Radioactive triphenylpyrazole compound

Abstract

Provided is a radioactive triphenylpyrazole compound that is useful as an active ingredient of a pharmaceutical composition, particularly an imaging agent, and is stable in vivo. 4-(4-[18F]fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-yl)phenoxy)butanoic acid or a salt thereof can be used as a radioactive triphenylpyrazole compound according to the present invention.

Description

Radioactive triphenylpyrazole compounds

[0001] The present invention relates to a radioactive triphenylpyrazole compound useful as an active ingredient in pharmaceutical compositions, particularly imaging agents. This application claims priority to Japanese Patent Application No. 2024-128131, filed August 2, 2024, the contents of which are incorporated herein by reference.

[0002] In nuclear medicine imaging diagnostics, single-photon emission computed tomography (SPECT) is widely used as an imaging agent for cardiac diseases. However, due to the low energy and long half-life of SPECT nuclides, the amount of radioactivity administered to patients is limited from the perspective of radiation protection, making it difficult to obtain clear images. In particular, due to the influence of radiation attenuation caused by body shape, such as large body types like Westerners and women's breasts, high accumulation of radioactive drugs in the liver and gallbladder, which are located near the heart, can cause false defects, making myocardial imaging diagnostics difficult (Non-Patent Document 1). To address this unmet medical need, there is a need for the establishment of positron emission tomography (PET) testing, which can obtain clearer images with higher energy (Non-Patent Document 2).

[0003] On the other hand, the cardiac PET drug that is currently in practical use in Japan is one with a half-life of about 10 minutes. １３ N-ammonia is approved for insurance, but in hospitals １３ The need for a cyclotron for N production, and rapid compound synthesis and purification are required, limiting its usefulness (Non-Patent Document 3). ８２ PET scans using Rb are also being performed, but this also has an extremely short half-life of 75 seconds. ８２ The generator required to produce Rb is also expensive, and is not currently in widespread use (Non-Patent Document 3).

[0004] As practically useful isotopes, １８ F has a half-life of 110 minutes, which is sufficient time for the synthesis and purification of the radiolabeled compound and its administration to PET imaging. １８ The relatively long half-life of F was measured from a cyclotron at another facility far from the hospital. １８This may allow for the delivery of F-labeled compounds.

[0005] １８ The disadvantages of F are the design of compounds incorporating fluorine, which is different from biological materials, and the generation of fluorine in cyclotrons. １８ The difficulty lies in the design and production of labeling precursors that efficiently utilize F.

[0006] For the above reasons, in PET １８ The use of F-labeled compounds is limited, and the only PET diagnostics currently available in Japan are １８ F-labeled myocardial preparations １８ The only diagnostic method available for the diagnosis of cardiac sarcoidosis inflammation is F-fluorodeoxyglucose (Non-Patent Document 3). On the other hand, in recent years, in order to meet this unmet medical need, １８ F-flurpiridaz has been developed as a myocardial perfusion imaging agent and is currently undergoing clinical development in the United States and Japan (Non-Patent Document 4). １８ Because F-flurpiridaz is a blood flow imaging agent, it cannot distinguish between areas of the myocardium damaged by ischemia-reperfusion injury where blood flow has recovered and normal areas. Furthermore, when severe stenosis or blockage occurs in the coronary arteries, an attempt is made to create a new blood flow pathway (collateral circulation) in the ischemic area, but blood flow imaging agents only reflect the blood flow in the collateral circulation, making it difficult to identify the exact damaged area. For this reason, in order to evaluate the viability of myocardial cells, repeated tests are required, once at rest and once under exercise stress, which is a test that places a great burden on the patient. In particular, exercise stress is a highly invasive test for patients with ischemic heart disease. Furthermore, １８ In F-Furupiridazu, １８ There is a drawback in that it is practically difficult to perform two repeated tests on the same day due to the supply of F preparations and their half-life of 110 minutes.

[0007] ​The fatty acid-binding protein FABP3 is highly expressed in cardiac muscle and is covered by insurance as a blood marker for acute myocardial infarction (Non-Patent Document 5). It is known that FABP3 leaks into the blood from cardiac muscle cytoplasm during myocardial infarction. However, FABP3 is also expressed in the brain, mammary gland, placenta, and skeletal muscle (Non-Patent Document 6). Therefore, blood markers of FABP3 cannot determine which organ or part is actually damaged. In particular, when a fall occurs during myocardial infarction, it is impossible to distinguish between skeletal muscle-derived FABP3 and cardiac muscle-derived FABP3 (Non-Patent Document 7).

[0008] To date, the only attempt to detect FABP3 expression by imaging diagnosis has been １２５ Although I-labeled anti-FABP3 antibodies are known (Non-Patent Document 8), they are antibody preparations and therefore have high nonspecific accumulation in the background, and radionuclides for in vivo diagnostic imaging are not available. １２３ Because it is a SPECT nuclide of I, it does not address the unmet medical need for the establishment of an examination using the PET method, which has higher energy and can obtain clearer images.

[0009] As a compound that specifically binds to FABP3, Patent Document 1 discloses a compound of formula (Ib-3), particularly a compound of formula (Ib-3) in which R １ is trifluoromethyl, and R ２ and R ３ is a hydrogen atom, and R ４ is a non-radioactive fluorine atom, and R ５ is a hydrogen atom has binding activity to FABP3, inhibits aggregation of α-synuclein, improves motor dysfunction and cognitive dysfunction, and has neuroprotective action, and is useful as a therapeutic agent for neurodegenerative diseases of the central nervous system.

[0010] International Publication No. 2024 / 063147

[0011] Burrell S. et al., J. Nucl. Med. Technol. 34, pp. 193-211 (2006) Alam L. et al., Curr. Cardiol. Rep. 25, pp. 281-293 (2023) Bengel F. M. et al., J. Am. Coll. Cardiol. 54, pp. 1-15 (2009) Matsumoto N. , Ann. Nucl. Cardiol. 9, pp. 91-93 (2023) Otaki Y. et al., Clin. Chem. Acta. 474, pp. 44-53 (2017) Binas B. et al., FASEB J. 13, pp. 805-812 (1999); Van Nieuwenhoven F.A. et al., Circulation. 92, pp. 2848-2854 (1995); Fukushima K. et al., Ann. Nucl. Cardiol. 8, pp. 14-20 (2022)

[0012] The present invention provides a radioactive compound that is useful as an active ingredient in pharmaceutical compositions, particularly imaging agents, and is stable in vivo.

