Fatty acid derivatives labeled with positron-emitting nuclides

Abstract

[Problem] To provide a labeled fatty acid derivative for diagnostic imaging that enables the quantification of myocardial fatty acid metabolic activity. [Solution] The inventors, engaging in diligent research into methods that enable the quantification of fatty acid metabolic activity, discovered that a labeled fatty acid derivative represented by formula (I), in which [18F] has been substituted at a specific position of a long-chain carboxylic acid compound containing a sulfur atom, or a salt thereof, has good accumulation in the myocardium, and enables imaging of fatty acid metabolic activity via positron emission tomography (PET). Therefore, the labeled fatty acid derivative according to the present invention can be used as a radiotracer for swift and noninvasive quantification of myocardial fatty acid metabolic activity, diagnostic imaging of heart diseases such as ischemic heart disease, diagnostic imaging of the therapeutic effects yielded by a heart disease therapeutic agent, and so forth.

Description

[Technical field]

[0001] The present invention relates to a fatty acid derivative or a salt thereof labeled with a positron-emitting nuclide. It also relates to a composition for diagnostic imaging containing the labeled fatty acid derivative or a salt thereof, and a kit for preparing the same. [Background technology]

[0002] The heart requires a large amount of adenosine triphosphate (ATP) to pump blood throughout the body, and most of it is produced by oxidative metabolism in mitochondria. Various substrates such as fatty acids and glucose are metabolized in the myocardium, and when oxygen is abundant in the myocardium, approximately 60-90% of the required ATP is produced by β-oxidation of fatty acids. On the other hand, it is known that the rate of oxidative metabolism decreases and the rate of ATP production by anaerobic metabolism increases under ischemic conditions (Expert Rev. Cardiovasc. Ther. 2007;5(6):1123-1134.). For this reason, quantifying fatty acid metabolic activity in the myocardium is one of the effective means for diagnosing heart disease.

[0003] The quantitative determination of fatty acid metabolic activity is carried out by positron emission tomography (PET) or single photon emission computed tomography (SPECT) using a labeled long-chain fatty acid derivative as a radiolabeled tracer. The radiolabeled tracer used in SPECT is 15-(p-[ 123 Iodophenyl)-3(R,S)-methylpentadecanoic acid (hereinafter, [ 123 I]BMIPP) has been reported (Non-Patent Document 1), and is actually used clinically for the diagnosis of heart diseases.

[0004] [ka] (In the formula, Me represents a methyl group. The same applies hereinafter.)

[0005] On the other hand, the radiolabeled tracer used in PET is 16-[ 18 F]Fluoro-4-thiahexadecanoic acid (16-[18 F]fluoro-4-thiapalmitic acid, hereinafter 18 F]FTP) is known (Patent Document 1).

[0006] [ka]

[0007] Similarly, the radiolabeled tracer used in PET is 18 F]FTP, which shows improved cardiac accumulation. 18 F]fluorotetradec-5-en-1-yl]sulfanyl}propanoic acid (18-[ 18 F]fluoro-4-thiaoleic acid, hereinafter 18 F]FTO) has been reported (Non-Patent Document 2).

[0008] [ka] However, it is used as a tracer in diagnostic imaging using SPECT. 123 I]BMIPP has issues with its low sensitivity and resolution, and the tracer [ 18 F]FTP and [ 18 Regarding FTO, 123 Although this is superior to SPECT using I]BMIPP, further improvements in sensitivity and resolution are required for more accurate diagnosis.

[0009] In addition, Patent Document 2, which was published after the priority date of the present application, discloses a radiolabeled tracer for use in PET, which is represented by the following formula: 3-{[(5Z)-3-[ 18 F]fluorotetradec-5-en-1-yl]sulfanyl}propanoic acid (7-[ 18 F]fluoro-4-thiaoleic acid, hereafter referred to as 7-[ 18 F]FTO is described.

[0010] [ka] [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2000 / 063216 [Patent Document 2] International Publication No. 2020 / 017620 [Non-patent literature]

[0012] [Non-Patent Document 1] Eur. J. Nucl. Med., 1989, 15, 341-345 [Non-Patent Document 2] J. Nucl. Med., 2010, 51(8), 1310-1317 Summary of the Invention [Problem to be solved by the invention]

[0013] There is a strong need for the development of radiolabeled tracers that have selective accumulation in the heart, have improved sensitivity and resolution, and enable accurate diagnosis of heart disease. [Means for solving the problem]

[0014] It is a known PET tracer [ 18 In PET imaging using F]FTO, not only the heart but also the bones are 18 Accumulation of [F] fluorine was observed, which resulted in an increase in background values ​​and a decrease in sensitivity and resolution (for example, [ 18 (See PET imaging with F]FTO).

