Novel compound

Abstract

To provide a labeling precursor for a compound suitable for imaging an intracerebral TRPV1 receptor.SOLUTION: The present invention provides a compound represented by a formula (IA) or a salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to novel compounds.

Background Art

[0002] In recent years, research has been conducted on various technologies for obtaining information in vivo. In particular, "molecular imaging," a technology capable of examining the behavior of target molecules, has attracted attention. Molecular imaging is considered useful for the early detection of various diseases and the development of effective pharmaceuticals with few side effects in a short period.

[0003] As molecular imaging for obtaining information in vivo, positron emission tomography (PET) is well known. PET is a technique for taking tomographic images using γ-rays emitted when a positron collides with an electron. Specifically, a molecule labeled with a radionuclide that emits a positron (so-called PET molecular probe) is administered into the body. When a positron emitted during the decay of the radionuclide collides with a nearby electron, two γ-rays with an energy of 511 KeV are emitted in opposite directions. By detecting these γ-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 disease diagnosis and the promotion of drug discovery research.

[0004] In the field of pain treatment, palliative care is the mainstream, and there is no radical treatment method. Regarding the evaluation of pain relief effects, although there are subjective indicators, there are no more accurate objective indicators and surrogate markers, and the evaluation of pain relief effects is limited to qualitative methods such as interviews, visual inspections, and palpations. As one means of objectively evaluating the pain relief effect, imaging diagnosis can be mentioned. In recent years, among imaging diagnoses, in particular, attempts have been made to use PET for the evaluation of pain relief effects. The reason is that PET has good resolution, there are various drugs that can be used for PET, and functional diagnosis is possible by PET. If PET can be used for the evaluation of pain relief effects, it will be possible to greatly improve medical technologies related to the diagnosis and / or treatment of pain without radical treatment methods.

[0005] The TRPV1 (Transient Receptor Potential Vanilloid 1) receptor is known as a nociceptor, and one of its functions is its function as a pain receptor. Therefore, TRPV1 receptor antagonists are expected to lead to the development of analgesics, and pharmaceutical companies are promoting the development of candidate compounds for TRPV1 receptor antagonists. In addition, the application of radiolabeled TRPV1 receptor antagonists as PET probes has also been proposed. As a PET probe using the TRPV1 receptor antagonists reported so far, for example, in Non-Patent Document 1, the 11 C-labeled PET probe ( 11

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] In the above 11 When imaging the TRPV1 receptor in the brain using CSB-366791, the TRPV1 receptor known to be present in the brain could not be effectively imaged.

[0008] One aspect of the present invention aims to provide a labeled precursor of a compound suitable for imaging the TRPV1 receptor in the brain.

Means for Solving the Problems

[0009] The compound according to one aspect of the present invention, or a salt thereof, is characterized in that, in order to solve the above problems, it is a compound represented by the following formula (IA) or formula (IB), or a salt thereof:

[0010]

Chemical formula

[0011]

Chemical formula

Advantages of the Invention

[0012] According to one aspect of the present invention, a labeled precursor of a compound capable of imaging the TRPV1 receptor in the brain can be provided.

Brief Description of the Drawings

[0013]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Embodiments for Carrying Out the Invention

[0014] One embodiment of the present invention will be described as follows, but the present invention is not limited thereto. The present invention is not limited to each configuration described below, and various modifications are possible within the scope shown in the claims. Embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in the technical scope of the present invention. In addition, all of the documents described in this specification are incorporated herein by reference.

[0015] 〔Embodiment 1〕 The compound according to this embodiment, or a salt thereof, is a compound represented by the following formula (I), or a salt thereof:

[0016]

Chemical formula

[0017] [In formula (I), R 1 is hydrogen or any organic group, R 2 is, when R 1 is hydrogen, an organic group having 2 or more carbon atoms, and when R 1 is other than hydrogen, is any organic group, R 1 and / or R 2 has a radioisotope].

[0018] The compound represented by formula (I), or a salt thereof, is a partial structure within SB-366791 and has a partial structure necessary for the binding between SB-366791 and the TRPV1 receptor. Therefore, the compound exhibits selective affinity for the TRPV1 receptor. Further, the compound has a radioisotope (for example, a short-lived radioisotope) at a site stable to metabolism. Therefore, the compound can not only visualize the distribution of the TRPV1 receptor but also accurately quantify the TRPV1 receptor. Further, the compound has high metabolic stability in vivo. Therefore, the compound is suitable for administration to a living body. Further, the compound tends to accumulate in the brain. Therefore, the compound is suitable for imaging of the central nervous system including the brain.

[0019] Here, R 1 in formula (I) is hydrogen or any organic group, and R 2 in formula (I) is, when R 1 is hydrogen, an organic group having 2 or more carbon atoms, and when R 1 is other than hydrogen, is any organic group. In the present specification, a substituent consisting only of hydrogen is not included in the "organic group".

[0020] R 1 and / or R 2The organic group in [compound] 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.