[0013] In order to achieve the above object, the inventors have １８ We synthesized compounds that can be labeled with F and conducted extensive research into their feasibility as imaging agents, particularly for image evaluation using the PET method. １８ The present inventors have found that F-labeled radioactive triphenylpyrazole compounds can be used for image evaluation by PET, particularly for diagnostic imaging of the myocardium, and have completed the present invention.

[0014] [1] 4-(4-[ １８ F] fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid, or a salt thereof.

[0015]

[0016] [2] A pharmaceutical composition comprising the compound of [1] or a salt thereof, and optionally further comprising a pharmaceutically acceptable excipient. [3] An imaging agent comprising the compound of [1] or a salt thereof. [4] The imaging agent of [3], which is an imaging agent for PET. [5] The imaging agent of [4], which is a diagnostic imaging agent. [6] The imaging agent of [4], which is an imaging agent for myocardium. [7] The imaging agent of [4], which is an imaging agent for tissues expressing FABP3.

[0017] [8] Formula (I):

[0018]

[0019] (In the formula, R １ is C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ Aralkyl, or C ６－１２ R represents aryl; ２ は-B(OR ３ ) ２ represents; R ３ are each independently H, C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ Aralkyl, or C ６－１２ aryl, or -B(OR ３ ) ２ are united,

[0020]

[0021] or a salt thereof, to a reaction for converting a carbon-boron bond into a carbon-fluorine bond [ １８ [9] A method for producing the compound of [1] or a salt thereof, comprising the introduction of fluorocarbon into the ester, and subjecting the ester to a reaction for converting the ester to a carboxylic acid to form a carboxyl group. １８ The production method of [8], which is a reaction with F ions in an organic solvent in the presence of a copper catalyst.

[0022]

[10] A compound of formula (I) or a salt thereof.

[0023]

[0024] (In the formula, R １ is C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ Aralkyl, or C ６－１２ R represents aryl; ２ は-B(OR ３ ) ２ represents; R ３ are each independently H, C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ Aralkyl, or C ６－１２ aryl, or -B(OR ３ ) ２ are united,

[0025]

[0026] It represents one of the following.)

[0027] The disclosure of this specification also encompasses the inventions described below.

[0028]

[11] Use of the compound of [1] or a salt thereof for producing an imaging agent.

[12] The compound of [1] or a salt thereof for producing an imaging agent.

[13] An imaging method comprising administering an effective amount of the compound of [1] or a salt thereof to a subject.

[0029]

[14] The imaging method of

[13] , which is imaging by a method selected from the group consisting of a PET method, a SPECT method, and a PET / CT method that combines a PET method and a CT method.

[15] The imaging method of

[13] , which is imaging by a PET method.

[16] The imaging method of

[15] , for imaging cardiac muscle, kidney, skeletal muscle, blood vessel, tumor, or brown fat cell.

[0030]

[17] A method for diagnosing a subject's myocardial condition, kidney condition, skeletal muscle condition, vascular condition, tumor condition, or brown adipocyte condition, comprising utilizing results obtained by the imaging method of

[16] .

[18] The diagnostic method of

[17] , which is a method for diagnosing heart disease, kidney disease, skeletal muscle disease, vascular disease, tumor, or brown adipocyte.

[19] The diagnostic method of

[18] , wherein the heart disease is selected from the group consisting of ischemic heart disease, myocardial infarction, heart failure, myocarditis, and cardiomyopathy.

[20] The diagnostic method of

[18] , wherein the renal disease is selected from the group consisting of acute kidney injury, drug-induced kidney injury, and chronic kidney injury.

[21] The diagnostic method of

[18] , wherein the skeletal muscle disease is selected from the group consisting of exercise-induced muscle damage, drug-induced skeletal muscle injury, rhabdomyolysis, and sarcopenia.

[22] The diagnostic method of

[18] , wherein the vascular disease is a vascular disease selected from the group consisting of arteriosclerosis, peripheral arterial disease, and pulmonary thromboembolism.

[23] The diagnostic method of

[18] , wherein the tumor is a tumor selected from the group consisting of gastric cancer, non-small cell lung cancer, and uterine sarcoma.

[24] The diagnostic method of

[18] , wherein the brown adipocytes are brown adipocytes used in the diagnosis of metabolic function in obesity or diabetes, or as a companion diagnostic for the development of anti-obesity drugs.

[0031] The radioactive triphenylpyrazole compounds of the present invention are useful as active ingredients in pharmaceutical compositions, particularly imaging agents, and are stable in vivo.

[0032] FIG. 1 is a diagram showing a time radioactivity curve after administration of the compound of Example 2 to normal mice. FIG. 2 is a diagram showing an example of whole-body PET imaging of the compound of Example 2 in normal mice. FIG. 3 is a diagram showing the effect of a carrier on the biodistribution of the compound of Example 2. FIG. 4 is a diagram showing the effect of a carrier on the organ-to-blood radioactivity ratio of the compound of Example 2. FIG. 5 is a diagram showing an example of PET imaging of the compound of Example 2 in a myocardial infarction model rat. FIG. 6 is a diagram showing an example of PET imaging of the compound of Example 2 in a myocarditis model rat. FIG. 7 is a diagram showing a comparison of cardiac accumulation of the compound of Example 2 in myocarditis model rats and normal rats. FIG. 8 is a diagram showing an example of PET imaging of the compound of Example 2 in an acute heart failure model mouse. FIG. 9 is a diagram showing the comparison of cardiac accumulation of the compound of Example 2 in a myocarditis model rat and a normal rat. １８FIG. 10 shows an example of PET imaging of [F]flurpiridaz (b).

[0033] As used herein, "C １－６ The term "alkyl" means a linear, branched, cyclic or partially cyclic alkyl having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropylmethyl. In one embodiment, C １－４ alkyl, and in another embodiment, C １－３ In yet another embodiment, it is methyl, ethyl, n-propyl, or isopropyl, in yet another embodiment, it is methyl or ethyl, and in yet another embodiment, it is ethyl.

[0034] "C ２－６ The term "alkenyl" refers to a monovalent hydrocarbon chain group having 2 to 6 carbon atoms, which may be linear, branched, cyclic, or partially cyclic and which has at least one double bond. Examples include vinyl, propenyl, allyl, isopropenyl, butenyl, pentenyl, 1-methylvinyl, 1-methylpropenyl, 1,3-butadienyl, 1,3-pentadienyl, cyclopentenyl, cyclohexenyl, and cyclopentenylmethyl. In one embodiment, C ２－３ In another embodiment, it is vinyl, propenyl, or allyl, and in yet another embodiment, it is allyl.

[0035] "C ７－１２ The term "aralkyl" refers to a monovalent group having 7 to 12 carbon atoms in which an aryl and an alkyl are bonded, and examples thereof include benzyl, phenethyl, and phenylpropyl. In one embodiment, it is benzyl or phenethyl, and in another embodiment, it is benzyl.

