JP7679000B2 - new compound - Google Patents

Description

The present invention relates to a novel compound.

In recent years, research has been conducted on various techniques for obtaining information inside the body, and in particular, "molecular imaging," a technique that can investigate the behavior of targeted molecules, has attracted attention. Molecular imaging is thought to be useful for the early detection of various diseases and for the rapid development of effective medicines with few side effects.

Positron emission tomography (PET) is a well-known molecular imaging technique for obtaining information within the body. PET is a technique for capturing tomographic images using gamma rays emitted when a positron collides with an electron. Specifically, a molecule labeled with a radioactive nuclide that emits positrons (a so-called PET molecular probe) is administered into the body. When a positron emitted during the decay of the radioactive nuclide collides with a nearby electron, two gamma rays with an energy of 511 KeV are emitted in a 180-degree direction. By detecting these gamma rays, the location of the PET molecular probe in the body and the amount of the substance can be quantitatively examined. Currently, the PET method is widely used as a molecular imaging technique for diagnosing diseases and promoting drug discovery research.

In the field of pain treatment, palliative care is the mainstream, and there is no cure. Although there are subjective indicators for evaluating the pain relief effect, there are no more accurate objective indicators or surrogate markers, and the evaluation of the pain relief effect is limited to qualitative methods such as interviews, visual inspection, and palpation. One method for objectively evaluating the pain relief effect is imaging diagnosis, and in recent years, attempts have been made to use imaging diagnosis, especially PET, to evaluate the pain relief effect. This is because PET has good resolution, a wide variety of drugs can be used with PET, and functional diagnosis is possible with PET. If PET could be used to evaluate the pain relief effect, it would be possible to significantly improve medical technology related to the diagnosis and/or treatment of pain for which there is no cure.

TRPV1 (Transient Receptor Potential Vanilloid 1) receptors are known as nociceptors, and one of their functions is as a pain receptor. Therefore, TRPV1 receptor antagonists are expected to lead to the development of analgesics, and pharmaceutical companies are developing candidate compounds for TRPV1 receptor antagonists. In addition, the application of radioisotope-labeled TRPV1 receptor antagonists as PET probes has also been proposed. As a PET probe using a TRPV1 receptor antagonist that has been reported so far, for example, Non-Patent Document 1 discloses a ¹¹ C-labeled PET probe ([ ¹¹ C]SB-366791) of the TRPV1 receptor antagonist SB-366791.

Daisy van Veghel et al., Nuclear Medicine and Biology, 40, 141-147, 2013

When imaging of the TRPV1 receptor in the brain was performed using the above-mentioned [ ¹¹ C]SB-366791, it was not possible to effectively image the TRPV1 receptor, which is known to be present in the brain.

One aspect of the present invention aims to provide a labeled precursor of a compound suitable for imaging the TRPV1 receptor in the brain.

In order to solve the above problems, the compound or salt thereof according to one embodiment of the present invention is characterized in that it is a compound or salt thereof represented by the following formula (IA) or formula (IB):

According to one aspect of the present invention, it is possible to provide a labeled precursor of a compound capable of imaging the TRPV1 receptor in the brain.

1 shows PET images of the brain (A) and whole body (B) when compound (14) according to the prior art was used. 1 shows images of the brain (A) and the whole body (B) by PET measurement when compound (15) according to one embodiment of the present invention was used. 1 shows images of the brain (A) and the whole body (B) by PET measurement when compound (16) according to one embodiment of the present invention was used. 1 shows images of the brain (A) and the whole body (B) by PET measurement when compound (17) according to one embodiment of the present invention was used. 1 shows PET images of the brain (A) and the whole body (B) when compound (18) according to one embodiment of the present invention was used. 1 shows PET images of the brain (A) and the whole body (B) when compound (19) according to one embodiment of the present invention was used. 1 is a graph showing changes in SUV over time in PET measurements in the brain when a compound according to an embodiment of the present invention and a compound according to the prior art are used. 1 is a graph showing the change in SUV over time in PET measurements of the body surface when a compound according to an embodiment of the present invention and a compound according to the prior art are used.

One embodiment of the present invention is described below, but the present invention is not limited to this. The present invention is not limited to the configurations described below, and various modifications are possible within the scope of the claims. The technical scope of the present invention also includes embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples. In addition, all of the documents described in this specification are incorporated herein by reference.

[Embodiment 1]
The compound according to the present embodiment, or a salt thereof, is a compound represented by the following formula (I), or a salt thereof:

[In formula (I),
^R1 is hydrogen or any organic group;
^R2 is an organic group having 2 or more carbon atoms when ^R1 is hydrogen, and is any organic group when ^R1 is other than hydrogen;
^R1 and/or ^R2 carry a radioisotope.

The compound represented by formula (I) or a salt thereof has a partial structure in SB-366791 that is necessary for the binding of SB-366791 to the TRPV1 receptor. Therefore, the compound exhibits selective affinity to the TRPV1 receptor. In addition, the compound has a radioisotope (e.g., a short-lived radioisotope) at a metabolically stable site. Therefore, the compound can not only visualize the distribution of the TRPV1 receptor, but also quantify the TRPV1 receptor with high accuracy. In addition, the compound has high metabolic stability in the living body. Therefore, the compound is suitable for administration to the living body. In addition, the compound is likely to accumulate in the brain. Therefore, the compound is suitable for imaging the central nervous system including the brain.

Here, ^R1 in formula (I) is hydrogen or any organic group, and ^R2 in formula (I) is an organic group having 2 or more carbon atoms when ^R1 is hydrogen, and is any organic group when ^R1 is other than hydrogen. In this specification, a substituent consisting only of hydrogen is not included in the "organic group".

The organic group in ^R1 and/or ^R2 is not particularly limited, and examples thereof include an aryl group, a heterocyclic group, an alkyl group, a fluoroalkyl group, an alkenyl group, a fluoroalkenyl group, an alkynyl group, a fluoroalkynyl group, an alkoxyl group, a fluoroalkoxyl group, an acetyl group, a carboxyalkyl group, and an alkylamide group.

The organic group in ^R1 is preferably an alkyl group, more preferably one having 20 or less carbon atoms, more preferably one having 10 or less carbon atoms, more preferably one having 5 or less carbon atoms, even more preferably one having 3 or less carbon atoms, and particularly preferably a methyl group. When ^R1 is such an organic group, the structure of the compound represented by formula (I) and its salts is stabilized, and the metabolic stability in the living body is improved.