[0015] Further investigation revealed that there are two pathways for the oxidation of long-chain fatty acids: β-oxidation and ω-oxidation. In ω-oxidation, fatty acids are metabolized from the terminal side farther from the carboxyl group. 18 During the metabolism of FTO, 18 F] fluoride ion is generated, and 18 F] Sodium fluoride accumulates in bones, 18 [F]FTO is produced during the metabolic process 18 We speculated that [F] fluoride ions may be the cause of nonspecific accumulation in bone.

[0016] Therefore, the present inventors have investigated the metabolic 18 As a result of our intensive research aimed at creating a labeled fatty acid derivative that is less likely to generate [F] fluoride ions, we unexpectedly found that a long-chain carboxylic acid compound containing a sulfur atom has a [ 18 The labeled fatty acid derivative represented by formula (I) in which F is substituted with fluorine is 18 Compared to FTO, 18 The present invention has been completed based on the discovery that fluoride ions have low accumulation in bones, selectively accumulate in the heart, and can be used as a radiolabeled tracer for imaging fatty acid metabolism in the myocardium with high sensitivity. 18 By introducing [F] fluorine, metabolic stability against ω-oxidation from the terminal side far from the carboxyl group was improved, and [ 18 It is presumed that this suppresses the production of [F] fluoride ions, resulting in reduced accumulation in bones.

[0017] That is, the present invention relates to a labeled fatty acid derivative represented by formula (I) or a salt thereof. [ka] (In the formula, L is C 2-4 is alkylene, R is C 6-14 is an alkyl group, 6-14 The alkyl group may have 1 to 3 double bonds. 6-14Three consecutive carbon atoms in the alkyl may be joined together to form a cyclopropane ring; However, this does not include the case where R is a (2Z)-undec-2-en-1-yl group.

[0018] Unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0019] The present invention also provides a method for producing a semiconductor device comprising the steps of: (1) A composition for diagnostic imaging, particularly a composition for diagnostic imaging of heart disease, more particularly ischemic heart disease, comprising a labeled fatty acid derivative of the formula (I) or a salt thereof and a pharma- ceutically acceptable carrier; (2) Use of a labeled fatty acid derivative of formula (I) or a salt thereof for the manufacture of a composition for diagnostic imaging of heart disease, particularly ischemic heart disease. (3) Use of a labeled fatty acid derivative of formula (I) or a salt thereof for diagnostic imaging of heart disease, particularly ischemic heart disease. (4) A labeled fatty acid derivative of formula (I) or a salt thereof for use in diagnostic imaging of heart disease, particularly ischemic heart disease. (5) A method for diagnostic imaging of heart disease, particularly ischemic heart disease, which comprises administering to a subject a detectable amount of a labeled fatty acid derivative of formula (I) or a salt thereof. (6) An intermediate compound or a salt thereof which can be converted into the labeled fatty acid derivative of formula (I) or a salt thereof. (7) A method for producing a labeled fatty acid derivative of formula (I) or a salt thereof from the intermediate compound of (6) or a salt thereof, and (8) The present invention also relates to a kit for diagnostic imaging, which comprises the intermediate compound of (6) or a salt thereof and is used for preparing the composition for diagnostic imaging of (1).

[0020] The "subject" refers to a human or other animal in need of the diagnosis, and in one embodiment, the subject is a human in need of the diagnosis. Effect of the Invention

[0021] The labeled fatty acid derivative or its salt represented by formula (I) of the present invention is a known labeled fatty acid.18 Compared with [F]FTO, there is no increase in background value due to accumulation in bone, and it has good accumulation in cardiac muscle, enabling imaging of fatty acid metabolic activity by PET. Therefore, the labeled fatty acid derivative represented by formula (I) of the present invention or a salt thereof can be used as a radiolabeled tracer for the identification of patients with heart disease, imaging diagnosis of the therapeutic effect of a heart disease therapeutic agent, etc. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows PET images of normal cynomolgus monkeys administered the compound of Reference Example 15 ([18F]FTO) and the compound of Example 6 in Example 8. PET images taken 60 minutes and 180 minutes after administration of [18F]FTO are shown in (A) and (B), respectively. PET images taken 60 minutes and 180 minutes after administration of the compound of Example 6 are shown in (C) and (D), respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention will be described in detail below.