[0036] "C ６－１２The term "aryl" refers to a monovalent group of an aromatic hydrocarbon ring having 6 to 12 carbon atoms, and examples thereof include phenyl, naphthyl, and azulenyl. In one embodiment, it is phenyl or naphthyl, and in another embodiment, it is phenyl.

[0037] In formula (I), R １ is C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ Aralkyl, or C ６－１２ aryl, and in one embodiment, C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ In another embodiment, C is aralkyl. １－６ Alkyl, C ２－６ In yet another embodiment, C is alkenyl. １－３ Alkyl, C ２－３ In another embodiment, it is alkenyl, in another embodiment, it is methyl, ethyl, or allyl, in another embodiment, it is ethyl.

[0038] In formula (I), R ２ は-B(OR ３ ) ２ In one embodiment, In another embodiment, is.

[0039] An embodiment of the compound of formula (I) is ethyl 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanoate.

[0040] The compound of formula (I) may exist in the form of tautomers or geometric isomers (including cis-trans isomers of compounds having saturated ring groups such as cycloalkyl) depending on the type of substituent. Even if the compound of formula (I) is described in this specification in the form of only one isomer, the present invention also includes other isomers, and also includes separated isomers and mixtures thereof.

[0041] The compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and therefore may exist as an optical isomer. The present invention also encompasses separated optical isomers of the compound of formula (I) or mixtures thereof.

[0042] The present invention relates to a 4-(4-[ １８ [F]fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid (hereinafter sometimes referred to as "Compound 1" in this specification) and pharmaceutically acceptable prodrugs of the compound of formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted into a carboxyl group by solvolysis or under physiological conditions, and examples of groups that form prodrugs include those described in Prog. Med. 5, pp. 2157-2161 (1985).

[0043] The salts of Compound 1 and the salts of the compound of Formula (I) are pharmaceutically acceptable salts, and may form acid addition salts or base addition salts depending on the type of substituent. Specific examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., and organic acids such as formic acid, acetic acid, oxalic acid, malonic acid, tartaric acid, p-toluenesulfonic acid, etc., salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, etc., and organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine, and ammonium salts.

[0044] The present invention also encompasses Compound 1 and its salts, as well as various hydrates and solvates, and crystalline polymorphic substances of the compound of formula (I) and its salts.

[0045] Compound 1 and its salts, and the compound of formula (I) and its salts can be produced by various known synthetic methods, taking advantage of the characteristics based on the basic skeleton or the type of substituents. In this case, depending on the type of functional group, it may be effective from the viewpoint of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage of a raw material or intermediate. Known protecting groups can be used as such protecting groups.

[0046] Compound 1 and its salts, and prodrugs of the compound of formula (I) and its salts can be produced by introducing a specific group into a raw material or intermediate, as in the case of the above-mentioned protecting group, or by further reacting the obtained compound 1 and its salts, and the compound of formula (I) and its salts. The reaction can be carried out by methods known to those skilled in the art, such as ordinary esterification and amidation.

[0047] An example of a method for producing Compound 1, including Steps 1 and 2, will be described below. Steps 1 and 2 can also be carried out as a so-called one-pot reaction. The method for producing Compound 1 is not limited to the example shown below, and Compound 1 can also be produced by using known methods or modifications thereof.

[0048]

[0049] (Step 1) A compound of formula (1) or a salt thereof is subjected to a reaction for converting a carbon-boron bond into a carbon-fluorine bond, １８ [F] Fluoro-introducing step This step is a reaction in which the boron atom of the compound of formula (1) or a salt thereof is substituted with fluoro using an equivalent amount of a fluorinating agent or an excess amount of either. In order to obtain a radioactive triphenylpyrazole compound, the fluorinating agent is [ １８ A fluorinating agent having a fluorine atom [F] can be generated using a cyclotron. １８ [F]HF may be used as the fluorinating agent. The reaction is carried out in a solvent inert to the reaction, under cooling or reflux, preferably at 0 to 200°C, and usually with stirring for 0.1 to 1 hour. For example, the compound can be produced by the method of Example 2. That is, a mixture of a boron compound and a catalyst is added with an oxidizing agent and [ １８ F] fluorine anion is reacted to convert the boron atom in the boron compound to [ １８ F] substituted with fluorine.

[0050] Examples of boron compounds include ethyl 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanoate, (4-(4-ethoxy-4-oxobutoxy)-3-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenyl)boronic acid, and ethyl 4-(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate. ethyl 4-(4-dimethoxyboraneyl)-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate, ethyl 4-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate, ethyl 4-(4-benzo[d][1,3,2]dioxaborol-2-yl)-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate, ethyl 4-(4-(13,15-dioxa-14-boradispiro[5.0.5] ７ .3 ６ ]pentadecan-14-yl)-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate; and one embodiment is 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanoate.

[0051] Examples of oxidizing agents that can be used include air, oxygen gas, and hydrogen peroxide, and in one embodiment, air can be used. A copper catalyst can be used, such as tetrakis(pyridine)copper(II) triflate, tetrakisacetonitrilecopper(I) triflate, chlorobis(tricyclohexylphosphine)copper(I), or copper iodide(I), and in one embodiment, tetrakis(pyridine)copper(II) triflate. １８ [F] fluorine anions include, for example, [ １８ F] hydrogen fluoride, [ １８ F] potassium fluoride, [ １８ F] tetrabutylammonium fluoride, and in one embodiment, [ １８ F] tetrabutylammonium fluoride, [ １８ F] potassium fluoride, and in another embodiment, １８ F] tetrabutylammonium fluoride.

[0052] As the solvent, an organic solvent can be used, for example, dimethylacetamide, dimethylformamide, dimethylsulfoxide, or acetonitrile, and in one embodiment, dimethylacetamide can be used.

[0053] This step can be performed with reference to, for example, the following documents: Tatsuo Ishiyama, J. Org. Chem., 1995, 60, 23, 7508-7510; Andrew V. Mossine, Org. Lett., 2015, 17, 23, 5780-5783; Hironobu Sakaguchi, J. Am. Chem. Soc., 2017, 139, 36, 12855-12862.

[0054] (Step 2) The [ １８ F] A step of forming a carboxyl group by subjecting the fluoro-substituted ester to a reaction of converting it into a carboxylic acid. １８ F] fluoro-substituted -C(=O)-OR １This is a process for converting the group into a —C(═O)—OH group by hydrolysis. Known techniques, such as hydrolysis reactions well known to those skilled in the art, can be used.