[0021] The organic group in the above-mentioned R 1 is preferably an alkyl group, and among them, those having 20 or less carbon atoms are preferable, those having 10 or less carbon atoms are more preferable, those having 5 or less carbon atoms are more preferable, those having 3 or less carbon atoms are more preferable, and a methyl group is particularly preferable. When R 1 is such an organic group, in the compound represented by the formula (I) and its salt, the structure is stabilized and the metabolic stability in vivo is improved.

[0022] The organic group in the above-mentioned R 2 is preferably an alkyl group, and among them, those having 20 or less carbon atoms are preferable, those having 10 or less carbon atoms are more preferable, those having 5 or less carbon atoms are more preferable, and those having 3 or less carbon atoms are more preferable. The organic group in the above-mentioned R 2 is preferably a fluoroalkyl group, and specifically, a fluoroethyl group, a fluoropropyl group, a fluorobutyl group, etc. can be exemplified. Also, when R 1 is hydrogen, R 2 may be a methyl group. When R 2 is such an organic group, in the compound represented by the formula (I) and its salt, the structure is stabilized and the metabolic stability in vivo is improved.

[0023] The above-mentioned R 1 and / or the above-mentioned R 2 any atom can be a radioisotope. The radioisotope is not particularly limited, but a short-lived radioisotope is preferable. Examples of the short-lived radioisotope include a radioisotope of carbon and a radioisotope of fluorine. Among them 11 C, 18F is preferred. As the long-lived radioisotope, 14 C is preferred.

[0024] 11 C (half-life: 20.4 minutes) has a short half-life, so the exposure when administered to a patient can be minimized. 18 F (half-life: 109.8 minutes) has a 11 longer half-life than 18 C, so the patient's exposure slightly increases, but 18 a time margin can be obtained from the synthesis of the compound having

[0025] F until its use. Since the compound according to this embodiment is not necessarily capable of in-situ preparation at the place of use,

[0026] [Embodiment 2] The imaging agent for TRPV1 receptor according to this embodiment contains, as an active ingredient, the compound or its salt according to Embodiment 1 of the present invention. The imaging agent for TRPV1 receptor according to this embodiment may be used for visualizing the brain (for example, visualizing a specific region of the brain) independently of the TRPV1 receptor. In this case, the imaging agent for TRPV1 receptor according to this embodiment can be a brain imaging agent.

[0027] The imaging agent according to this embodiment can be used for evaluating a pathological condition that affects the expression level of TRPV1 receptor (in other words, correlates with the expression level of TRPV1 receptor). Examples of the pathological condition include, but are not limited to, pain, cancer, osteoarthritis, postherpetic neuralgia, lung diseases (such as cough attacks and bronchial asthma), inflammatory bowel disease, and irritable bowel syndrome, and any pathological condition accompanied by pain. The cancer includes all solid cancers and blood cancers. Examples of the cancer that is particularly accompanied by severe pain include cancers that occur in bones, such as osteosarcoma and cancer with bone metastasis.

[0028] The imaging agent according to this embodiment can quantitatively image the TRPV1 receptor. Therefore, with the imaging agent according to this embodiment, the severity of the pathological condition can be quantitatively diagnosed.

[0029] As a method for evaluating the pathological condition, PET is preferable, but not limited thereto, and for example, SPECT (Single photon emission computed tomography) may also be used. Further, when the compound or its salt used is a 13 C-labeled substance, metabolite mass analysis by LC-MS (Liquid chromatography-mass spectrometry) is used. When the compound or its salt used is a 14 C-labeled substance, metabolite mass analysis by AMS (Accelerator mass spectrometry) can be used as a method for evaluating the pathological condition.

[0030] The imaging agent according to this embodiment can be used for PET imaging. When the imaging agent is used in PET, since the dosage of the imaging agent administered to the subject can be very small, pharmacological effects (such as pain relief and induction of a burning sensation) due to inhibition of the TRPV1 receptor do not appear in the subject, and it is safe. Further, with the imaging agent according to this embodiment, exposure to radioisotopes can be minimized.

[0031] The administration method of the imaging agent is not particularly limited. Specifically, examples of the administration method include injection administration (for example, intravenous administration and arterial administration), oral administration, nasal administration, oral mucosal administration, and transdermal administration. Therefore, the imaging agent for TRPV1 receptor according to the present embodiment can be an injection, an oral medicine, a nasal medicine, or an external medicine. The imaging agent may be prepared as either a solution or a suspension liquid preparation, or may be prepared as a solid preparation suitable for dissolving or suspending in a liquid (for example, a buffer solution).

[0032] Since the TRPV1 receptor functions as a pain receptor, it is known as a target molecule for analgesics and the like. Therefore, the imaging agent can be utilized for screening of pharmaceuticals targeting the TRPV1 receptor. As the screening method, for example, a method of visualizing the TRPV1 receptor with the imaging agent and screening a drug candidate substance whose expression level of the TRPV1 receptor changes by administration as a pharmaceutical can be considered. Examples of the drug candidate substance and the pharmaceutical include, but are not limited to, low molecular weight compounds, nucleic acids, peptides, and proteins such as antibodies. The screening can be carried out either in vitro or in vivo.