The organic group in ^R2 is preferably an alkyl group, and more preferably has 20 or less carbon atoms, more preferably has 10 or less carbon atoms, more preferably has 5 or less carbon atoms, and more preferably has 3 or less carbon atoms. The organic group in ^R2 is preferably a fluoroalkyl group, and specific examples thereof include a fluoroethyl group, a fluoropropyl group, and a fluorobutyl group. In addition, when ^R1 is hydrogen, ^R2 may be a methyl group. If ^R2 is such an organic group, the structure of the compound represented by formula (I) and its salt is stabilized, and the metabolic stability in the living body is improved.

In the ^R1 and/or ^R2 , any atom may be a radioisotope. The radioisotope is not particularly limited, but a short-lived radioisotope is preferred. Examples of the short-lived radioisotope include a carbon radioisotope and a fluorine radioisotope, and among these, ^11C and ^18F are preferred. As a long-lived radioisotope, ^14C is preferred.

¹¹ C (half-life: 20.4 minutes) has a short half-life, so radiation exposure when administered to a patient can be minimized. ¹⁸ F (half-life: 109.8 minutes) has a long half-life compared to ¹¹ C, so radiation exposure to a patient increases slightly, but it is possible to obtain a time leeway from synthesis of a compound having ¹⁸ F to use. Since the compound according to this embodiment cannot necessarily be prepared at the site of use, a compound having ¹⁸ F is advantageous in that it can be synthesized in a dedicated synthesis facility or the like and then delivered to the site of use.

The salt of the compound represented by formula (I) above is not particularly limited and may be any salt. Examples of such salts include metal salts (sodium salt, magnesium salt, calcium salt, and potassium salt).

[Embodiment 2]
The TRPV1 receptor imaging agent according to the present embodiment contains the compound or a salt thereof according to embodiment 1 of the present invention as an active ingredient. The TRPV1 receptor imaging agent according to the present embodiment may be used to visualize the brain (e.g., visualize a specific region of the brain) independently of the TRPV1 receptor. In this case, the TRPV1 receptor imaging agent according to the present embodiment may be a brain imaging agent.

The imaging agent according to the present embodiment can be used to evaluate a pathology that affects the expression level of the TRPV1 receptor (in other words, correlates with the expression level of the TRPV1 receptor). Examples of the pathology include, but are not limited to, any pathology accompanied by pain, such as pain, cancer, osteoarthritis, postherpetic neuralgia, pulmonary disease (e.g., coughing attacks and bronchial asthma), inflammatory bowel disease, and irritable bowel syndrome. The cancer includes any solid cancer and blood cancer. Examples of the cancer that are particularly painful include cancers occurring in the bone, such as osteosarcoma and cancers that have metastasized to the bone.

The imaging agent according to the present embodiment can quantitatively image the TRPV1 receptor. Therefore, the imaging agent according to the present embodiment can quantitatively diagnose the severity of the pathology.

The method for evaluating the pathological condition is preferably PET, but is not limited thereto, and may be, for example, SPECT (Single photon emission computed tomography), etc. When the compound or its salt used is a ¹³ C-labeled product, metabolite amount analysis by LC-MS (Liquid chromatography-mass spectrometry) can be used as a method for evaluating the pathological condition, and when the compound or its salt used is a ¹⁴ C-labeled product, metabolite amount analysis by AMS (Accelerator mass spectrometry) can be used as a method for evaluating the pathological condition.

The imaging agent according to the present embodiment can be used for PET imaging. When the imaging agent is used in PET, only a small amount of the imaging agent is administered to the subject, so the pharmacological effects (such as pain relief and induction of a burn sensation) caused by inhibition of the TRPV1 receptor are not experienced by the subject, and the imaging agent according to the present embodiment is safe. Furthermore, the imaging agent according to the present embodiment can minimize exposure to radioisotopes.

The method of administration of the imaging agent is not particularly limited. Specific examples of administration methods include injection (e.g., intravenous administration and intraarterial administration), oral administration, nasal administration, oral mucosal administration, and transdermal administration. Therefore, the imaging agent for the TRPV1 receptor according to this embodiment may be an injection, an oral drug, an intranasal drug, or an external drug. The imaging agent may be prepared as a liquid formulation, either a solution or a suspension, or as a solid formulation suitable for dissolving or suspending in a liquid (e.g., a buffer solution).

The TRPV1 receptor functions as a pain receptor and is therefore known as a target molecule for analgesics and the like. Therefore, the imaging agent can be used to screen for drugs that target the TRPV1 receptor. As an example of the screening method, the imaging agent can be used to visualize the TRPV1 receptor, and drug candidate substances that change the expression level of the TRPV1 receptor upon administration can be screened as drugs. Examples of the drug candidate substances and drugs include, but are not limited to, low molecular weight compounds, nucleic acids, peptides, and proteins such as antibodies. The screening can be performed either in vitro or in vivo.

The amount of the active ingredient in the imaging agent of the present embodiment is not particularly limited, and may be, for example, 0.001% to 100% by weight, 0.01% to 100% by weight, 0.1% to 100% by weight, 0.1% to 95% by weight, 0.1% to 90% by weight, 0.1% to 80% by weight, 0.1% to 70% by weight, 0.1% to 60% by weight, 0.1% to 50% by weight, 0.1% to 40% by weight, 0.1% to 30% by weight, 0.1% to 20% by weight, or 0.1% to 10% by weight, relative to the imaging agent.

The imaging agent of the present embodiment may contain ingredients (pharmaceutical acceptable carriers) other than the active ingredient. When the imaging agent of the present embodiment is provided as a solid formulation, the ingredients other than the active ingredient may include excipients, lubricants, binders, and disintegrants, and when the imaging agent of the present embodiment is provided as a liquid formulation, the ingredients other than the active ingredient may include solvents, solubilizers, suspending agents, isotonicity agents, buffers, and soothing agents. Other ingredients other than the active ingredient may include preservatives, antioxidants, and stabilizers.

Examples of the above "excipients" include, but are not limited to, lactose, sucrose, D-mannitol, xylitol, sorbitol, erythritol, starch, and crystalline cellulose.

Examples of the "lubricant" include, but are not limited to, magnesium stearate, calcium stearate, wax, talc, and colloidal silica.

Examples of the "binder" include, but are not limited to, pregelatinized starch, methylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

Examples of the "disintegrants" include, but are not limited to, starch, carboxymethylcellulose, low-substituted hydroxypropylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, and sodium carboxymethylstarch.

Examples of the above "solvents" include, but are not limited to, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and tricaprylin.

Examples of the "solubilizing agent" include, but are not limited to, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

Examples of the "suspending agent" include, but are not limited to, surfactants (e.g., stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate) and hydrophilic polymers (e.g., polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose).

Examples of the above-mentioned "isotonicity agent" include, but are not limited to, sodium chloride, glycerin, and D-mannitol.

Examples of the above "buffering agent" include, but are not limited to, phosphates, acetates, carbonates, and citrates.