[0055] Next, an example of a method for producing the compound of formula (I) will be described. The method for producing the compound of formula (I) is not limited to the example shown below, and the compound can also be produced by using known methods or modifications thereof.

[0056]

[0057] This step involves preparing a compound of formula (II) １ is R in the compound of formula (I) １ and X represents a halogen.) with a boron compound to obtain a compound of formula (I). The reaction is carried out by reacting a compound of formula (II) with R ２ and a boron compound corresponding to the formula (I) are used in equal amounts or in excess of one of the two, and a mixture of these is stirred in a solvent inert to the reaction or without a solvent, under cooling to reflux, preferably at -20 to 200°C, preferably 0 to 120°C, more preferably 0 to 100°C, for usually 0.1 to 5 days, preferably 0.5 to 17 hours, more preferably 0.5 to 1 hour. For example, this can be produced by the method of the fifth step in Example 1. That is, a halogen compound, a boron source, a base, and a catalyst are added to a solvent and stirred.

[0058] Examples of halogen compounds include ethyl 4-(4-bromo-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate, ethyl 4-(4-iodo-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate, and ethyl 4-(4-fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate; one embodiment is ethyl 4-(4-bromo-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate.

[0059] Examples of boron sources that can be used include bis(pinacolato)diboron, bis(neopentylglycolato)diboron, bis(catecholato)diboron, pinacolborane, and diboronic acid. In one embodiment, bis(pinacolato)diboron can be used. Examples of bases that can be used include potassium acetate, sodium acetate, sodium bicarbonate, potassium bicarbonate, triethylamine, and diisopropylethylamine. In one embodiment, potassium acetate can be used.

[0060] Examples of the catalyst include 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II), tetrakis(triphenylphosphine)palladium(0), dichlorobis(tri-o-tolylphosphine)palladium(II), and tris{tris[3,5-bis(trifluoromethyl)phenyl]phosphine}palladium(0). One embodiment is 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II). The catalyst may be prepared in situ by adding triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-o-tolylphosphine, or tris[3,5-bis(trifluoromethyl)phenyl]phosphine to palladium chloride. The catalyst may also be prepared in situ by adding triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-o-tolylphosphine, or tris[3,5-bis(trifluoromethyl)phenyl]phosphine to palladium acetate. A catalyst may be prepared in the reaction system by adding triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-o-tolylphosphine, or tris[3,5-bis(trifluoromethyl)phenyl]phosphine to palladium carbon.

[0061] Examples of the solvent that can be used include dimethyl sulfoxide, dimethylformamide, dioxane, ethyl acetate, and toluene, and in one embodiment, dimethyl sulfoxide can be used. The reaction may be carried out without a solvent.

[0062] This step can be performed with reference to, for example, the following literature: Ishiyama, T.; Murata, M.; Miyaura, N., J. Org. Chem., 1995, 60, 7508. Murata, M.; Watanabe, S.; Masuda, Y., J. Org. Chem., 1997, 62, 6458. MURATA, M.; Oyama, T.; Watanabe, S.; Masuda, Y., J. Org. Chem., 2000, 65, 164. Takagi, J.; Takahashi, K.; Ishiyama, T. ; Miyaura, N.; , J. Am. Chem. Soc. , 2002, 124, 8001.

[0063] The compound of formula (II) can be produced by or with reference to the method described in Patent Document 1 or a modified method thereof.

[0064] Compound 1 and the compound of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates, or crystalline polymorphs. Salts can also be produced by conventional salt formation reactions. Isolation and purification are carried out using conventional chemical procedures such as extraction, fractional crystallization, and various fractional chromatography. Various isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing differences in physicochemical properties between isomers.

[0065] In some embodiments of the present invention, Compound 1 or a salt thereof may be administered as a prodrug and converted to an active compound in vivo. In some embodiments of the present invention, Compound 1 or a salt thereof may be administered alone or in a mixture with a pharmaceutically acceptable excipient.

[0066] Compound 1 or a salt thereof can be used in the form of a pharmaceutical preparation, for example, in solid, semi-solid, or liquid form, containing Compound 1 or a salt thereof as an active ingredient mixed with an organic or inorganic excipient suitable for external (topical), enteral, intravenous, intramuscular, parenteral, or intramucosal application. The active ingredient can be formulated using conventional non-toxic pharmaceutically acceptable excipients for, for example, ointments, creams, plasters, tablets, pellets, capsules, suppositories, liquids (e.g., saline), emulsions, suspensions (e.g., olive oil), aerosols, pills, powders, syrups, injections, troches, poultices, perfumes, lotions, buccal tablets, sublingual tablets, nasal drops, and any other form suitable for use. Excipients that can be used include water, wax, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea, and other excipients suitable for use in the manufacture of preparations in solid, semi-solid, or liquid form; in addition, auxiliary substances, stabilizers, thickeners, and coloring agents, as well as flavorings, can be used. Compound 1 of the present invention or a salt thereof is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect on the process or condition of the disease.

[0067] The pharmaceutical composition of the present invention is administered to a subject, particularly a human or non-human animal, intravenously, intramuscularly, via the lungs, or orally, or by inhalation. The effective amount of Compound 1 or a salt thereof varies depending on the age and condition of each individual subject to be treated, the route of administration, etc., but when used as a myocardial imaging agent, a radioactivity of 74 MBq to 555 MBq may be administered in one embodiment, or 185 MBq to 370 MBq in another embodiment. It is usually administered intravenously.

[0068] A "subject" is a human or a non-human animal such as, but not limited to, a mouse, rat, monkey, guinea pig, chimpanzee, sheep, goat, dog, cat, pig, cow, or horse. In one embodiment, the subject is a human.

[0069] The imaging method includes a PET method, a SPECT method, and a PET / CT method that combines PET and CT. In one embodiment, the imaging method is PET.

[0070] In the present invention, the imaging agent for tissues expressing FABP3 can be used for diagnosing heart disease, kidney disease, skeletal muscle disease, vascular disease, tumors, and brown adipocytes.