[0024] In this specification, " 18 "F labeling reagent" means [ 18 F] is a reagent containing fluoride ion, e.g., 18 F] Tetra-n-butylammonium fluoride (hereinafter [ 18 F]TBAF), [ 18 F] Potassium fluoride (hereinafter [ 18 F]KF) etc.

[0025] In the present specification, the term "optionally substituted" means unsubstituted or bonded to one or more optional substituents.

[0026] In this specification, "C 2-4 "Alkylene" means a straight or branched alkylene having 2 to 4 carbon atoms (hereinafter, C 2-4and the like. In one embodiment, it is ethylene, trimethylene, or tetramethylene, and in another embodiment, it is ethylene or trimethylene, and in another embodiment, it is ethylene.

[0027] "C 6-14 "Alkyl" means a straight or branched C 6-14 For example, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, isooctyl, 4-ethylheptyl, or 3,3-dimethyldecyl. 6-14 In one embodiment, it is n-octyl, n-nonyl, n-decyl, n-undecyl, or n-dodecyl. In one embodiment, it is n-undecyl.

[0028] "C 6-14 The term "alkyl may have 1 to 3 double bonds" means that the C 6-14 This means including groups in which the carbon-carbon single bond contained in the alkyl is replaced with a double bond. In one embodiment, R is n-undecyl having 1 to 3 double bonds. In another embodiment, R is (2E)-undec-2-en-1-yl, (2Z,5Z)-undeca-2,5-dien-1-yl, or (2Z,5Z,8Z)-undeca-2,5,8-trien-1-yl.

[0029] "C 6-14 "Three consecutive carbon atoms in the alkyl may be joined together to form a cyclopropane ring" means that the C 6-14 It means that the carbon atoms at both ends of the three consecutive carbon atoms contained in the alkyl are bonded with a single bond. In one embodiment, the C 6-14Three consecutive carbon atoms in the alkyl may be joined to form 1 to 3 cyclopropane rings, and in one embodiment, R is (2-octylcyclopropyl)methyl.

[0030] "Lower alkyl" means a straight or branched C 1-6 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc. 1-4 In one embodiment, it is alkyl, and in another embodiment, it is methyl, ethyl, or t-butyl, and in another embodiment, it is methyl.

[0031] The term "leaving group" refers to a substituent that is eliminated by a nucleophilic substitution reaction, and includes, but is not limited to, a sulfonyloxy group and a halogen. Examples of the sulfonyloxy group include a p-toluenesulfonyloxy group, a p-nitrobenzenesulfonyloxy group, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group, and in one embodiment, the group is a p-toluenesulfonyloxy group or a p-nitrobenzenesulfonyloxy group. Examples of the halogen group include Cl, Br, and I, and in one embodiment, the group is Br.

[0032] "Labeled" means that a particular atom in a compound is substituted with a radioisotope. In one embodiment, a fluorine atom is 18 It means that it is substituted with F.

[0033] Certain embodiments of the labeled fatty acid derivative represented by formula (I) or a salt thereof are shown below.

[0034] (1-1) A labeled fatty acid derivative or a salt thereof, wherein L is ethylene. (1-2) A labeled fatty acid derivative or a salt thereof, wherein L is tetramethylene. (2-1) R is C 6-14 A labeled fatty acid derivative or a salt thereof, which is alkyl. (2-2) R is C having 1 to 3 double bonds 6-14A labeled fatty acid derivative or a salt thereof, wherein R is an alkyl group, except where R is (2Z)-undec-2-en-1-yl. (2-3) R is C 6-14 Alkyl, 6-14 A labeled fatty acid derivative or a salt thereof, in which three consecutive carbon atoms of an alkyl are combined to form a cyclopropane ring. (3) A labeled fatty acid derivative or a salt thereof, which is a combination of the embodiment described in (1-1) or (1-2) above and the embodiment described in any one of (2-1) to (2-3).