The above-mentioned "soothing agent" includes, but is not limited to, benzyl alcohol.

Examples of the "preservatives" include, but are not limited to, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

Examples of the "antioxidants" include, but are not limited to, sulfites and ascorbic acid.

The "stabilizer" mentioned above is not particularly limited and may be any that is commonly used in the pharmaceutical field.

The amount of ingredients other than the active ingredient in the imaging agent of this embodiment is not particularly limited, and may be, for example, 0% to 99.999% by weight, 0% to 99.99% by weight, 0% to 99.9% by weight, 5% to 99.9% by weight, 10% to 99.9% by weight, 20% to 99.9% by weight, 30% to 99.9% by weight, 40% to 99.9% by weight, 50% to 99.9% by weight, 60% to 99.9% by weight, 70% to 99.9% by weight, 80% to 99.9% by weight, or 90% to 99.9% by weight, relative to the imaging agent.

[Embodiment 3]
The TRPV1 receptor imaging kit according to the present embodiment includes the compound described in the above-mentioned [Embodiment 1] or a salt thereof. The TRPV1 receptor imaging kit according to the present embodiment may be used to visualize the brain (e.g., visualize a specific region of the brain) independently of the TRPV1 receptor. In this case, the TRPV1 receptor imaging kit according to the present embodiment may be a brain imaging kit.

By using the TRPV1 receptor imaging kit according to this embodiment, the TRPV1 receptor imaging agent can be easily prepared and/or the TRPV1 receptor imaging agent can be easily administered to a subject.

The compounds and their salts provided in the kit of this embodiment have been described in [Embodiment 1], so description thereof will be omitted here.

The imaging kit may include components other than the compound or salt thereof described in the above-mentioned [Embodiment 1] (in other words, the active ingredient in the imaging agent for the TRPV1 receptor).

Examples of the above components include excipients, lubricants, binders, and disintegrants. In this case, the imaging kit of this embodiment can be used to easily prepare an imaging agent for the TRPV1 receptor, which is a solid formulation. Examples of the components include solvents, solubilizers, suspending agents, isotonicity agents, buffers, and soothing agents. In this case, the imaging kit of this embodiment can be used to easily prepare an imaging agent for the TRPV1 receptor, which is a liquid formulation. Examples of the components include preservatives, antioxidants, and stabilizers. In this case, the imaging kit of this embodiment can be used to easily prepare an imaging agent for the TRPV1 receptor that can be stored for a long period of time.

Another example of the above configuration is a syringe. In this case, the imaging kit of this embodiment can be used to easily administer an imaging agent for the TRPV1 receptor to a subject.

〔summary〕
In order to solve the above-mentioned problems, a compound according to one aspect of the present invention, or a salt thereof, is characterized in that it is a compound represented by the following formula (I) or a salt thereof:

[In formula (I),
^R1 is hydrogen or any organic group;
^R2 is an organic group having 2 or more carbon atoms when ^R1 is hydrogen, and is any organic group when ^R1 is other than hydrogen;
^R1 and/or ^R2 carry a radioisotope.

In order to solve the above-mentioned problems, the imaging agent for the TRPV1 receptor according to one embodiment of the present invention is characterized in that it contains a compound according to one embodiment of the present invention or a salt thereof as an active ingredient.

The TRPV1 receptor imaging agent according to one embodiment of the present invention is preferably used for PET imaging or for evaluating a pathology that affects the expression level of the TRPV1 receptor.

In one embodiment of the imaging agent for the TRPV1 receptor of the present invention, the pathological condition is preferably pain, cancer, osteoarthritis, postherpetic neuralgia, pulmonary disease, inflammatory bowel disease, or irritable bowel syndrome.

In order to solve the above problems, the TRPV1 receptor imaging kit according to one embodiment of the present invention is characterized by comprising a compound represented by the following formula (I) or a salt thereof:

[In formula (I),
^R1 is hydrogen or any organic group;
^R2 is an organic group having 2 or more carbon atoms when ^R1 is hydrogen, and is any organic group when ^R1 is other than hydrogen;
^R1 and/or ^R2 carry a radioisotope.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.

[Synthesis of Compounds]
(I) Synthesis of labeled precursors Compound (4) ((2E)-3-(4-chlorophenyl)-N-(4-methoxyphenyl)-2-propenamide) (SB366791), compound (5) ((2E)-3-(4-chlorophenyl)-N-[4-(2-fluoroethoxy)-phenyl]-2-propenamide), and compound (6) ((2E)-3-(4-chlorophenyl)-N-[4-(3-fluoropropoxy)-phenyl]-2-propenamide) were synthesized according to the following synthetic scheme.

Compound (7) ((2E)-3-(4-Chlorophenyl)-N-[4-(tetrahydropyran-2-yl)oxyphenyl]-2-propenamide), Compound (8) ((2E)-3-(4-Chlorophenyl)-N-[4-(hydroxyphenyl)-N-methyl-2-propenamide), Compound (9) (2-Fluoroethyl compound (10) (3-Fluoropropyl methanesulfonate), compound (11) ((2E)-3-(4-Chlorophenyl)-N-(4-methoxyphenyl)-N-methyl-2-propenamide), Compound (12) ((2E)-3-(4-Chlorophenyl)-N-[4-(3-fluoroethoxyphenyl)-N-methyl-2-propenamide), Compound (13) ((2E)- 3-(4-Chlorophenyl)-N-[4-(3-fluoropropoxyphenyl)-N-methyl-2-propenamide) was synthesized according to the following synthesis scheme.

The synthesis method for each compound is explained in detail below.

(i) Synthesis of Compound (1) ((2E)-3-(4-Chlorophenyl)-N-(4-hydroxyphenyl-2-propenamide) Compound (1) was synthesized according to the following synthesis scheme.

4-chlorocinnamic acid (3.1 g, 17 mmol) was added to a dried eggplant flask (200 mL), and then anhydrous DMF (70 mL) was added. While cooling the eggplant flask with ice water, WSCI HCL (Water Soluble Carbodiimide hydrochloride: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) (3.6 g, 19 mmol) was further added. After stirring the solution in the eggplant flask at the same temperature for about 10 minutes, the eggplant flask was removed from the ice water bath, and HOBt (2.5 g, 19 mmol) and DMAP (2.3 g, 18.7 mmol) were added to the eggplant flask. After the addition, the solution in the eggplant flask was stirred for about 20 minutes, and then 3-hydroxyaniline (2.5 g, 19 mmol) was added to the eggplant flask, and the solution in the eggplant flask was stirred at room temperature overnight to allow the reaction to occur. The reaction mixture was poured into purified water (200 mL) and extracted with ethyl acetate. The extract was washed with purified water and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized using ethyl acetate:n-hexane to obtain compound (1) (2.8 g, 61%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.09 (1H, br. s), 9.43 (1H, s), 7.65 (2H d, J = 8.8 Hz, 4 Hz), 7.56 (1H, d, J = 14.8 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.30 (1H, t, J = 2 Hz), 7.09 (1H, dd, J = 8.0 Hz, 7.6 Hz), 7.05 (1H, dt, J =8.4 Hz, 1.6 Hz), 6.88 (1H, d, J = 8.4 Hz), 6.47 (1H, dt, J = 8.0 Hz, 1.6 Hz), ^13C -NMR (DMSO-d ₆ ) δ: 163. 1, 157.6, 140.2, 138.5, 134.1, 133.7, 129.4, 129.3, 129.0, 123.3, 110.6, 110.0, 106.4.:.