[0071] Examples of cardiac disease diagnostic targets include ischemic heart disease, myocardial infarction, heart failure, myocarditis, cardiomyopathy, cardiac fibrosis, myocardial viability assessment, prognosis diagnosis, treatment effect diagnosis, and risk stratification (Reference: Cardiac Nuclear Medicine Examination Guidelines (2010 revised edition)). Examples of kidney disease diagnostic targets include acute kidney injury, drug-induced kidney injury, and chronic kidney injury. Examples of skeletal muscle disease diagnostic targets include exercise-induced muscle injury, drug-induced skeletal muscle injury, rhabdomyolysis, and sarcopenia. Examples of vascular disease diagnostic targets include arteriosclerosis, peripheral arterial disease, and pulmonary thromboembolism. Examples of tumor diagnostic targets include gastric cancer, non-small cell lung cancer, and uterine sarcoma (McKillop I.H. et al., Cell.Signal., 62, 109336, (2019)). Examples of diagnostic targets for brown adipocytes (Vergens L. et al., J. Biol. Chem., 286, pp. 380-390, (2011); Yamamto T. et al., Biotechnol. Lett., 33, pp. 237-242, (2011)) include metabolic function diagnosis in obesity and diabetes, and use as a companion diagnostic agent for the development of anti-obesity drugs.

[0072] One embodiment of the pharmaceutical composition of the present invention comprises Compound 1 or a salt thereof. One embodiment of the imaging agent of the present invention comprises Compound 1 or a salt thereof. In one embodiment, the imaging agent of the present invention is an imaging agent for PET. In another embodiment, it is a diagnostic imaging agent. In yet another embodiment, it is an imaging agent for myocardium. In yet another embodiment, it is an imaging agent for tissues expressing FABP3. Another embodiment of the present invention includes a composition package containing Compound (I) or a salt thereof. This composition package containing Compound (I) or a salt thereof may be a composition package used for preparing a pharmaceutical composition, particularly an imaging agent, containing Compound 1 or a salt thereof. Note that this composition package may contain only Compound (I) or a salt thereof, or may contain Compound (I) or a salt thereof together with other excipients, such as excipients useful for preparing pharmaceutical compositions containing Compound 1 or a salt thereof.

[0073] The present invention will be specifically described below using examples, but the present invention is not limited thereto. The intermediates and target compounds in the following production methods can also be converted into other compounds included in the present invention by appropriately converting their functional groups. The starting materials and intermediates in the following production methods can be obtained by purchasing commercially available products, synthesizing them from known literature, or synthesizing them from known compounds by known methods. Furthermore, salts of the starting materials and intermediates may be used as needed.

[0074] [Example 1]

[0075]

[0076] Ethyl 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanoate

[0077] (First Step) Preparation of (E)-1-(5-bromo-2-hydroxyphenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

[0078]

[0079] Sodium hydroxide (28 g) was added to methanol (250 mL) and dissolved. 5-Bromo-2-hydroxyacetophenone (30 g) and 2-(trifluoromethyl)benzaldehyde (26 g) were further added, and the mixture was stirred at 40°C for 24 hours. 2 M hydrochloric acid (400 mL) was added to the reaction mixture, and the precipitated solid was filtered and washed with water. The obtained solid was dried under reduced pressure at 30°C to obtain the title compound (50 g). The obtained title compound was used in the next step without purification.

[0080] １ H NMR (400MHz, CDCl ３ ) δ (ppm): 12.57 (s, 1H), 8.29 (1H, d, J=15.6Hz), 7.99 (1H, d, J=2.0Hz), 7.88 (1H, d, J=7.2Hz), 7.77 (1H, d, J=7.7Hz), 7.64-7.68 (1H, m), 7.54-7.58 (2H, m), 7.50 (1H, d, J=15.6Hz), 6.96 (1H, d, J=9.2Hz). Mass spectrometry ESI (+): 371, 373 (calculated value: 370).

[0081] (Second Step) Preparation of Ethyl (E)-4-(4-bromo-2-(3-(2-(trifluoromethyl)phenyl)acryloyl)phenoxy)butanoate

[0082]

[0083] Potassium carbonate (20 g) and ethyl 4-bromobutanoate (23 g) were added to a solution of the compound obtained in the first step (40 g) in N,N-dimethylformamide (200 mL), and the mixture was stirred at 40°C for 24 hours. Water (400 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and washed with water. The organic layer was dehydrated and concentrated under reduced pressure, and then recrystallized from ethanol to obtain the title compound (41 g). The purity measured by HPLC (high performance liquid chromatography) was 99%.

[0084] １ H NMR (400MHz, CDCl ３ ​​) δ (ppm): 7.95 (1H, d, J=16.0Hz), 7.78 (1H, d, J=8.0Hz), 7.70-7.73 (1H, m), 7.45-7.61 (3H, m), 7.28 (1H, d, J=16.0Hz), 6.87 (1H, J=8.7Hz), 4.03-4.09 (4H, m), 2.39 (2H, t, J=7.1Hz), 2.04-2.10 (2H, m), 1.19 (3H, t, J=7.3Hz). Mass spectrometry ESI (+): 485, 487 (calculated value: 484).

[0085] (Third Step) Preparation of ethyl 4-(4-bromo-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)butanoate

[0086]

[0087] Phenylhydrazine (10 g) was added to a solution of the compound (30 g) obtained in the second step in ethanol (450 mL), and the mixture was stirred under reflux for 8 hours. The reaction mixture was cooled, and the precipitated solid was filtered to obtain the title compound (25 g) as a pale yellow solid. The HPLC purity was 99%.

[0088] １ H NMR (400MHz, CDCl ３ ) δ (ppm): 8.11 (1H, d, J=2.7Hz), 7.72 (1H, d, J=7.8Hz), 7.38-7.44 (1H, m), 7.33-7.36 (3H, m), 7.16-7.20 (2H, m), 6.98-7.00 (2H, m), 6.73-6.81 (2H, m), 5.66-5.70 (1H, m), 3.95-4.14 (5H, m), 3.18-3.24 (1H, m), 2.41 (2H, t, J=7.3Hz), 2.07 (2H, q, J=6.7Hz), 1.24 (3H, t, J=7.2Hz). Mass spectrometry ESI (+): 575, 577 (calculated value: 574).

[0089] ​(Fourth Step) Preparation of ethyl 4-(4-bromo-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate

[0090]

[0091] Manganese dioxide (42 g) was added to a solution of the compound (35 g) obtained in the third step in ethyl acetate (105 mL), and the mixture was stirred under reflux for 5 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated to obtain the title compound (35 g) as a yellow oil. The title compound obtained was used in the next step without purification.

[0092] １ H NMR (400MHz, CDCl ３ ) δ (ppm): 8.28 (1H, d, J=2.7Hz), 7.79 (1H, d, J=8.0Hz), 7.42-7.51 (2H, m), 7.37-7.39 (1H, m), 7.18-7.30 (6H, m), 7.08 (1H, s), 6.85 (1H, d, J=8.7Hz), 4.08-4.13 (4H, m), 2.52 (2H, t, J=7.3Hz), 2.13-2.20 (2H, m), 1.21 (3H, t, J=7.2Hz). Mass spectrometry ESI (+): 573, 575 (calculated value: 572).

