R ₄ are each independently alkyloxy,
R ₈ is haloalkyloxy, halopolyethyleneoxy, [ ¹²³ I] iodoalkyloxy, [ ¹²⁴ I] iodoalkyloxy, [ ¹²⁵ I] iodoalkyloxy, [ ¹³¹ I] iodoalkyloxy, [ ¹²³ I ] Iodopolyethyleneoxy, [ ¹²⁴ I] iodopolyethyleneoxy, [ ¹²⁵ I] iodopolyethyleneoxy, [ ¹³¹ I] iodopolyethyleneoxy, [ ⁷⁶ Br] bromoalkyloxy, [ ⁷⁶ Br] bromopolyethyleneoxy , [ ⁷⁷ Br] bromoalkyloxy, [ ⁷⁷ Br] bromopolyethyleneoxy, [ ¹⁸ F] fluoroalkyloxy or [ ¹⁸ F] fluoropolyethyleneoxy. The method of claim 1,
Halo is fluoro, chloro, bromo, or iodo;
Alkyl is C ₁ -C ₈ alkyl;
Halopolyethyleneoxy is halo (ethoxy) n-, wherein n = 1-8, or a pharmaceutically acceptable salt thereof. The method of claim 1,
Compounds or pharmaceutically acceptable salts thereof, wherein the compound of Formula 1 is any one selected from the group consisting of

, And

R = F, ¹⁸ F A compound of Formula 2 or a pharmaceutically acceptable salt thereof:
(2)

In this formula,
W, X and Y are each independently N, Z is C,
R ₁ , R ₂ , R ₄ , R ₅ , and R ₉ are each independently H,
R ₃ is monoalkylamino, dialkylamino, or [ ¹¹ C] monoalkylamino,
R ₆ , and R ₇ are each independently free of substituents,
R ₈ is haloalkyl. 5. The method of claim 4,
Haloalkyl is fluoroalkyl, chloroalkyl, bromoalkyl, or iodoalkyl,
Alkyl is C ₁ -C ₈ alkyl, or a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
A compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula 2 is any one selected from the group consisting of

, And

R = F, ¹⁸ F A pharmaceutical composition comprising the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, the pharmaceutical composition comprising preventing, treating and diagnosing Alzheimer's disease. delete The method of claim 7, wherein
The pharmaceutical composition is a pharmaceutical composition, characterized in that formulated as an injection, tablet, capsule or skin patch. A pharmaceutical composition as a diagnostic imaging agent comprising the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 10,
The pharmaceutical composition is a pharmaceutical composition as a diagnostic imaging agent, characterized in that preventing, treating and diagnosing Alzheimer's disease. The method of claim 10,
The pharmaceutical composition is a pharmaceutical composition as a diagnostic imaging agent, characterized in that formulated as injections, tablets, capsules or skin patches.

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