(ii) Synthesis of Compound (2) (2-Fluoroethyl p-toluenesulfonate) Compound (2) was synthesized according to the following synthesis scheme.

Et ₃ N (2.38 mL, 17 mmol) was added to a solution of 2-fluoroethanol (1.0 g, 15 mmol) in CHCl ₃ (10 mL) stirred under ice-water cooling. The solution was stirred at the same temperature for a while, and then p-TsCl (p-Toluenesulfonyl chloride) (3.3 g, 17 mmol) was added to the stirred solution over about 50 minutes. After the addition was completed, the solution was stirred at room temperature overnight to react. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (20 mL). The solution was washed with purified water and saturated saline, and then dried over anhydrous MgSO _4. The solution was then concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: AcOEt: n-hexane) to obtain oily compound (2) (2.1 g, 63%).

¹ H-NMR (CDCl ₃ ) δ: 7.8 (2H, d, J = 8.4 Hz), 7.36 (2H, d, J = 8.4 Hz), 4.65-4.61 (1H, m), 4.53-4.49 (1H, m), 4.32-4.28 (1H, m), 4.25-4.21 (1H, m), 2.46 (3H, s):.

(iii) Synthesis of Compound (3) (3-Fluoropropyl p-toluenesulfonate) Compound (3) was synthesized according to the following synthesis scheme.

Et ₃ N (3.17 mL, 23 mmol) was added to a methylene chloride (13 mL) solution containing 3-fluoropropanol (1.6 g, 20 mmol) while being stirred under ice-water cooling. The solution was stirred at the same temperature for a while, and then p-TsCl (4.2 g, 22 mmol) was added to the stirred solution over about 50 minutes. After the addition was completed, the solution was stirred at room temperature overnight to react. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (50 mL), and the solution was washed with purified water and saturated saline, and then dried with anhydrous MgSO _4. The solution was then concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: ethyl acetate: n-hexane) to obtain an oily compound (3) (2.1 g, 63%).

¹ H-NMR (CDCl ₃ ) δ: 7.8 (2H, d, J = 8, 4 Hz), 7.36 (2H d, J = 8.4 Hz), 4.65-4.61 (1H, m), 4.53-4.49 (1H, m), 4.32-4.28 (1H, m), 4.25-4.21 (1H, m), 2.46 (3H, s).:.

(iv) Synthesis of Compound (4) (SB366791) Compound (4) was synthesized according to the following synthesis scheme.

Compound (1) (500 mg, 1.8 mmol), K ₂ CO ₃ (127 mg, 0.9 mmol), and anhydrous DMF (6.3 mL) were added to a dry screw-cap vial (10 mL). After stirring the suspension at room temperature for about 20 minutes, CH ₃ I (125 μL, 2 mmol) was added to the suspension, and the screw-cap vial was placed in an oil bath at 80° C. and reacted with stirring for 15.5 hours. After cooling, the reaction mixture was poured into cold purified water, and the resulting solid was filtered to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent CHCl ₃ :CH ₃ OH=100:0→95:5) to obtain the target compound (4) (214 mg, 40%).

¹ H-NMR (DMSO-d ₆ ) δ: 9.75 (1H, 7.49 H, d, J = 15. 6Hz), 7.45-7.37 (4H, m, Ar-H), 7.25 (1H, t, J= 7.8 Hz), 6.78 (1H, dq, J = 8 Hz, 2 Hz), 6.72 (1H, dq, J = 8 Hz, 2 Hz), 6.68 (1H, t, J = 2 Hz), 6.43 (1H, d, J = 15.6 Hz), 3.25 (3H, s); ¹³ C-NMR (DMSO-d ₆ ) δ: 164.4, 158.2, 144.2, 139.0, 134.0, 133.6, 130.2, 129.3, 129.0, 128.9, 119.9, 117.6, 114.6, 113.9.:

(v) Synthesis of Compound (5) Compound (5) was synthesized according to the following synthesis scheme.

Compound (1) (400 mg, 1.5 mmol), _{K2CO3 (} 111 mg, 0.8 mmol), and anhydrous DMF (4 mL) were added to a screw cap vial (10 mL) to form a suspension, and the suspension was stirred at room temperature for about 20 minutes, after which an anhydrous DMF (1 mL) solution containing compound (2) (349 mg, 1.6 mmol) was added to the suspension, and the suspension was stirred in an oil bath at 80 ° C. for 26 hours to react. After cooling, the reaction mixture was poured into cold water, and the resulting solid was filtered to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent _CHCl3 : _CH3OH100 :0→99:1) to obtain the target compound (5) (214 mg, 45%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.21 (1H, br. s), 7.66 (2H, d, J = 15.6 Hz ), 7.58 (1H, d, J = 15.6 Hz), 7.51 (2H, m) 7.46 (1H, m), 4.21 (dt, 30 ¹³ C-NMR (DMSO-d ₆ ) δ: 163.3, 158.4, 140.3, 138.8, 134.2, 133.6, 129. 7, 123.0, 112.0, 109.3, 105.8, 82.9, 81.3, 67.1, 66.9.:.

(vi) Synthesis of Compound (6) Compound (6) was synthesized according to the following synthesis scheme.