[0093] (Fifth Step) Preparation of ethyl 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanoate

[0094]

[0095] ​The compound obtained in the fourth step (4 g), bis(pinacolato)diboron (2 g), potassium acetate (2 g), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (30 mg) were added to dimethyl sulfoxide (20 mL) and heated at 100°C under a nitrogen atmosphere for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. Column purification gave the title compound (1 g).

[0096] １ H NMR (400MHz, CDCl ３ ) δ (ppm): 8.50 (1H, d, J=1.8Hz), 7.75-7.79 (2H, m), 7.43-7.47 (2H, m), 7.18-7.33 (6H, m), 7.03 (1H, s), 6.97 (1H, s), 4.07-4.16 (4H, m), 2.53 (2H, t, J=7.3Hz), 2.16-2.19 (2H, m), 1.34 (12H, s), 1.18-1.22 (3H, m). Mass spectrometry ESI (+): 621 (calculated value: 620).

[0097] [Example 2]

[0098]

[0099] 4-(4-[ １８ F] fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid

[0100] (First step) Protons accelerated by a cyclotron (HM-20, Sumitomo Heavy Industries) are １８ O]H ２ Irradiate O and １８ After irradiation, [F]HF was generated. １８ F]HF to [ １８ O]H ２ The recovered [ １８ [F]F anion in 1M KHCO ３ The mixture was adsorbed onto Sep-Pak QMA carbonate light, which had been pretreated with 5 mL of aqueous solution and 8 mL of water.​１８ O]H ２ After collecting O, a methanol solution of tetrabutylammonium trifluoromethanesulfonate (10 mg (25.5 mmol) / 0.5 mL) was added to [ １８ The F]F anion was eluted into a reaction vessel. The reaction vessel was heated to 100°C under a helium stream to evaporate the solvent, and then cooled to room temperature. 5 mg (8.1 mmol) of the compound of Example 1 and tetrakis(pyridine)copper(II) triflate (Cu(OTf)) were added to the cooled reaction solution. ２ (py) ４ A dimethylacetamide solution (0.5 mL) containing 6 mg (8.8 mmol) of benzophenone was added, and the atmosphere in the reaction vessel was replaced with air. The reaction vessel was heated at 50° C. for 5 minutes and then at 120° C. for 20 minutes. １８ F-fluorination ( １８ After cooling the reaction vessel to room temperature, 0.4 mL of 1 M NaOH aqueous solution was added, and the mixture was heated again at 120°C for 5 minutes. After cooling the reaction solution to room temperature, 0.4 mL of 1 M hydrochloric acid and 0.8 mL of a 1:1 mixture of preparative HPLC solvent and water were added for neutralization. The crude product after neutralization was purified using a preparative HPLC system under the conditions of an HPLC column (YMC-Pack Pro C18 RS, 5 μm, 10 × 250 mm), mobile phase: acetonitrile / 50 mM acetic acid / 50 mM ammonium acetate = 600 / 200 / 200, flow rate 5 mL / min, and detection wavelength 254 nm, and the radioactive peak with a retention time of approximately 20 minutes was collected. The collected fraction was diluted with 40 mL of water and passed through a Sep-Pak tC18 short pretreated with 0.5 mL of ethanol and 40 mL of water to adsorb the title compound. After washing the tC18 short with 15 mL of water, the compound was eluted with 1.5 mL of ethanol into 12 mL of physiological saline containing 67 μL of Tween 80. The product was then sterile-filtered using a Millex GV filter, and the target product was collected in a sterile vial to serve as the final formulation of the title compound.

[0101] After measuring the volume of the final formulation, the radioactivity was measured using a dose calibrator (CRC-55tR, CAPINTEC). A portion was taken and the radiochemical purity and concentration of the title compound were measured using an analytical UPLC system [column: Titan C18 (1.9 μm, 2.1 × 50 mm, Supelco), mobile phase: acetonitrile / 50 mM acetic acid / 50 mM ammonium acetate = 600 / 200 / 200, flow rate: 0.25 mL / min, wavelength: 254 nm]. The specific radioactivity was calculated from the measured concentration and volume. Table 1 shows the results of the labeled synthesis of the compound of Example 2 (n = 8). The yield is shown as a value after decay correction.

[0102]

[0103] [Example 3] Biodistribution in normal mice The compound of Example 2 (2.1 MBq / 0.2 mL, 23 pmol) was rapidly administered into the tail vein of 20 9-week-old male ddY mice without anesthesia, and four mice were euthanized by cervical dislocation at 1, 5, 15, 30, and 60 minutes after administration. Immediately after euthanasia, blood was collected from the heart, and the heart, lungs, liver, pancreas, kidneys, spleen, muscle, femur, and brain were removed and their radioactivity and wet weight were measured using an auto-γ counter. The radioactivity was expressed in SUV (Standardized Uptake Value: unitless).

[0104]

[0105] Table 2 shows the results of the biodistribution test (SUV, n=4), and Figure 1 shows the time-radioactivity curve. The compound of Example 2 was rapidly eliminated from the blood after administration and showed high accumulation in the heart and kidney. On the other hand, accumulation in the brain was hardly observed. Furthermore, accumulation in the bone, which is an indicator of defluoridation in the body, was low, and １８ F-label stability was considered high.

[0106]

[0107] Example 4 PET Imaging in Normal Mice The compound of Example 2 (8.4 MBq, 45 pmol) was rapidly administered to a 9-week-old male C57BL / 6J mouse (25 g) via the tail vein without anesthesia, and imaging was performed for 60 minutes immediately after administration using a small animal whole-body PET / CT device (Si-78, Bruker Biospin).

[0108] Figure 2 shows the average images taken 50 to 60 minutes after administration. Similar to the results of the biodistribution test, the cardiac muscle tissue was clearly visualized, as high radioactivity accumulation in the heart and low radioactivity accumulation in the background areas of the lungs and liver were observed. Furthermore, brown adipose tissue could also be visualized, although its accumulation was lower than that of cardiac muscle tissue.