[0033] The amount of the active ingredient in the imaging agent of the present embodiment is not particularly limited. For example, it may be 0.001% by weight to 100% by weight, 0.01% by weight to 100% by weight, 0.1% by weight to 100% by weight, 0.1% by weight to 95% by weight, 0.1% by weight to 90% by weight, 0.1% by weight to 80% by weight, 0.1% by weight to 70% by weight, 0.1% by weight to 60% by weight, 0.1% by weight to 50% by weight, 0.1% by weight to 40% by weight, 0.1% by weight to 30% by weight, 0.1% by weight to 20% by weight, or 0.1% by weight to 10% by weight with respect to the imaging agent.

[0034] The imaging agent of the present embodiment may contain components other than the active ingredient (pharmaceutically acceptable carrier). Examples of components other than the active ingredient include excipients, lubricants, binders, and disintegrants when the imaging agent of the present embodiment is provided as a solid preparation, and solvents, solubilizers, suspending agents, isotonic agents, buffers, and soothing agents when the imaging agent of the present embodiment is provided as a liquid preparation. In addition, preservatives, antioxidants, and stabilizers can also be mentioned as components other than the active ingredient.

[0035] Examples of the above-mentioned "excipient" include, but are not limited to, lactose, sucrose, D-mannitol, xylitol, sorbitol, erythritol, starch, and crystalline cellulose.

[0036] Examples of the above-mentioned "lubricant" include, but are not limited to, magnesium stearate, calcium stearate, wax, talc, and colloidal silica.

[0037] Examples of the above-mentioned "binder" include, but are not limited to, pregelatinized starch, methylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

[0038] Examples of the above-mentioned "disintegrant" include, but are not limited to, starch, carboxymethylcellulose, low-substituted hydroxypropylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, and sodium carboxymethyl starch.

[0039] Examples of the above-mentioned "solvent" include, but are not limited to, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and tricaprylin.

[0040] Examples of the above-mentioned "dissolution aid" include, but are not limited to, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

[0041] Examples of the above-mentioned "suspending agent" include, but are not limited to, surfactants (e.g., stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate) and hydrophilic polymers (e.g., polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose).

[0042] Examples of the above-mentioned "isotonic agent" include, but are not limited to, sodium chloride, glycerin, and D-mannitol.

[0043] Examples of the above-mentioned "buffer" include, but are not limited to, phosphates, acetates, carbonates, and citrates.

[0044] Examples of the above-mentioned "anesthetic" include, but are not limited to, benzyl alcohol.

[0045] Examples of the above-mentioned "preservative" include, but are not limited to, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0046] Examples of the above-mentioned "antioxidant" include, but are not limited to, sulfites and ascorbic acid.

[0047] The above-mentioned "stabilizer" may be any one commonly used in the pharmaceutical field and is not particularly limited.

[0048] The amount of components other than the active ingredient in the imaging agent of the present embodiment is not particularly limited. For example, it may be 0 wt% to 99.999 wt%, 0 wt% to 99.99 wt%, 0 wt% to 99.9 wt%, 5 wt% to 99.9 wt%, 10 wt% to 99.9 wt%, 20 wt% to 99.9 wt%, 30 wt% to 99.9 wt%, 40 wt% to 99.9 wt%, 50 wt% to 99.9 wt%, 60 wt% to 99.9 wt%, 70 wt% to 99.9 wt%, 80 wt% to 99.9 wt%, or 90 wt% to 99.9 wt% with respect to the imaging agent.

[0049] 〔Embodiment 3〕 The imaging kit for TRPV1 receptor according to the present embodiment includes the compound described in [Embodiment 1] above, or a salt thereof. The imaging kit for TRPV1 receptor according to the present embodiment may be used to visualize the brain (for example, visualize a specific region of the brain) regardless of the TRPV1 receptor. In this case, the imaging kit for TRPV1 receptor according to the present embodiment may be a brain imaging kit.

[0050] By using the imaging kit for TRPV1 receptor according to the present embodiment, an imaging agent for TRPV1 receptor can be easily prepared and / or an imaging agent for TRPV1 receptor can be easily administered to a subject.

[0051] Since the compound and its salt provided in the kit of the present embodiment have been described in [Embodiment 1], the description thereof is omitted here.

[0052] The above imaging kit may include a configuration other than the compound described in [Embodiment 1] above, or a salt thereof (in other words, the active ingredient in the imaging agent for TRPV1 receptor).

[0053] Examples of the above configuration include excipients, lubricants, binders, and disintegrants. In this case, using the imaging kit of the present embodiment, an imaging agent for the TRPV1 receptor, which is a solid preparation, can be easily prepared. Further, examples of the configuration include solvents, solubilizing agents, suspending agents, isotonic agents, buffering agents, and soothing agents. In this case, using the imaging kit of the present embodiment, an imaging agent for the TRPV1 receptor, which is a liquid preparation, can be easily prepared. Further, examples of the configuration include preservatives, antioxidants, and stabilizers. In this case, using the imaging kit of the present embodiment, an imaging agent for the TRPV1 receptor that can be stored for a long time can be easily prepared.

[0054] Further, an example of the above configuration is a syringe. In this case, using the imaging kit of the present embodiment, an imaging agent for the TRPV1 receptor can be easily administered to a subject.