Compound (1) (400 mg, 1.5 mmol), K ₂ CO ₃ (111 mg, 0.8 mmol), and anhydrous DMF (5 mL) were added to a screw cap vial (10 mL). After stirring the suspension at room temperature for about 20 minutes, an anhydrous DMF (1 mL) solution containing compound (3) (371 mg, 1.6 mmol) was added to the suspension, and the suspension was stirred in an oil bath at 80° C. for 24 hours to react. Since residual raw materials were observed, 3-fluoropropyl tosylate (123 mg, 0.5 mmol) and K ₂ CO ₃ (37 mg, 0.27 mmol) were added, and the reaction was continued (20 hours). After cooling the reaction mixture, it was poured into cold purified water, and the resulting solid was filtered to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent; CHCl ₃ :CH ₃ OH=100:0→80:20) to obtain the desired compound (6) (145 mg, 30%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, br. s), 7.67-7.63 (2H, m, Ar-H), 7.56 (1H, d, J = 5. 6 Hz), 7.53-7.49 (2H, m, Ar-H), 7.45 (1H, m), 7.26-7.17 (2H, m, Ar-H), 6.82 (1H, d, J = 15.6 Hz), 6.70-6.66 (1H, m), 4.62 (2H, dt, J _HF = 47.2 Hz, J _HH = 6.0 Hz), 4.06 (1H, t, J = 6Hz), 2.12 (2H, dq, J _HF = 26 Hz, J _HH = 6 ¹³ C-NMR (DMSO-d ₆ ) δ: 163.3, 158.4, 140.3, 138.8, 134.2, 133.6, 129.4, 129.0, 123.0, 112.0, 109.3, 105.8, 82.9, 81.3, 67.0, 66.9.:.

(vii) Synthesis of Compound (7) Compound (7) was synthesized according to the following synthesis scheme.

PPTS (pyridinium p-toluenesulfonate) (80 mg, 0.3 mmol) was added to a mixed solution (CH ₂ Cl ₂ , 25 mL) of compound (1) (2.0 g, 7.3 mmol) and DHP (dihydropyrane) (1.5 g, 17.8 mmol), and the mixture was stirred at room temperature for 24 hours to react. Since the raw material was found to remain, the mixture was further stirred for 24 hours to react. The reaction solution was diluted with CH ₂ Cl ₂ (75 mL), washed with NaOH aq. (1 mol/L), purified water, and saturated saline, dried over anhydrous MgSO ₄ , and then concentrated under reduced pressure to obtain a crude product (2.3 g). The crude product was recrystallized using ethyl acetate and n-hexane to obtain compound (7) (1.8 g, 68%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.20 (1H, br. s), 7.67-7.63 (2H, m, Ar-H), 7.56 (1H, d, 16 Hz), 7.53-7.45 (3H, m), 7.32-7.18 (3H, m, Ar-H), 6.81 (1H, d, J = 16 Hz), 6.76-6.69 (1H, m, Ar-H), 3.82-3.70 (1H, m), 3.61-3.49 (1H, m), 1.94-1.44 (6H, m), ¹³ C-NMR (DMSO-d ₆ ) δ: 163.3, 156.9, 140.2, 138.7, 134.2, 133.7, 129.3, 129.0, 123.1, 112.5, 111.4, 107.5, 95.9, 61.6, 29.9, 24.6, 18.6.:

(viii) Synthesis of Compound (8) Compound (8) was synthesized by the method shown in the following scheme.

Compound (7) (500 mg, 1.4 mmol) and KOH (235 mg, 4 mmol/mortar crushed product) were added to a two-neck flask equipped with a balloon-equipped three-way stopcock, a septum rubber, and a stirrer, in which argon was sealed, and anhydrous DMF (6 mL) was further added by syringe while the two-neck flask was immersed in an ice-water bath. After stirring at the same temperature for about 10 minutes, CH ₃ I (263 μL, 4.2 mmol) was added. After stirring at the same temperature for about 10 minutes and at room temperature for 30 minutes, the two-neck flask was transferred to an oil bath at 60° C. and reacted for 15.5 hours. The reaction mixture was allowed to cool to room temperature, poured into purified water, and extracted with ethyl acetate. The extract was washed with purified water and saturated saline, and then dried with anhydrous MgSO ₄ . The extract was concentrated to dryness to give a paste-like crude product (414 mg), which was subjected to silica gel column chromatography (eluent: CHCl ₃ :CH ₃ OH=100:1→50:1) to obtain 365 mg (90%) of compound (8).

¹ H-NMR (DMSO-d ₆ ) δ: 9.75 (1H, s), 7.49 (1H, d, J = 15.6 Hz), 7.45-6.37 (4H, m, Ar-H), 7.25 (1H, m), 6.81-6.75 (1H, m), 6.74-6.69 (1H, ¹³ C-NMR ₍ DMSO-d 6 ) δ: 164.4, 158.2, 144.2, 139.0, 134.0, 133.6, 130.2, 129.3, 128.8, 119.9, 117.6, 114.6, 113.9.:

(ix) Synthesis of Compound (9) Compound (9) was synthesized according to the following synthesis scheme.

Et ₃ N (2.6 mL, 18.7 mmol) was added to a CH ₂ Cl ₂ (20 mL) solution containing 2-fluoroethanol (1.0 g, 15 mmol) while being stirred under ice-water cooling. The solution was stirred at the same temperature for a while, and then a methylene chloride (10 mL) solution containing methanesulfonyl chloride (2.1 g, 19 mmol) was added dropwise to the solution over about 5 minutes. After the dropwise addition, the solution was stirred overnight at room temperature to react. After the reaction was completed, the reaction mixture was washed with dilute hydrochloric acid (0.1 mol/L), purified water, and saturated saline, and dried with anhydrous MgSO _4. The solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: AcOEt: n-hexane) to obtain a pale brown oily compound (9) (1.8 g, 80%). The compound (9) obtained by this method could be used in the next step (O-alkylation reaction) without further purification.

¹ H-NMR (CDCl ₃ ) δ: 4.61 (2H, dm, J _HF = 47.6 Hz), 4.35 (2H, dm, J _HF = 28.4 Hz), 3.01 (3H, S):.

(x) Synthesis of Compound (10) Compound (10) was synthesized according to the following synthesis scheme.

Et ₃ N (1.9 mL, 19 mmol) was added to a CH ₂ Cl ₂ (20 mL) solution containing 3-Fluoropropanol (1.2 g, 15 mmol) under ice-water cooling. The solution was stirred at the same temperature for a while, and then p-MsCl (2.1 g, 19 mmol) was added to the solution over about 50 minutes. After the addition, the solution was stirred at room temperature overnight to react. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (20 mL). The solution was washed with purified water and saturated saline, dried over anhydrous MgSO ₄ , and then the extract was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: AcOEt/n-hexane) to obtain oily compound (10) (2.0 g, 83%) in quantitative yield.

¹ H-NMR (CDCl ₃ ) δ: 4.59 (2H, dt, J _HF = 46.8 Hz, J _HH = 6.0 Hz), 4.38 (2H, d, J = 6.0 Hz), 3.04 (3H, s), 2.15 (2H, dq, J _H,F = 25.6 Hz, J _H,H = 6.0 Hz):.

(xi) Synthesis of Compound (11) Compound (11) was synthesized according to the following synthesis scheme.