[0109] Example 5: Metabolic analysis of the compound of Example 2 in mouse blood and tissues. Metabolic analysis was performed to confirm the chemical form of the compound of Example 2 in mouse blood and target tissues. Six 9-week-old male ddY mice were rapidly administered the compound of Example 2 (37 MBq, 0.1 nmol) into the tail vein without anesthesia. Three mice were euthanized by cervical dislocation 15 and 30 minutes after administration. Immediately after euthanasia, blood was collected from the heart, and the hearts were excised. The whole blood was separated from the plasma using a centrifuge (Chibitan-R, Merck Millipore). 0.2 mL of acetonitrile was added to 0.1 mL of plasma for deproteinization, followed by centrifugation again. The supernatant was used as the sample for analysis. The hearts were thoroughly washed with distilled water, and 0.1 mg of a sample was taken, and 0.1 mL of distilled water was added and homogenized (ULTRA-TURRAX®, IKA). 0.2 mL of acetonitrile was added to 0.1 mL of the homogenized sample to remove proteins, followed by centrifugation. The supernatant was used as the analytical sample. Metabolite analysis was performed by TLC (Sil60 F254S Merck Millipore, dichloromethane / ethanol = 20:1). The developed TLC was contacted with an imaging plate to obtain an autoradiogram (Amersham Typhoo scanner, Cytiva).

[0110] The results of the metabolic analysis are shown in Table 3. The compound of Example 2 was stable in the mouse body and existed almost unchanged in the blood and myocardium. The fact that the compound is almost unchanged in the blood and target tissues is very important in terms of the reliability and quantitation of PET measurements.

[0111]

[0112] [Example 6] Effect of carrier on pharmacokinetics of the compound of Example 2 The effect of carrier (unlabeled corresponding to the compound of Example 2) on the accumulation of the compound of Example 2 in each organ １９ The effects of the compound of Example 2 (1.8 MBq / 0.1 mL, 4 pmol) and the carrier (1 mg / kg) were investigated. In the carrier-administered group, four 9-week-old male ddY mice were rapidly and simultaneously administered intravenously to the tail vein without anesthesia. In the control group, four 9-week-old male ddY mice were rapidly and simultaneously administered intravenously to the tail vein without anesthesia. The compound of Example 2 (1.8 MBq / 0.1 mL, 4 pmol) and a mixture of 10% v / v dimethyl sulfoxide / physiological saline were rapidly and simultaneously administered intravenously to the tail vein without anesthesia. Both groups were euthanized by cervical dislocation 60 minutes after administration. Immediately after euthanasia, blood was collected from the heart, and the heart, lungs, liver, kidneys, and muscles were removed and their radioactivity and wet weights were measured using an auto-gamma counter. The radioactivity was expressed in SUV.

[0113] The results of biodistribution are shown in Figure 3. With administration of the carrier, the concentration of the compound of Example 2 in the blood increased. Accordingly, radioactivity accumulation in the liver significantly increased. Meanwhile, radioactivity accumulation in the kidney and muscle significantly decreased. In the heart, expression of FBPA3, which is thought to be the target molecule of the compound of Example 2, was high, and sufficient binding inhibition did not occur with 1 mg / kg of the carrier. On the other hand, it is thought that an inhibitory effect was observed in the kidney and muscle, where the expression level of FABP3 is lower than in cardiomyocytes.

[0114] The increase in blood concentration of the compound of Example 2 was thought to be due to the release of the compound of Example 2 from peripheral tissues such as adipose tissues by the carrier. Therefore, when the tissue radioactivity concentration was corrected by the radioactivity concentration in blood, a significant decrease in the blood ratio was observed in the organs expressing FABP3, namely, the heart, lungs, kidneys, and muscle, but the increase in accumulation was negated in the liver, which does not express FABP3 (Figure 4). This indicates that the compound of Example 2 specifically and selectively binds to the target molecule FABP3 in vivo. In each graph of Figures 3 and 4, "Control" indicates the control group, and "Block" indicates the carrier-administered group.

[0115] Example 7 PET Imaging Using Myocardial Infarction Model Rat with the Compound of Example 2 FABP3 is covered by insurance as a blood marker for acute myocardial infarction, and it is known that FABP3 leaks from the myocardium into the blood during myocardial infarction. Since FABP3 decreases in damaged cardiomyocytes in the heart during myocardial infarction, it is assumed that the compound of the present invention can identify the site of infarction. Therefore, in order to verify whether the site of infarction can actually be identified, a surgically treated myocardial infarction model rat was used to verify whether the site of myocardial infarction can be accurately detected.

[0116] The left anterior descending artery of an 8-week-old male Wistar rat was ligated, and two days later, the compound of Example 2 (125 MBq, 0.3 nmol) was rapidly administered into the tail vein without anesthesia, and images were taken mainly of the chest for 20 minutes from 30 minutes after administration using a semiconductor PET device (MIP-100, Sumitomo Heavy Industries, Ltd.) designed for small animals.

[0117] The compound of Example 2 was able to visualize the myocardial infarction area corresponding to the area of ​​the blood vessels supplied by the left anterior descending artery and beyond as a defect image (Figure 5). １３ N]NH ３ When compared with １３ N]NH ３ However, the accumulation in the liver was high, making it difficult to visualize the affected area.

[0118] Example 8 PET Imaging Using a Myocarditis Model Rat with the Compound of Example 2 It is known that most cases of myocarditis are caused by bacterial or viral infections. In recent years, it has been suggested that not only is COVID-19 infection causing direct myocardial damage by the SARS-CoV-2 virus, leading to viral myocarditis, but also that COVID-19 infection may indirectly damage the heart through a systemic immune response, creating a need for a diagnostic method for myocarditis. Since elevated blood FBPA3 levels have also been reported in cases of myocarditis, the ability of the compound of Example 2 to detect myocardial lesions was examined using a rat model of autoimmune myocarditis.

[0119] A giant cell myocarditis model was created by administering purified porcine myocardial myosin to the sole of 6-week-old male Lewis rats (Kodama M. et al., Circ. Res. 75, pp. 278-284 (1994)). Three weeks after the start of immunization, the compound of Example 2 (127 MBq, 0.3 nmol) was rapidly administered into the tail vein without anesthesia. Images were taken of the chest area for 20 to 30 minutes after administration using a semiconductor PET device designed for small animals. After imaging, the rats were euthanized by exsanguination of the abdominal aorta under isoflurane anesthesia, and the hearts were removed. The radioactivity and wet weight were measured using an auto-gamma counter. The radioactivity was expressed in SUV (Standardized Uptake Value).

[0120] The compound of Example 2 was able to visualize defects at multiple sites corresponding to the lesions (Figure 6). As the myocardium / body weight ratio, which is an index of the severity of the myocarditis model, increased, the compound of Example 2's accumulation in the myocardium decreased. Furthermore, compared with normal rats, the compound showed a significantly reduced amount of myocardial accumulation (Figure 7).

[0121] Example 9 Biodistribution of the Compound of Example 2 in a Mouse Heart Failure Model Cardiotoxicity is known to be a serious side effect in cancer survivors treated with anticancer drugs, and cardio-oncology, a field relating to cancer and heart disease, has been proposed. Furthermore, elevated blood FABP3 levels have been reported in drug-induced myocardial injury models. Therefore, we used doxorubicin-induced heart failure mice as a drug-induced heart failure model to verify whether the compound of Example 2 could be evaluated.