[0055] 〔Summary〕 The compound or its salt according to one aspect of the present invention is characterized in that, in order to solve the above problems, it is a compound represented by the following formula (I) or its salt:

[0056] [Chemical formula]

[0057] [In formula (I), R 1 is hydrogen or any organic group, R 2 is an organic group having 2 or more carbon atoms when R 1 is hydrogen, and is any organic group when R 1 is other than hydrogen, R 1 and / or R 2 has a radioisotope].

[0058] The imaging agent for TRPV1 receptor according to one aspect of the present invention is characterized by containing, as an active ingredient, a compound according to one aspect of the present invention or a salt thereof in order to solve the above problems.

[0059] The imaging agent for TRPV1 receptor according to one aspect of the present invention is preferably used for PET imaging or for evaluating a pathological condition that affects the expression level of TRPV1 receptor.

[0060] In the imaging agent for TRPV1 receptor according to one aspect of the present invention, it is preferable that the pathological condition is pain, cancer, osteoarthritis, postherpetic neuralgia, lung disease, inflammatory bowel disease, or irritable bowel syndrome.

[0061] The imaging kit for TRPV1 receptor according to one aspect of the present invention is characterized by comprising a compound represented by the following formula (I) or a salt thereof in order to solve the above problems:

[0062] [Chemical formula]

[0063] [In formula (I), R 1 is hydrogen or an arbitrary organic group, R 2 is an organic group having 2 or more carbon atoms when R 1 is hydrogen, and is an arbitrary organic group when R 1 is other than hydrogen, R 1 and / or R 2 has a radioisotope]. [Examples]

[0064] Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to the following examples.

[0065] [Synthesis of compound] (I) Synthesis of labeled precursor Compounds (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.

[0066]

Chemical formula

[0067] Compounds (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 methanesulfonate), 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), and compound (13) ((2E)- 3-(4-Chlorophenyl)-N-[4-(3-fluoropropoxyphenyl)-N-methyl-2-propenamide) were synthesized according to the following synthetic scheme.

[0068]

Chemical formula

[0069] The synthesis methods for each compound will be specifically described below.

[0070] (i) Synthesis of compound (1) ((2E)-3-(4-Chlorophenyl)-N-(4-hydroxyphenyl-2-propenamide) Compound (1) was synthesized according to the following synthetic scheme.

[0071]

Chemical formula

[0072] 4-chlorocinnamic acid (3.1 g, 17 mmol) was added to a dried eggplant flask (200 mL), and then anhydrous DMF (70 mL) was further added. While cooling this eggplant flask in an ice water bath, 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 taken out of 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. The solution in the eggplant flask was stirred overnight at room temperature to carry out the reaction. This reaction mixture was poured into purified water (200 mL) and extracted with ethyl acetate. The extract was washed with purified water and saturated brine, and after drying the extract with anhydrous magnesium sulfate, it was 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%).

[0073] 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), 13 C-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.:。

[0074] (ii) Synthesis of Compound (2) (2-Fluoroethyl p-toluenesulfonate) Compound (2) was synthesized according to the following synthetic scheme.

[0075]

Chemical Structure

[0076] To a solution of 2-Fluoroethanol (1.0 g, 15 mmol) in CHCl 3 (10 mL) stirred under ice-water cooling was added Et 3 N (2.38 mL, 17 mmol). 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 complete, the solution was stirred at room temperature overnight to effect the reaction. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (20 mL). The resulting solution was washed with purified water and saturated brine, and then anhydrous MgSO 4After drying using [specific method], this solution was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent; AcOEt:n-hexane) to obtain an oily compound (2) (2.1 g, 63%).

[0077] 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):

[0078] (iii) Synthesis of compound (3) (3-Fluoropropyl p-toluenesulfonate) Compound (3) was synthesized according to the following synthetic scheme.

[0079]

Chemical Structure

[0080] To a solution of methylene chloride (13 mL) containing 3-fluoropropanol (1.6 g, 20 mmol) stirred under ice-water cooling, Et 3 N (3.17 mL, 23 mmol) was added. 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 complete, the solution was stirred at room temperature overnight to allow the reaction to proceed. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (50 mL). The resulting solution was washed with purified water and saturated brine, and then dried using anhydrous MgSO 4 After drying, this solution was 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%).

[0081] 1 H-NMR (CDCl3 ) 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).:。

[0082] (iv) Synthesis of Compound (4) (SB366791) Compound (4) was synthesized according to the following synthetic scheme.

[0083]

Chemical Structure

[0084] To a dried screw-cap vial (10 mL) were added Compound (1) (500 mg, 1.8 mmol), K 2 CO 3 (127 mg, 0.9 mmol), and anhydrous DMF (6.3 mL). The suspension was stirred at room temperature for about 20 minutes, then CH 3 I (125 μL, 2 mmol) was added to the suspension. The screw-cap vial was placed in an 80 °C oil bath and stirred for 15.5 hours for the reaction. After the reaction mixture was allowed to cool, it was poured into cold purified water, and the resulting solid was collected by filtration to obtain the 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%).

[0085] 1 1H-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.:。

[0086] (v) Synthesis of compound (5) Compound (5) was synthesized according to the following synthetic scheme.