Compound (8) (200 mg, 0.7 mmol), KOH (62 mg, 1.1 mmol), and dry DMF were added to a screw-cap vial (10 mL), and compound (8) and KOH were suspended in dry DMF. Methyl iodide (156 mg, 1.1 mmol) was added to the solution while stirring under ice-water cooling. The solution was stirred at the same temperature for a while, and then stirred in an oil bath at 60°C for 16 hours to react. The reaction mixture was allowed to cool, poured into purified water, and extracted with ethyl acetate. The extract was washed with purified water and saturated saline, dried with magnesium sulfate, and concentrated under reduced pressure to obtain a paste-like crude product. The crude product was subjected to silica gel column chromatography (eluent ethyl acetate: n-hexane) to obtain compound (11) (178 mg, 84%).

¹ H-NMR (DMSO-d ₆ ) δ: 7.49 (1H, d, J = 15.6 Hz), 7.46-7.33 (4H, m, Ar-H), 6.97-6.92 (2H, m, Ar-H), 6.88-6.85 (1H, m, Ar-H), 6.44 (1H, d, J = 15.6 Hz), 3.77 (3H, s), 3.28 (3H, s), ; ¹³ C-NMR (DMSO-d ₆ ) δ : 164.4, 160.0, 144.4, 139.1, 134.0, 133.6, 130.2, 129.3, 128.9, 119.9, 113.2, 112.7, 55.3, 37.0.:.

(xii) Synthesis of Compound (12) Compound (12) was synthesized according to the following synthesis scheme.

In a screw-cap vial (10 mL), a solution was prepared by dissolving compound (8) (150 mg, 0.55 mmol), compound (9) (85 mg, 0.6 mmol), and tetrabutyl ammonium hydroxide (1 M soln. 660 μL, 0.6 mmol) in dry DMF. This solution was stirred in an oil bath at 60°C for about 24 hours to react. The reaction mixture was allowed to cool, poured into purified water, and extracted with ethyl acetate. This extract was washed with purified water and saturated saline, dried with magnesium sulfate, and then concentrated under reduced pressure to obtain a paste-like crude product. The crude product was subjected to silica gel column chromatography (eluent ethyl acetate: n-hexane) to obtain compound (12) (120 mg, 68%). In addition, 19 mg of unreacted raw materials were also collected.

¹ H-NMR (DMSO-d ₆ ) δ: 7.49 (1H, d, J = 15.6 Hz), 7.46-7.34 (4H, m, Ar-H), 7.02-6.96 (2H, m, Ar-H), 6.91-6.86 (1H, m, Ar-H), 6.44 (1H, br.d, ₁₃ C-NMR (DMSO ^- _{d 6} ) δ: 164.4, 158.9, 144.4, 139.1, 134.0, 133.6, 130.2, 129.3, 128.9, 119.9, 119.8, 113.8, 113.3, 82.8, 81.2, 67.3, 67.1, 37.0.:

(xiii) Synthesis of Compound (13) Compound (13) was synthesized according to the following synthesis scheme.

Compound (8) (200 mg, 0.7 mmol), tetrabutyl ammonium hydroxide (62 mg, 1.1 mmol), and dry DMF were added to a screw-cap vial (10 mL), and compound (8) and tetrabutyl ammonium hydroxide were suspended in the dry DMF. Compound (10) (164 mg, 1.1 mmol) was added to the solution while stirring under ice-water cooling. The solution was stirred at the same temperature for a while, and then stirred in an oil bath at 60°C for about 16 hours to react. The reaction mixture was allowed to cool, poured into purified water, and extracted with ethyl acetate. The extract was washed with purified water and saturated saline, dried with magnesium sulfate, and concentrated under reduced pressure to obtain a paste-like crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate: n-hexane) to obtain compound (13) (104 mg, 43%). In addition, 59 mg of unreacted raw materials were also collected.

¹ H-NMR (DMSO-d ₆ ) δ: 7.52 (1H, d, J = 15.6 Hz), 7.46-7.33 (4H, m, Ar-H), 6.97-6.92 (2H, m, Ar-H), 6.88-6.85 (1H, m, Ar-H), 6.44 (1H, d, J = 15.6 Hz), 3.77 (3H, s), 3.28 (3H, s); ¹³ C-NMR (DMSO-d ₆ ) δ: 164.4, 160.0, 144.4, 139.1, 134.0, 133.6, 130.2, 129.3, 128.9, 119.9, 113.2, 112.7, 55.3, 37.0.:.

(II) Synthesis of Labeled Compounds (i) Synthesis of Compound (14) ([ ¹¹ C]SB366791) Compound (14) was synthesized according to the following synthesis scheme.

The production of ¹¹ C nuclei was carried out by ^{a 14} N(p,α) ¹¹ C nucleus synthesis reaction (current value 50 μA, irradiation time 51 minutes) using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. The synthesis of [ ¹¹ C]methyl iodide was carried out using a dedicated labeling synthesis device (manufactured by Sumitomo Heavy Industries, Ltd.). Specifically, ¹¹ CO ₂ gas was used as the starting material, and the materials were converted in the order of ¹¹ CO ₂ , ¹¹ CH ₃ OH, and ¹¹ CH ₃ I in the first reaction vessel to synthesize ¹¹ CH ₃ I. A phenol precursor (0.4 mg, 1.5 μmol), cesium carbonate (Cs ₂ CO ₃ ) (4.0 mg, 12.3 μmol), and DMF (300 μL) were placed in the second reaction vessel in advance, and then ¹¹ CH ₃ I synthesized in the first reaction vessel was transferred by distillation to the second reaction vessel. Then, the solution in the second reaction vessel was heated at 90° C. for 4 minutes to carry out a reaction. After the heating reaction, the second reaction vessel was cooled to room temperature, and the reaction product was subjected to HPLC (High performance liquid chromatography). The HPLC separation conditions were as follows: column: COSMOSIL 5- _C18AR -II 10x20 mm, 10x250 mm, developing solvent: _CH3CN : _H2O = 60:40, flow rate: 6.0 mL/min, retention time: 8.7 min, detection: UV 254 nm, RI. The separated solution was concentrated using an evaporator, and then diluted and passed through a membrane filter to recover the target compound (14) (424 MBq, 62 GBq/μmol) in a vial.

(ii) Synthesis of compound (15) ([ ¹⁸ F](2E)-3-(4-Chlorophenyl)-N-[4-(2-fluoroethoxy)-phenyl]-2-propenamide) Compound (15) was synthesized according to the following synthesis scheme.