[0035] Further, an embodiment of the labeled fatty acid derivative represented by formula (I) of the present invention or a salt thereof is the following labeled fatty acid derivative or a salt thereof. (1) 3-{[(5Z,8Z,11Z)-3-[ 18 F]fluorotetradeca-5,8,11-trien-1-yl]sulfanyl}propanoic acid (2) 3-[(3-[ 18 F]fluorododecyl)sulfanyl]propanoic acid (3) 3-{[(5Z,8Z)-3-[ 18 F]fluorotetradeca-5,8-dien-1-yl]sulfanyl}propanoic acid (4) 3-[(3-[ 18 F]fluorotetradecyl)sulfanyl]propanoic acid (5) 3-{[(5E)-3-[ 18 F]fluorotetradec-5-en-1-yl]sulfanyl}propanoic acid (6) 3-{[3-[ 18 F]fluoro-4-(2-octylcyclopropyl)butyl]sulfanyl}propanoic acid (7) 5-[(3-[ 18 F]fluoroundecyl)sulfanyl]pentanoic acid

[0036] The labeled fatty acid derivatives of the present invention represented by formula (I) or salts thereof are used as radiolabeled tracers in imaging diagnostics such as PET. The labeled fatty acid derivatives of the present invention have the ability to accumulate in myocardium in vivo, and enable imaging of the fatty acid metabolic activity by PET and similar imaging methods, and can be used in imaging diagnostics of heart disease, particularly ischemic heart disease. In small animal tests, they can be used as in vivo imaging diagnostic means in small animal PET systems as well as in Planar Positron Imaging System (PPIS), a device that obtains planar accumulation images rather than tomographic images. Furthermore, they can be used in autoradiography, which is an image analysis means for slices of excised organs, and in the evaluation of accumulation in excised organs using a gamma counter.

[0037] The positron-emitting nuclide used in the labeled fatty acid derivative of the present invention is 18 It's F. In general, 18 F is produced by a device called a cyclotron. 18 The compound of formula (I) can be labeled with F. A desired nuclide can be obtained from a (ultra) small cyclotron installed in the facility to be used, and the labeled fatty acid derivative of formula (I) of the present invention or a salt thereof can be produced by a method known in the art, to prepare a composition for diagnostic imaging.

[0038] The labeled fatty acid derivative represented by formula (I) of the present invention or its salt may have an asymmetric center, and may have an enantiomer (optical isomer) based on the asymmetric center. The compound of formula (I) or its salt includes any of the isolated individual enantiomers such as (R) and (S) bodies, and mixtures thereof (including racemic or non-racemic mixtures).

[0039] In addition, the labeled fatty acid derivative of formula (I) of the present invention may form a salt depending on the conditions, and these salts are also included in the present invention. Examples of the salt include salts with metal cations such as sodium, potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, and ethanolamine, salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, and ornithine, and ammonium salts.

[0040] Furthermore, the labeled fatty acid derivative of the formula (I) of the present invention or a salt thereof may be provided as a hydrate, solvate or polymorphic crystal substance, and the present invention includes these.

[0041] The present invention includes an intermediate compound or a salt thereof that can be converted into a labeled fatty acid derivative of formula (I) or a salt thereof. An example of an intermediate compound that can be converted into a labeled fatty acid derivative of formula (I) or a salt thereof is a compound represented by the following formula (1g). Another embodiment includes a compound represented by the following formula (1f), which is a precursor of the compound represented by (1g). [ka] (In the formula, R' is H or an optionally substituted lower alkyl group, and X is a leaving group. The same applies below.)

[0042] Certain embodiments of compounds represented by formula (1g) are shown below.

[0043] (A-1) The compound in which R' is optionally substituted lower alkyl. (A-2) The compound in which R' is lower alkyl. (B-1) L is C 2-4 A compound that is an alkylene. (B-2) A compound in which L is ethylene. (B-3) A compound in which L is tetramethylene. (C-1) R is C 6-14 is an alkyl group, 6-14 The alkyl group may have 1 to 3 double bonds. 6-14A compound in which three consecutive carbon atoms in an alkyl group may be joined together to form a cyclopropane ring, except when R is a (2Z)-undec-2-en-1-yl group. (C-2) R is C 6-14 A compound that is an alkyl. (C-3) C in which R has 1 to 3 double bonds 6-14 The compound where R is alkyl, except when R is (2Z)-undec-2-en-1-yl. (C-4) R is C 6-14 Alkyl, 6-14 A compound in which three consecutive carbon atoms of an alkyl group join together to form a cyclopropane ring. (D) A compound which is a combination of the embodiments described in (A-1) to (C-4) above.