[0087]

Chemical Structure

[0088] Into a screw - cap vial (10 mL), compound (1) (400 mg, 1.5 mmol), K 2 CO 3 (111 mg, 0.8 mmol), and anhydrous DMF (4 mL) were added to form a suspension. After stirring this suspension at room temperature for about 20 minutes, a solution of compound (2) (349 mg, 1.6 mmol) in anhydrous DMF (1 mL) was added to the suspension. The suspension was stirred in an oil bath at 80 °C for 26 hours to carry out the reaction. After the reaction mixture was allowed to cool, it was poured into cold water, and the resulting solid was collected by filtration to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent CHCl 3 :CH 3 OH 100:0 → 99:1), and the target compound (5) (214 mg, 45%) was obtained.

[0089] 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 Hz, 4 Hz), 4.75 (dt, 48 Hz, 4 Hz). 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.:。

[0090] (vi) Synthesis of compound (6) Compound (6) was synthesized according to the following synthetic scheme.

[0091]

Chemical Structure

[0092] To a screw-cap vial (10 mL) were added compound (1) (400 mg, 1.5 mmol), K 2 CO 3 (111 mg, 0.8 mmol), and anhydrous DMF (5 mL). After stirring this suspension at room temperature for about 20 minutes, a solution of compound (3) (371 mg, 1.6 mmol) in anhydrous DMF (1 mL) was added to the suspension, and the suspension was stirred in an oil bath at 80 °C for 24 hours to effect the reaction. 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 (for 20 hours). After allowing the reaction mixture to cool, it was poured into cold purified water, and the resulting solid was collected by filtration to obtain the 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 target compound (6) (145 mg, 30%).

[0093] 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 H-F = 47.2 Hz, J H-H = 6.0 Hz), 4.06 (1H, t, J = 6Hz), 2.12 (2H, dq, J H-F = 26 Hz, J H-H = 6 Hz,); 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.:。

[0094] (vii) Synthesis of Compound (7) Compound (7) was synthesized according to the following synthetic scheme.

[0095] [Chemical formula]

[0096] A mixed solution of compound (1) (2.0 g, 7.3 mmol) and DHP (dihydropyrane) (1.5 g, 17.8 mmol) in CH 2 Cl 2 , 25 mL) was added with PPTS (Pyridinium p-toluenesulfonate) (80 mg, 0.3 mmol), and stirred at room temperature for 24 hours to cause a reaction. Since the residue of the raw material was observed, it was further stirred for 24 hours to cause a reaction. The reaction solution was CH 2 Cl2 (75 mL) was diluted, and the reaction solution was washed with NaOH aq. (1 mol / L), purified water, and saturated brine, and dried over anhydrous MgSO 4 . After drying, it was 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%).

[0097] 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.:。

[0098] (viii) Synthesis of Compound (8) Compound (8) was synthesized by the method shown in the following scheme.

[0099]

Chemical formula

[0100] To a three-way stopcock with a balloon, a septum rubber, and a two-necked flask equipped with a stir bar, which was filled with argon, were added compound (7) (500 mg, 1.4 mmol) and KOH (235 mg, 4 mmol, ground in a mortar). While immersing the two-necked flask in an ice-water bath, anhydrous DMF (6 mL) was further added thereto with a syringe. 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-necked 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 brine, and then dried over anhydrous MgSO 4 . The pasty crude product (414 mg) obtained by concentrating and drying the extract was subjected to silica gel column chromatography (eluent CHCl 3 :CH 3 OH = 100:1 → 50:1), and 365 mg (90%) of compound (8) was obtained.

[0101] 1 1H-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, m), 6.68 - 6.67 (1H, m), 6.43 (1H, d, J = 15.6 Hz), 3.25 (2H, s); 13 13C-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.:。

[0102] (ix) Synthesis of compound (9) Compound (9) was synthesized according to the following synthetic scheme.

[0103] [Chemical formula]

[0104] A solution of CH 2 Cl 2 (20 mL) containing 2-fluoroethanol (1.0 g, 15 mmol) was stirred under ice-cooling, and Et 3 N (2.6 mL, 18.7 mmol) was added. The solution was stirred at the same temperature for a while, and then a solution of methylene chloride (10 mL) containing methanesulfonyl chloride (2.1 g, 19 mmol) was added dropwise thereto over about 5 minutes. After the addition, the solution was stirred at room temperature overnight to effect the reaction. After completion of the reaction, the reaction mixture was washed with dilute hydrochloric acid (0.1 mol / L), purified water, and saturated brine, and dried over 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 light 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.

[0105] 1 1H-NMR (CDCl 3 ) δ: 4.61 (2H, dm, J H-F = 47.6 Hz), 4.35 (2H, dm, J H-F = 28.4 Hz), 3.01 (3H, S):.

[0106] (x) Synthesis of compound (10) Compound (10) was synthesized according to the following synthetic scheme.