[ ¹⁸ F] fluoride ions were produced by the nuclear synthesis reaction of 18 O(p,n) 18 F by irradiating [ ¹⁸ O] water (Taiyo Nippon Sanso, about 2 mL) with a ¹² MeV electron beam (current value 35 μA, irradiation time 40 minutes) using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. The [ ¹⁸ O] aqueous solution containing about 40 GBq of [ ¹⁸ F] fluoride ions was transferred to a labeling synthesis apparatus (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and the [ ¹⁸ F] fluoride ions were adsorbed onto an anion exchange resin cartridge (Sep- ^Pak light QMA, manufactured by Waters). An aqueous acetonitrile solution (acetonitrile:water=700 μL:200 μL solution, 900 μL) containing Kryptofix 222 (K ₂₂₂ ) (14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through this cartridge to elute [ ¹⁸ F]KF, and the solution containing [ ¹⁸ F]KF was added to the first reaction vessel. This solution was heated to 120° C. under reduced pressure while flowing He gas, and was dried to solidification. Next, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were removed by azeotropy.

2-Bromoethyl tosylate (10 μL, 36 μmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, and the mixture was heated at 150° C. for 4 minutes, and the distillate was collected in the second reaction vessel. Phenol precursor (1.7 mg, 6.2 μmol), tetrabutylammonium hydroxide (1 M methanol solution, 2.5 μL, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and 2-[ ¹⁸ F]fluoroethyl bromide was transferred by distillation to the second reaction vessel, and the second reaction vessel was heated at 130° C. for 7 minutes. The second reaction vessel was cooled to room temperature, and the reaction product was subjected to HPLC. The HPLC conditions for fractionation were as follows: column: COSMOSIL _5C18 -AR-II 10x20 mm, 10x250 mm, developing solvent: _CH3CN : _H2O = 57:43, retention time: 10 min, flow rate: 6 mL/min, detection: UV 254 nm, RI. The fractionated solution was concentrated using an evaporator, diluted, and then passed through a membrane filter to recover the target compound (15) (2.04 GBq, 317 GBq/μmol) in a vial.

(iii) Synthesis of compound (16) ([ ¹⁸ F](2E)-3-(4-Chlorophenyl)-N-[4-(3-fluoropropoxy)-phenyl]-2-propenamide) Compound (16) was synthesized according to the following synthesis scheme.

[ ¹⁸ F] fluoride ions were produced by the nuclear synthesis reaction of 18 O(p,n) 18 F by irradiating [ ¹⁸ O] water (Taiyo Nippon Sanso, about 2 mL) with a ¹² MeV electron beam (current value 35 μA, irradiation time 40 minutes) using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. The [ ¹⁸ O] aqueous solution containing about 40 GBq of [ ¹⁸ F] fluoride ions was transferred to a labeling synthesis apparatus (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and the [ ¹⁸ F] fluoride ions were adsorbed onto an anion exchange resin cartridge (Sep- ^Pak light QMA, manufactured by Waters). An aqueous acetonitrile solution (acetonitrile:water=700 μL:200 μL solution, 900 μL) containing Kryptofix 222 (K ₂₂₂ ) (14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through this cartridge to elute [ ¹⁸ F]KF, and the solution containing [ ¹⁸ F]KF was added to the first reaction vessel. This solution was heated to 120° C. under reduced pressure while flowing He gas, and was dried to solid. Next, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were removed by azeotropy.

3-Bromopropyl tosylate (10 μL, 34 mmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, and the mixture was heated at 150° C. for 4 minutes, and the distillate was collected in the second reaction vessel. Phenol precursor (2.0 mg, 7.3 μmol), tetrabutylammonium hydroxide (1 M methanol solution, 2.5 μL, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and 3-[ ¹⁸ F]fluoropropyl bromide was transferred by distillation to the second reaction vessel, and the second reaction vessel was heated at 130° C. for 7 minutes. The second reaction vessel was cooled to room temperature, and the reaction mixture was subjected to HPLC. The HPLC conditions for fractionation were as follows: column: COSMOSIL _5C18 -AR-II 10x20 mm, 10x250 mm, developing solvent: _CH3CN : _H2O = 57:43, retention time: 13 minutes, flow rate: 6 mL/min, detection: UV 254 nm, RI. The fractionated solution was concentrated using an evaporator, and the solution was diluted and then passed through a membrane filter to recover the target compound (16) (1.18 GBq, 247 GBq/μmol) in a vial.

(iv) Synthesis of compound (17) ([ ¹¹ C](2E)-3-(4-Chlorophenyl)-N-(4-methoxyphenyl)-N-methyl-2-propenamide) Compound (17) was synthesized according to the following synthesis scheme.

The production of ¹¹ C nuclei was carried out by ^{a 14} N(p,α) ¹¹ C nucleus synthesis reaction (current value 50 μA, irradiation time 52 minutes) using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. The synthesis of [ ¹¹ C]methyl iodide was carried out using a dedicated labeling synthesis device (manufactured by Sumitomo Heavy Industries, Ltd.). Specifically, ¹¹ CO ₂ gas was used as the starting material, and the materials were converted in the first reaction vessel in the order of ¹¹ CO ₂ , ¹¹ CH ₃ OH, and ¹¹ CH ₃ I to synthesize ¹¹ CH ₃ I. The phenol precursor (0.86 mg, 3.0 μmol), cesium carbonate (Cs ₂ CO ₃ ) (2.0 mg, 6.1 μmol), and DMF (300 μL) were placed in the second reaction vessel in advance, and then ¹¹ CH ₃ I synthesized in the first reaction vessel was transferred by distillation to the second reaction vessel. The solution in the second reaction vessel was then heated to 90° C. for 4 minutes to carry out the reaction. After the heating reaction, the second reaction vessel was cooled to room temperature, and the reaction product was subjected to HPLC. The separation conditions in HPLC were as follows: column: COSMOSIL 5-C ₁₈ AR-II 10×20 mm, 10×250 mm, developing solvent: CH ₃ CN:H ₂ O=60:40, flow rate: 6.0 mL/min, retention time: 10.2 min, detection: UV 254 nm, RI. The collected solution was concentrated using an evaporator, then the solution was diluted and passed through a membrane filter to recover the target compound (17) (4060 MBq, 48 GBq/μmol) in a vial.

(v) Synthesis of Compound (18) ([ ¹⁸ F](2E)-3-(4-Chlorophenyl)-N-[4-(3-fluoroethoxyphenyl)-N-methyl-2-propenamide) Compound (18) was synthesized according to the following synthesis scheme.

[ ¹⁸ F] fluoride ions were produced by the nuclear synthesis reaction of 18 O(p,n) 18 F by irradiating [ ¹⁸ O] water (Taiyo Nippon Sanso, about 2 mL) with a ¹² MeV electron beam (current value 35 μA, irradiation time 40 minutes) using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. The [ ¹⁸ O] aqueous solution containing about 40 GBq of [ ¹⁸ F] fluoride ions was transferred to a labeling synthesis apparatus (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and the [ ¹⁸ F] fluoride ions were adsorbed onto an anion exchange resin cartridge (Sep- ^Pak light QMA, manufactured by Waters). An aqueous acetonitrile solution (acetonitrile:water=700 μL:200 μL solution, 900 μL) containing Kryptofix 222 (K ₂₂₂ ) (14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through this cartridge to elute [ ¹⁸ F]KF, and the solution containing [ ¹⁸ F]KF was added to the first reaction vessel. This solution was heated to 120° C. under reduced pressure while flowing He gas, and was dried to solid. Next, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were removed by azeotropy.