[0044] The present invention also relates to an intermediate compound or a salt thereof that can be converted into a labeled fatty acid derivative of formula (I) or a salt thereof, 18 The present invention also encompasses a method for producing a labeled fatty acid derivative of formula (I) or a salt thereof, comprising the step of reacting a compound represented by the formula (I) with a [F] fluoride ion.

[0045] Furthermore, the present invention encompasses a kit for preparing a composition for diagnostic imaging, comprising at least an intermediate compound or a salt thereof that can be converted into a labeled fatty acid derivative of formula (I) or a salt thereof. One embodiment of the kit of the present invention is a kit for rapid synthesis of the labeled fatty acid derivative of the present invention. The kit comprises an intermediate compound or a salt thereof that can be converted into a labeled fatty acid derivative of formula (I) or a salt thereof, 18The present invention also includes a kit for preparing a diagnostic imaging composition, which comprises a reagent for F labeling, and optionally also comprises other reagents, solvents, etc., and can be used to prepare the diagnostic imaging composition of the present invention when necessary. An embodiment of an intermediate compound or a salt thereof that can be converted to a labeled fatty acid derivative of formula (I) or a salt thereof included in the kit of the present invention includes a compound of formula (1g) or a salt thereof. The kit may also include equipment known in the art, such as a reaction vessel, an apparatus for transferring isotopic material to the reaction vessel, a pre-filled separation column for separating the product from excess reactants, a shield, etc.

[0046] (Manufacturing method) The labeled fatty acid derivative of formula (I) or its salt can be produced by applying various known synthesis methods, utilizing the characteristics based on the basic structure or the type of substituent. In this case, depending on the type of functional group, it may be effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis (5th Edition, 2014)" by PGM Wuts, and may be appropriately selected and used depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as necessary.

[0047] Representative methods for producing the labeled fatty acid derivative of formula (I) or its salt are described below. Each method can be performed by referring to the references attached to the description. The production method of the present invention is not limited to the examples shown below.

[0048] In addition, the following abbreviations may be used in this specification. DBU® = 1,8-diazabicyclo[5.4.0]-7-undecene, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, EtOAc = ethyl acetate, HMPA = hexamethylphosphoric triamide, MeCN = acetonitrile, MeOH = methanol, Ph = phenyl, PyFluor = pyridine-2-sulfonyl fluoride, TBAF = tetra-n-butylammonium fluoride, TBS = t-butyldimethylsilyl, TBDPS = t-butyldiphenylsilyl, TFA = trifluoroacetic acid, THF = tetrahydrofuran, Ts = p-toluenesulfonyl.

[0049] (first step) [ka] (Wherein, R is C 6-14 is an alkyl group, 6-14 The alkyl group may have 1 to 3 double bonds. 6-14 Three consecutive carbon atoms in the alkyl group may be bonded together to form a cyclopropane ring, except when R is a (2Z)-undec-2-en-1-yl group. The same applies below.)

[0050] Compound (1b) can be produced by deprotecting the protecting group TBS of compound (1a). The deprotection can be carried out by a method well known to those skilled in the art, for example, by stirring in a solvent inert to the reaction in the presence of a fluorine reagent or an acid at −78° C. to room temperature, usually for 0.1 hours to 3 days. Examples of the fluorine reagent include TBAF, pyridine hydrofluoric acid, etc., and acetic acid may be added at this time. Examples of the acid include hydrochloric acid, p-toluenesulfonic acid, etc.

[0051] (Second process) [ka]

[0052] Compound (1c) can be produced by converting the hydroxyl group of compound (1b) to iodine by an iodination reaction. The iodination reaction is carried out by stirring compound (1b) and iodine in a solvent inert to the reaction in the presence of triphenylphosphine and a base under ice-cooling to room temperature, usually for 0.1 hours to 3 days. Examples of the base include imidazole and triethylamine. Examples of the solvent include dichloromethane and THF.

[0053] (Third step) [ka] (Wherein, L is C 2-4 R' represents H or an optionally substituted lower alkyl group. The same applies below.)