[0107] [Chemical formula]

[0108] A solution of CH 2 Cl2 (20 mL) of the solution was added with Et 3 N (1.9 mL, 19 mmol). The solution was stirred briefly at the same temperature, 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 for reaction. The reaction mixture was concentrated under reduced pressure, the residue was redissolved in ethyl acetate (20 mL), and the resulting solution was washed with purified water and saturated brine, and dried using anhydrous MgSO 4 . After drying, the extract was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: AcOEt / n-hexane) to obtain an oily compound (10) (2.0 g, 83%) in quantitative yield.

[0109] 1 H-NMR (CDCl 3 ) δ: 4.59 (2H, dt, J H-F = 46.8 Hz, J H-H = 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):.

[0110] (xi) Synthesis of compound (11) Compound (11) was synthesized according to the following synthetic scheme.

[0111]

Chemical formula

[0112] To a screw-cap vial (10 mL), compound (8) (200 mg, 0.7 mmol), KOH (62 mg, 1.1 mmol), and dry DMF were added, and compound (8) and KOH were suspended in dry DMF. While stirring this solution under ice-cooling, methyl iodide (156 mg, 1.1 mmol) was added to the solution. After stirring the solution at the same temperature for a while, it was stirred in an oil bath at 60 °C for 16 hours to cause a reaction. 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 brine, dried using magnesium sulfate, and then concentrated under reduced pressure to obtain a pasty crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate:n-hexane) to obtain compound (11) (178 mg, 84%).

[0113] 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..

[0114] (xii) Synthesis of compound (12) Compound (12) was synthesized according to the following synthetic scheme.

[0115] [Chemical formula]

[0116] 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 brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a pasty crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate:n-hexane) to obtain compound (12) (120 mg, 68%). Additionally, 19 mg of unreacted starting material was also recovered.

[0117] 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, J = 12.8 Hz), 4.73 (2H, dm, J H-F = 48 Hz), 4.26 (2H, dm, J H-F = 30.4 Hz), 3.28 (3H, s); 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.:。

[0118] (xiii) Synthesis of compound (13) Compound (13) was synthesized according to the following synthetic scheme.

[0119]

Chemical formula

[0120] To a screw cap vial (10 mL), compound (8) (200 mg, 0.7 mmol), tetrabutyl ammonium hydroxide (62 mg, 1.1 mmol), and dry DMF were added, and compound (8) and tetrabutyl ammonium hydroxide were suspended in dry DMF. While stirring this solution under ice-cooling, compound (10) (164 mg, 1.1 mmol) was added to the solution. After stirring the solution at the same temperature for a while, it was stirred in an oil bath at 60 °C for about 16 hours to cause a reaction. 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 brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a pasty 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 material was also recovered.

[0121] 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.:。

[0122] (II) Synthesis of labeled compound (i) Synthesis of compound (14)( 11 C]SB366791) Compound (14) was synthesized according to the following synthetic scheme.

[0123] [Chemical formula]

[0124] 11 The production of the C nucleus was carried out using the cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. 14 N(p,α) 11 The nuclear synthesis reaction of C (current value 50 μA, irradiation time 51 minutes) was performed. 11 The synthesis of [C] methyl iodide was carried out using a dedicated labeling synthesis apparatus (manufactured by Sumitomo Heavy Industries, Ltd.). Specifically, 11 CO 2 gas was used as the starting material, and in the first reaction vessel, 11 CO 2 , 11 CH 3 OH, 11 CH 3 I were converted in sequence 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 distilled and transferred into the second reaction vessel. Subsequently, the solution in the second reaction vessel was heated at 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 (High Performance Liquid Chromatography). The fractionation 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 2O = 60:40, flow rate: 6.0 mL / min, retention time: 8.7 min, detection: UV254 nm, RI. The collected solution was concentrated using an evaporator, then diluted, passed through a membrane filter, and the target compound (14) (424 MBq, 62 GBq / μmol) was recovered in a vial.

[0125] (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 synthetic scheme.

[0126]

Chemical Structure

[0127] 18 F] Fluoride ions were produced by irradiating 18 O] water (Taiyo Nisso Co., Ltd., approximately 2 mL) with a 12 MeV electron beam 18 O(p,n) 18 F nuclear synthesis reaction (current value 35 μA, irradiation time 40 minutes). Approximately 40 GBq of 18 F] fluoride ion-containing 18 O] aqueous solution was transferred to a labeling synthesis apparatus (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell and adsorbed onto an anion exchange resin cartridge (Sep-Pak light QMA, manufactured by Waters). 18 F] Fluoride ions were adsorbed onto this cartridge. An acetonitrile aqueous solution (acetonitrile: water = 700 μL: 200 μL solution, 900 μL) containing cryptofix 222 (K 222 )(14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through, 18 F] KF was eluted, and the 18 ​A solution containing [F]KF was added into the first reaction vessel. This solution was heated at 120 °C under reduced pressure while flowing He gas to dry it. Subsequently, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were removed by azeotropic distillation.

[0128] 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 into the second reaction vessel. A phenol precursor (1.7 mg, 6.2 μmol), tetrabutylammonium hydroxide (2.5 μL of 1 M methanol solution, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and further 18 [F]Fluoroethyl bromide was distilled and transferred 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 preparative conditions in HPLC were as follows: column: COSMOSIL 5C 18 -AR-II 10×20 mm, 10×250 mm, developing solvent: CH 3 CN:H 2 O = 57:43, retention time: 10 minutes, flow rate: 6 mL / min, detection: UV254 nm, RI. The collected solution was concentrated by an evaporator, diluted after that, passed through a membrane filter, and the target compound (15) (2.04 GBq, 317 GBq / μmol) was recovered in a vial.