[0122] An acute heart failure model was used in which 8-week-old male C57BL6 / J mice were intraperitoneally administered a single dose of 20 mg / kg of doxorubicin. One week after the final doxorubicin administration, the mice were rapidly administered the compound of Example 2 (0.5 MBq / 0.2 mL, 1 pmol) into the tail vein without anesthesia, and 60 minutes after administration, the mice were euthanized by cervical dislocation. Immediately after euthanasia, the hearts were removed, and the radioactivity and wet weight were measured using an auto-gamma counter. The radioactivity was expressed as SUV (Standardized Uptake Value).

[0123] In the acute heart failure model, the myocardial accumulation of the compound of Example 2 was significantly reduced compared to the healthy control group (FIG. 8).

[0124] [Example 10] The compound of Example 2 and [ １８ F] Comparison with flurpiridaz. Clinical development of the compound of Example 2 is currently underway in the United States and Japan to predict its myocardial imaging ability in anticipation of clinical use. １８ F] compared with flurpiridaz.

[0125] Nine-week-old male C57BL / 6J mice were injected with the compound of Example 2 (8 MBq, 40 pmol) and [ １８ [F] Flurpiridaz (8 MBq, 44 pmol) was rapidly administered to four animals in each group via the tail vein under anesthesia, and images were taken for 60 minutes immediately after administration using a small animal whole-body PET / CT scanner (Si-78, Bruker Biospin).

[0126] As shown in Figure 9, the heart was clearly visualized in the small animal PET / CT, and the accumulation kinetics of the compound of Example 2 (Figure 9a) was an accumulation type. The maximum myocardial accumulation of the compound of Example 2 (SUV = 6.0 ± 0.3, 55 minutes) was [ １８ F] flurpiridaz (Fig. 9b) (6.4±0.4, 6.5 min), but the maximum heart / liver ratio was higher for the compound of Example 2 (7.3±1.1, 55 min) than for the compound of Example 2 (7.3±1.1, 55 min). １８ F] flurpiridaz (5.2±1.1, 0.3 min) (p<0.05, unpaired t test with Welch's correction).

[0127] The radioactive triphenylpyrazole compound of the present invention is stable in vivo and can be used as an imaging agent in the PET method. In particular, by specifically binding to the fatty acid binding protein FBPA3, it is useful for diagnostic imaging of tissues expressing FABP3.

Claims

1. 4-(4-[ １８ F] fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid, or a salt thereof.

2. A pharmaceutical composition comprising the compound of claim 1 or a salt thereof, and optionally further comprising a pharmaceutically acceptable excipient.

3. An imaging agent comprising the compound of claim 1 or a salt thereof.

4. The imaging agent according to claim 3, which is an imaging agent for PET.

5. The imaging agent of claim 4, which is a diagnostic imaging agent.

6. The imaging agent of claim 4, which is an imaging agent for myocardium.

7. The imaging agent according to claim 4, which is an imaging agent for tissues expressing FABP3.

8. Formula (I): (In the formula, R １ is C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ Aralkyl, or C ６－１２ R represents aryl; ２ は-B(OR ３ ) ２ represents; R ３ are each independently H, C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ Aralkyl, or C ６－１２ aryl, or -B(OR ３ ) ２ are united, or a salt thereof, to a reaction for converting a carbon-boron bond into a carbon-fluorine bond [ １８ 2. A method for producing the compound according to claim 1 or a salt thereof, comprising the steps of: introducing [F] fluoro into the ester; and subjecting the ester to a reaction for converting into a carboxylic acid to form a carboxyl group.

9. The reaction of converting the carbon-boron bond to a carbon-fluorine bond is carried out by using a boronic acid compound represented by formula (I) or a salt thereof and a cyclotron-prepared boronic acid compound or a salt thereof. １８ The method according to claim 8, wherein the reaction is carried out with F ions in an organic solvent in the presence of a copper catalyst.

10. A compound of formula (I) or a salt thereof. (In the formula, R １ is C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ Aralkyl, or C ６－１２ R represents aryl; ２ は-B(OR ３ ) ２ represents; R ３ are each independently H, C １－６ Alkyl, C ２－６ Alkenyl, C ７－１２ Aralkyl, or C ６－１２ aryl, or -B(OR ３ ) ２ are united, It represents one of the following.) 11. Use of the compound or salt thereof according to claim 1 for the production of an imaging agent.

12. The compound or salt thereof according to claim 1 for use in the manufacture of an imaging agent.

13. An imaging method comprising administering to a subject an effective amount of the compound of claim 1 or a salt thereof.

14. The imaging method according to claim 13, wherein imaging is performed by a method selected from the group consisting of a PET method, a SPECT method, and a PET / CT method that combines a PET method and a CT method.

15. The imaging method according to claim 13, which is imaging by PET.

16. The imaging method of claim 15 for imaging cardiac muscle, kidney, skeletal muscle, blood vessels, tumors, or brown adipocytes.

17. A method for diagnosing a subject's myocardial condition, renal condition, skeletal muscle condition, vascular condition, tumor condition, or brown adipocyte condition, comprising utilizing results obtained by the imaging method of claim 16.

18. The diagnostic method according to claim 17, which is a method for diagnosing heart disease, kidney disease, skeletal muscle disease, vascular disease, tumor, or brown adipocytes.

19. The diagnostic method according to claim 18, wherein the heart disease is a heart disease selected from the group consisting of ischemic heart disease, myocardial infarction, heart failure, myocarditis, and cardiomyopathy.

20. The diagnostic method according to claim 18, wherein the renal disease is a renal disease selected from the group consisting of acute renal injury, drug-induced renal injury, and chronic renal injury.

21. The diagnostic method according to claim 18, wherein the skeletal muscle disease is a skeletal muscle disease selected from the group consisting of exercise-induced muscle damage, drug-induced skeletal muscle disorder, rhabdomyolysis, and sarcopenia.

22. The diagnostic method according to claim 18, wherein the vascular disease is a vascular disease selected from the group consisting of arteriosclerosis, peripheral arterial disease, and pulmonary thromboembolism.

23. The diagnostic method according to claim 18, wherein the tumor is a tumor selected from the group consisting of gastric cancer, non-small cell lung cancer, and uterine sarcoma.

24. The diagnostic method according to claim 18, wherein the brown adipocytes are brown adipocytes used for the diagnosis of metabolic function in obesity or diabetes, or as a companion diagnostic agent for the development of anti-obesity drugs.

Images