[0054] Compound (1e) can be produced from compound (1c) and compound (1d). This reaction is carried out by stirring compound (1c) and compound (1d) in the presence of a base in a solvent inert to the reaction at ice-cooling to room temperature for 0.1 hours to 3 days. Examples of the solvent include THF and 1,4-dioxane. Examples of the base include sodium hydride and potassium t-butoxide.

[0055] (Fourth step) [ka]

[0056] Compound (1f) can be produced by deprotecting the protecting group TBDPS of compound (1e). The deprotection can be carried out in the same manner as in the first step.

[0057] (Fifth step) [ka]

[0058] Compound (1g) can be prepared by converting the hydroxyl group of compound (1f) to a leaving group. When compound (1g) in which the leaving group is a sulfonyloxy group is produced, compound (1f) and a sulfonylating agent are stirred in a solvent inert to the reaction in the presence of a base at ice-cooling to room temperature, usually for 0.1 hours to 3 days. Examples of the sulfonylating agent include p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, etc. Examples of the solvent include dichloromethane, THF, etc. Examples of the base include triethylamine, diisopropylethylamine, etc. Trimethylamine hydrochloride may be added in this step.

[0059] In addition, when compound (1g) in which the leaving group is halogen is produced, compound (1f) and a halogenating agent are stirred in a solvent inert to the reaction in the presence of triphenylphosphine at ice-cooling to room temperature for usually 0.1 hours to 3 days. Examples of the halogenating agent include carbon tetrabromide and iodine. Examples of the solvent include carbon tetrachloride, dichloromethane, THF, etc. At this time, a base such as imidazole or triethylamine may be added.

[0060] (Sixth step) [ka]

[0061] (Sixth step-1) Compound (1h) can be prepared, for example, by reacting compound (1g) with a positron-emitting nuclide produced by a cyclotron using methods well known to those skilled in the art. 18 A reagent containing F, 18 F] fluoride ion aqueous solution, [ 18 F] Tetra-n-butylammonium fluoride ([ 18 F]TBAF), [ 18 F] potassium fluoride, etc. under heating.

[0062] (Sixth step-2) Compound (I) can be produced from compound (1h) by a method well known to those skilled in the art, for example, by stirring in a solvent inert to the reaction in the presence of an aqueous base solution at ice-cooling to 110°C for usually 0.1 hours to 3 days. Examples of the base include sodium hydroxide and potassium hydroxide. When R' is H, the sixth step-2 is omitted.

[0063] The compound of formula (I) or a salt thereof thus produced can be isolated and purified by applying conventional chemical procedures such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. Various isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing the difference in physicochemical properties between isomers. For example, optical isomers can be obtained by a general optical resolution method of a racemate (e.g., fractional crystallization leading to a diastereomeric salt with an optically active base or acid, chromatography using a chiral column, etc.), or can be produced from an appropriate optically active starting compound.

[0064] The diagnostic imaging composition of the present invention can be produced by combining the labeled fatty acid derivative with at least one pharma- ceutically acceptable carrier. The diagnostic imaging composition of the present invention is preferably in a dosage form suitable for intravenous administration, for example, an injection for intravenous administration. Examples of the injection include those containing sterile aqueous or non-aqueous liquids, suspensions, and emulsions. Examples of aqueous solvents include distilled water for injection and physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name), and the like. Such compositions may further contain an isotonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, and a solubilizing agent. These are sterilized, for example, by filtration through a bacteria-retaining filter, by blending with a bactericide, or by irradiation. In addition, these can be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile injectable solvent before use. In one embodiment, the diagnostic imaging composition of the present invention is an injection for intravenous administration. In another embodiment, the composition is an aqueous liquid.

[0065] The diagnostic imaging composition of the present invention can be used by adjusting the dosage depending on the imaging method (PET, etc.) used, the type of disease, the age and condition of the patient, the examination site, and the purpose of imaging. The diagnostic imaging composition of the present invention must contain a detectable amount of the labeled fatty acid derivative, but sufficient attention must be paid to the amount of radiation exposure of the patient. For example, 18 The radioactivity of the composition for diagnostic imaging of the present invention labeled with F is about 1.85 to 740 megabecquerels (MBq), about 1.85 to 37 MBq in one embodiment, and about 37 to 740 MBq in another embodiment, which is administered once or in divided doses, or administered continuously by drip infusion. EXAMPLES

[0066] The method for producing the labeled fatty acid derivative of the present invention and its effects will be described in more detail below with reference to examples. However, the present invention is not limited to the compounds described in the following examples.