[0129] (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 synthetic scheme.

[0130]

Chemical formula

[0131] 18 ​F] Fluoride ions were irradiated with a 12 MeV electron beam using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. into 18 O] water (Taiyo Nisso Co., Ltd., approximately 2 mL) (current value 35 μA, irradiation time 40 minutes), 18 O(p,n) 18 F was produced by nuclear synthesis reaction. Approximately 40 GBq of 18 F] fluoride ion-containing 18 O] aqueous solution was transferred to a labeling synthesis apparatus (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and adsorbed onto an anion exchange resin cartridge (Sep-Pak light QMA, manufactured by Waters). 18 F] Fluoride ions were adsorbed onto this cartridge. An acetonitrile aqueous solution (acetonitrile: water = 700 μL: 200 μL solution, 900 μL) containing cryptofix 222 (K 222 )(14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through, 18 F] KF was eluted, and the solution containing the 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 dried to dryness. Subsequently, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were removed by azeotropic distillation.

[0132] 3-Bromopropyl tosylate (10 μL, 34 mmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, heated at 150 °C for 4 minutes, and the distillate was collected in the second reaction vessel. A phenol precursor (2.0 mg, 7.3 μmol), tetrabutylammonium hydroxide (2.5 μL of 1 M methanol solution, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and further 18 F] fluoropropyl bromide was distilled and transferred 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 fractionation conditions in HPLC were column: COSMOSIL 5C 18 -AR-II 10×20 mm, 10×250 mm, developing solvent: CH3 CN:H 2 O = 57:43, retention time: 13 minutes, flow rate: 6 mL / min, detection: UV254 nm, RI. The collected solution was concentrated using an evaporator, diluted, passed through a membrane filter, and the target compound (16) (1.18 GBq, 247 GBq / μmol) was recovered in a vial.

[0133] (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 synthetic scheme.

[0134]

Chemical formula

[0135] 11 The production of 11C nuclei was carried out using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. 14 N(p,α) 11 11C nuclear synthesis reaction (current value 50 μA, irradiation time 52 minutes). 11 The synthesis of methyl iodide labeled with 11C was carried out using a dedicated synthesis device for labeling (manufactured by Sumitomo Heavy Industries, Ltd.). Specifically, 11 CO 2 gas was used as the starting material, and in the first reaction vessel 11 CO 2 , 11 CH 3 OH, 11 CH 3 I were successively converted to materials to 11 CH 3 I was synthesized. A phenolic 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 3I was distilled and transferred into the second reaction vessel. Subsequently, the solution in the second reaction vessel was heated at 90 °C for 4 minutes to conduct the reaction. After the heating reaction, the second reaction vessel was cooled to room temperature, and the reaction product was subjected to HPLC. The fractionation 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: UV254 nm, RI. The fractionated solution was concentrated using an evaporator, then the solution was diluted and passed through a membrane filter, and the target compound (17) (4060 MBq, 48 GBq / μmol) was recovered in a vial.

[0136] (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 synthetic scheme.

[0137]

Chemical formula

[0138] 18 F] Fluoride ions were produced by irradiating 18 O] water (manufactured by Taiyo Nisso Co., Ltd., approximately 2 mL) with a 12 MeV electron beam using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. (current value 35 μA, irradiation time 40 minutes), 18 O(p,n) 18 F nuclear synthesis reaction. An aqueous solution containing approximately 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 passed through an anion exchange resin cartridge (Sep-Pak light QMA, manufactured by Waters). 18 O] aqueous solution was transferred to a labeling synthesis apparatus (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell and passed through an anion exchange resin cartridge (Sep-Pak light QMA, manufactured by Waters). 18 ​F]Fluoride ions were adsorbed. To this cartridge, an acetonitrile aqueous solution (acetonitrile: water = 700 μL: 200 μL solution, 900 μL) containing cryptofix 222 (K 222 )(14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through, 18 F]KF was eluted, and the solution containing the 18 F]KF was added into the first reaction vessel. This solution was heated at 120 °C under reduced pressure while flowing He gas to dryness. Subsequently, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were removed by azeotropic distillation.

[0139] 2-Bromoethyl tosylate (10 μL, 36 μmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, heated at 150 °C for 4 minutes, and the distillate was collected into the second reaction vessel. The phenol precursor (1.4 mg, 4.7 μmol), tetrabutylammonium hydroxide (2.5 μL of 1 M methanol solution, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel. Furthermore, 18 F]fluoroethyl bromide was distilled and transferred 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 preparative conditions in HPLC were column: COSMOSIL 5C 18 -AR-II 10×20 mm, 10×250 mm, developing solvent: CH 3 CN:H 2 O = 57:43, retention time: 10 minutes, flow rate: 6 mL / min, detection: UV254 nm, RI. The collected solution was concentrated by an evaporator, diluted, passed through a membrane filter, and the target compound (18) (2.81 GBq, 669 GBq / μmol) was recovered in a vial.