2-Bromoethyl tosylate (10 μL, 36 μmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, and the mixture was heated at 150° C. for 4 minutes, and the distillate was collected in the second reaction vessel. Phenol precursor (1.4 mg, 4.7 μmol), tetrabutylammonium hydroxide (1 M methanol solution, 2.5 μL, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and 2-[ ¹⁸ F]fluoroethyl bromide was transferred by distillation to the second reaction vessel, and the second reaction vessel was heated at 130° C. for 7 minutes. The second reaction vessel was cooled to room temperature, and the reaction mixture was subjected to HPLC. The HPLC conditions for fractionation were as follows: column: COSMOSIL _5C18 -AR-II 10x20 mm, 10x250 mm, developing solvent: _CH3CN : _H2O = 57:43, retention time: 10 min, flow rate: 6 mL/min, detection: UV 254 nm, RI. The fractionated solution was concentrated using an evaporator, and the solution was diluted and then passed through a membrane filter to recover the target compound (18) (2.81 GBq, 669 GBq/μmol) in a vial.

(vi) Synthesis of compound (19) ([ ¹⁸ F](2E)-3-(4-Chlorophenyl)-N-[4-(3-fluoropropoxyphenyl)-N-methyl-2-propenamide) Compound (19) was synthesized according to the following synthesis scheme.

[ ¹⁸ F] fluoride ions were produced by the nuclear synthesis reaction of 18 O(p,n) 18 F by irradiating [ ¹⁸ O] water (Taiyo Nippon Sanso, about 2 mL) with a ¹² MeV electron beam (current value 35 μA, irradiation time 40 minutes) using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. The [ ¹⁸ O] aqueous solution containing about 40 GBq of [ ¹⁸ F] fluoride ions was transferred to a labeling synthesis apparatus (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and the [ ¹⁸ F] fluoride ions were adsorbed onto an anion exchange resin cartridge (Sep- ^Pak light QMA, manufactured by Waters). An aqueous acetonitrile solution (acetonitrile:water=700 μL:200 μL solution, 900 μL) containing Kryptofix 222 (K ₂₂₂ ) (14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through this cartridge to elute [ ¹⁸ F]KF, and the solution containing [ ¹⁸ F]KF was added to the first reaction vessel. This solution was heated to 120° C. under reduced pressure while flowing He gas, and was dried to solid. Next, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were removed by azeotropy.

3-Bromopropyl tosylate (10 μL, 34 mmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, and the mixture was heated at 150° C. for 4 minutes, and the distillate was collected in the second reaction vessel. Phenol precursor (1.9 mg, 6.6 μmol), tetrabutylammonium hydroxide (1 M methanol solution, 2.5 μL, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and 3-[ ¹⁸ F]fluoropropyl bromide was distilled and transferred to the second reaction vessel, which was heated at 130° C. for 7 minutes. The second reaction vessel was cooled to room temperature, and the reaction mixture was subjected to HPLC. The HPLC conditions for fractionation were as follows: column: COSMOSIL _5C18 -AR-II 10x20 mm, 10x250 mm, developing solvent: _CH3CN : _H2O = 57:43, retention time: 15 min, flow rate: 6 mL/min, detection: UV 254 nm, RI. The fractionated solution was concentrated using an evaporator, diluted, and then passed through a membrane filter to recover the target compound (19) (1.93 GBq, 410 GBq/μmol) in a vial.

[Evaluation of Compounds]
(PET measurement)
PET measurements were performed using 9-week-old male SD rats using a microPET F220 (Siemens) device.

In the PET measurements, after a 30-minute transmission scan, one of the test substances (14) to (19) was injected intravenously into the tail vein, and scanning was performed for 90 minutes. The administration conditions for each compound are shown in Table 1.

Accumulation of each compound in the brain was evaluated using MAP (Maximum a posterior) images accumulated over 3-20 minutes. Accumulation of each compound in the whole body was evaluated using MIP (Minimum intensity projection) images accumulated over 0-90 minutes.

(Test Results)
1 to 6 are images showing the results of PET measurements using the control labeled compounds [ ¹¹ C]SB366791 (compound (14)), compound (15), compound (16), compound (17), compound (18) and compound (19) according to the prior art, respectively. More specifically, (A) in each figure is an image showing the results of PET measurements in the brain, and (B) in each figure is an image showing the results of PET measurements in the whole body.

As is clear from (A) of each figure, compounds (15) to (19) all showed improved accumulation in the brain compared to compound (14).

As is clear from (B) of each figure, the accumulation of the compounds in the whole body was significantly improved, especially in compounds (17) to (19). This is thought to be because the introduction of a methyl group into ^R1 converted the amide group, which is easily decomposed in the body, into a methylamide group, improving metabolic stability. In addition, accumulation in the liver, intestinal tract, and bladder (kidneys) was observed for all compounds. This is thought to be due to the observation that the localization of the compounds changes from the liver to the intestinal tract and bladder (kidneys) in the body, and that they are then reabsorbed.

Compounds (15) to (19) were also observed to accumulate on the body surface and in areas sensitive to touch, such as the neck, armpits, and thighs. These areas are thought to be areas where the TRPV1 receptor is highly expressed, and this is believed to be the result of accurate imaging of the TRPV1 receptor.

7 and 8 show the results of calculating the standard uptake values (SUVs) in the brain and skin and plotting the time-radioactivity curves for compounds (14) to (19). The SUVs were calculated by normalizing with the animal's body weight and the administered radioactivity according to the following formula:
SUV=(tissue radioactivity (Bq)/tissue weight (g))/(administered radioactivity (Bq)/body weight (g)).

As is clear from Figure 7, compounds (15), (16), and (19) showed improved accumulation in the brain compared to the control compound (14). As is clear from Figure 8, compounds (16) to (19) showed improved accumulation on the body surface compared to the control compound (14).

In this way, the present invention not only makes it possible to visualize the distribution of TRPV1 receptors, but also allows for accurate quantification of TRPV1 receptors. The present invention makes it possible to image and quantify TRPV1 receptors with high accuracy, with improved accumulation in the brain and throughout the body, including the skin.

The present invention can be used for imaging the TRPV1 receptor.

Claims (2)

A compound represented by the following formula (IA) or a salt thereof:
A compound represented by the following formula (IB) or a salt thereof:

Images