[0067] Furthermore, the following abbreviations may be used in the Examples, Reference Examples and Tables below. Ex: Example number (the sub-number indicates which step in the Example the compound was obtained as a result of. For example, a compound with an Example number of Ex1-3 means that it was obtained in the third step of Example 1), Ref: Reference Example number, Str: Chemical structure, DAT: Physicochemical data, ESI+: m / z value in mass spectrometry (ESI ionization method, [M+H] unless otherwise noted) + ), ESI-: m / z value in mass spectrometry (ionization method ESI, unless otherwise noted [MH] - ), CI+: m / z value in mass spectrometry (ionization method CI, unless otherwise specified [M+H] + ), NMR: δ value (ppm) of signal in 1H-NMR in CDCl3, J: coupling constant, s: singlet, d: doublet, t: triplet, m: multiplet, Ci: unit of radioactivity, Curie (1 Ci = 3.7 × 10 10 Bq) are shown respectively.

[0068] For convenience, the concentration (mol / L) is expressed as M. For example, a 1 M aqueous solution of sodium hydroxide means a 1 mol / L aqueous solution of sodium hydroxide.

[0069] Example 1 The synthesis method of 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-[(2Z,5Z,8Z)-undeca-2,5,8-trien-1-yl]-4,8-dioxa-3,9-disilaundecan, which is the starting material in the first step, is shown in Reference Example 8.

[0070] First step: 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-[(2Z,5Z,8Z)-undeca-2,5,8-trien-1-yl]-4,8-dioxa-3,9-disilaundecan (2.27 g) was dissolved in a mixture of THF (23 mL) and water (1.15 mL), and p-toluenesulfonic acid monohydrate (375 mg) was added at room temperature and stirred overnight at the same temperature. Sodium bicarbonate water and ethyl acetate were added, and the organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain (5Z,8Z,11Z)-3-{[t-butyl(diphenyl)silyl]oxy}tetradeca-5,8,11-trien-1-ol (1.83 g) as an oily substance.

[0071] Second step: Under a nitrogen stream, triphenylphosphine (1.66 g) was dissolved in dichloromethane (90 mL), iodine (1.61 g) and imidazole (0.54 g) were added, and the mixture was stirred at room temperature for 10 minutes. A solution of (5Z,8Z,11Z)-3-{[t-butyl(diphenyl)silyl]oxy}tetradeca-5,8,11-trien-1-ol (1.83 g) in dichloromethane (9 mL) was added, and the mixture was stirred at room temperature for 30 minutes. An aqueous solution of sodium thiosulfate was added, and the mixture was stirred for 5 minutes, and chloroform and water were added to perform a liquid separation operation. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. To the residue was added n-hexane, and the precipitated solid was removed by filtration. The mixture was then purified using silica gel column chromatography (EtOAc / n-hexane) to obtain t-butyl{[(5Z,8Z,11Z)-1-iodotetradec-5,8,11-trien-3-yl]oxy}diphenylsilane (1.73 g) as an oily substance.

[0072] Third step: A solution of methyl 3-sulfanylpropionate (0.49 mL) in THF (35 mL) was ice-cooled under a nitrogen stream, and sodium hydride (60% mineral oil dispersion, 180 mg) was added. Stirred at the same temperature for 30 minutes, and then a solution of t-butyl{[(5Z,8Z,11Z)-1-iodotetradeca-5,8,11-trien-3-yl]oxy}diphenylsilane (1.73 g) in THF (8 mL) was added, followed by stirring overnight at room temperature. An aqueous solution of ammonium chloride was added, followed by adding water and ethyl acetate, and the mixture was separated. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to give methyl 3-{[(5Z,8Z,11Z)-3-{[t-butyl(diphenyl)silyl]oxy}tetradec-5,8,11-trien-1-yl]sulfanyl}propanoate (1.65 g) as an oily substance.