[0140] (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 synthetic scheme.

[0141] [Chemical formula]

[0142] 18 F] Fluoride ions were irradiated with a 12 MeV electron beam using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. 18 O] Water (Taiyo Nisso Co., Ltd., approximately 2 mL) (current value 35 μA, irradiation time 40 minutes), 18 O(p,n) 18 F was produced by nuclear synthesis reaction. Approximately 40 GBq of 18 F] fluoride ion-containing 18 O] aqueous solution was transferred to a labeling synthesis apparatus (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and adsorbed onto an anion exchange resin cartridge (Sep-Pak light QMA, manufactured by Waters). 18 F] Fluoride ions were adsorbed. To this cartridge, an acetonitrile aqueous solution (acetonitrile: water = 700 μL: 200 μL solution, 900 μL) containing cryptofix 222 (K 222 )(14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through, 18 F] KF was eluted, and the solution containing the 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 dried to dryness. Subsequently, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were removed by azeotropic distillation.

[0143] To the first reaction vessel, 3-bromopropyl tosylate (10 μL, 34 mmol) and 1,2-dichlorobenzene (400 μL) were added, heated at 150 °C for 4 minutes, and the distillate was collected in the second reaction vessel. A phenol precursor (1.9 mg, 6.6 μmol), tetrabutylammonium hydroxide (2.5 μL of 1 M methanol solution, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and further, 3-​18 F] The fluoropropyl bromide was distilled and transferred 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 fractionation conditions in HPLC were as follows: column: COSMOSIL 5C 18 -AR-II 10×20 mm, 10×250 mm, developing solvent: CH 3 CN:H 2 O = 57:43, retention time: 15 minutes, flow rate: 6 mL / min, detection: UV254nm, RI. The fractionated solution was concentrated using an evaporator, diluted, passed through a membrane filter, and the target compound (19) (1.93 GBq, 410 GBq / μmol) was recovered in a vial.

[0144] 〔Evaluation of Compounds〕 (PET Measurement) PET measurements were performed using 9-week-old male SD rats. The apparatus used was (microPET F220, manufactured by Siemens).

[0145] In the PET measurement, after a 30-minute transmission scan, one of the test substances of compounds (14) to (19) was injected into the tail vein by intravenous injection, and a 90-minute scan was performed. Table 1 shows the administration conditions of each compound.

[0146]

Table 1

[0147] The accumulation of each compound in the brain was evaluated using MAP (Maximum a posterior) with an integrated image of 3 - 20 minutes. The accumulation of each compound in the whole body was evaluated using MIP (Minimum intensity projection) with an integrated image of 0 - 90 minutes.

[0148] (Test Results) Figures 1 to 6 are, respectively, control labeled compounds according to the prior art 11Images showing the results of PET measurements using [[C]]SB366791 (Compound (14)), Compound (15), Compound (16), Compound (17), Compound (18), and Compound (19)). 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 throughout the body.

[0149] As is clear from (A) in each figure, for all of Compound (15) - (19), accumulation in the brain was improved compared to Compound (14).

[0150] Accumulation of the compounds throughout the body was significantly improved, particularly for Compound (17) - (19), as is clear from (B) in each figure. 1 It is thought that introducing a methyl group to [[R]]converted the easily decomposed amide group in vivo to a methylamide group, improving metabolic stability. In addition, accumulation in the liver, intestine, and bladder (kidney) was observed for all compounds. It is thought that this shows that localization changed from the liver to the intestine and bladder (kidney) in vivo and was then reabsorbed.

[0151] In addition, for Compound (15) - (19), accumulation was observed in the surface area of the body and in sensitive tactile areas such as the neck, axilla, and thigh. Since these areas are thought to be sites of high TRPV1 receptor expression, it is thought that this is the result of accurately imaging the TRPV1 receptor.

[0152] Figures 7 and 8 show the results of calculating the SUV (Standard Uptake Value) for the brain and skin in Compound (14) - (19) and plotting the time - radioactivity curve. The SUV was calculated by normalizing by the animal's body weight and administered radioactivity according to the following formula: SUV = (Tissue radioactivity (Bq) / Tissue weight (g)) / (Administered radioactivity (Bq) / Body weight (g)).

[0153] As is clear from Fig. 7, compared with the control compound (14), compounds (15), (16), and (19) showed improved accumulation in the brain. As is clear from Fig. 8, compared with the control compound (14), compounds (16) to (19) showed improved accumulation in the body surface part.

[0154] Thus, by using the present invention, not only can the distribution of the TRPV1 receptor be visualized, but the TRPV1 receptor can also be accurately quantified. According to the present invention, highly accurate imaging and quantification of the TRPV1 receptor with improved accumulation in the brain and accumulation in the whole body such as the skin have become possible.

Industrial Applicability

[0155] The present invention can be used for imaging of the TRPV1 receptor.

Claims

1. A compound represented by the following formula (IA) or a salt thereof: 【Chemistry 1】

2. A compound represented by the following formula (IB) or a salt thereof: 【Chemistry 2】

Images