[0073] Fourth step: Under a nitrogen stream, methyl 3-{[(5Z,8Z,11Z)-3-{[t-butyl(diphenyl)silyl]oxy}tetradeca-5,8,11-trien-1-yl]sulfanyl}propanoate (1.65 g) was dissolved in THF (33 mL) and cooled on ice. TBAF (1 M THF solution, 15 mL) was added and stirred at room temperature overnight. After dilution with ethyl acetate, the mixture was washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain methyl 3-{[(5Z,8Z,11Z)-3-hydroxytetradeca-5,8,11-trien-1-yl]sulfanyl}propanoate (0.62 g) as an oily substance.

[0074] Fifth step: Under a nitrogen stream, methyl 3-{[(5Z,8Z,11Z)-3-hydroxytetradec-5,8,11-trien-1-yl]sulfanyl}propanoate (120 mg) was dissolved in dichloromethane (2.4 mL), triethylamine (0.13 mL) and trimethylamine hydrochloride (35 mg) were added, and the mixture was cooled to a bath temperature of -5°C. p-Toluenesulfonyl chloride (105 mg) was added little by little, and the mixture was stirred at the same temperature for 30 minutes, sodium bicarbonate water and chloroform were added, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain methyl 3-({(5Z,8Z,11Z)-3-[(4-methylbenzene-1-sulfonyl)oxy]tetradec-5,8,11-trien-1-yl}sulfanyl)propanoate (141 mg) as an oily substance.

[0075] Sixth step: Cyclotron-derived [ 18 The aqueous solution of [F] fluoride ions was adsorbed onto a preconditioned anion exchange resin (Sep-Pak (registered trademark) Light QMA), and then eluted with a mixture of 75 mM tetra-n-butylammonium bicarbonate (0.20 mL) and MeCN (0.8 mL). The eluate was concentrated under reduced pressure at 140°C, and then MeCN (1 mL) was added and concentrated under reduced pressure at 140°C. MeCN (1 mL) was added again and concentrated under reduced pressure at 120°C to obtain the [ 18F]TBAF was obtained. A solution of 3-({(5Z,8Z,11Z)-3-[(4-methylbenzene-1-sulfonyl)oxy]tetradeca-5,8,11-trien-1-yl}sulfanyl)methyl propanoate (4 μL) in MeCN (0.8 mL) was added thereto and heated at 130°C for 10 minutes. A 0.2 M aqueous potassium hydroxide solution (0.2 mL) was added to the reaction solution and heated at 110°C for 4 minutes. A 50% aqueous MeCN solution (1.8 mL) and acetic acid (25 μL) were added to the reaction solution and purified by HPLC (0.005% aqueous TFA solution / 0.005% TFA-MeCN solution (30:70), column: YMC-Pack Pro C18, S-5μm, 10×250 mm, flow rate: 5 mL / min). The obtained 3-{[(5Z,8Z,11Z)-3-[ 18 Water (15 mL) was added to the [F]fluorotetradeca-5,8,11-trien-1-yl]sulfanyl}propanoic acid fraction, and the mixture was passed through a Sep-Pak (registered trademark) Light C18 and washed with 35% aqueous ethanol (5 mL). The target substance was then eluted with ethanol (1 mL) and mixed with 1% aqueous ascorbic acid (1 mL). 0.5% Tween (registered trademark) 80-saline (10 mL) was passed through the column, combined with the previous eluate, and 3-{[(5Z,8Z,11Z)-3-[ 18 A liquid preparation containing [F]fluorotetradeca-5,8,11-trien-1-yl]sulfanyl}propanoic acid was obtained (66.0 mCi). The formation of the compound was confirmed by the fact that the retention time in HPLC was consistent with that of the non-radiolabeled compound shown in Reference Example 1.

[0076] Example 2 The synthesis method of 2,2,9,9,10,10-hexamethyl-5-nonyl-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane, which is the starting material in the first step, is shown in Reference Example 9.

[0077] First step: 3-{[t-butyl(diphenyl)silyl]oxy}dodecan-1-ol was obtained in the same manner as in the first step of Example 1, except that 2,2,9,9,10,10-hexamethyl-5-nonyl-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane was used as the raw material.

[0078] Second step: t-Butyl[(1-iodododecan-3-yl)oxy]diphenylsilane was obtained in the same manner as in the second step of Example 1, except that 3-{[t-butyl(diphenyl)silyl]oxy}dodecan-1-ol was used as the raw material.

[0079] Third step: Methyl 3-[(3-{[t-butyl(diphenyl)silyl]oxy}dodecyl)sulfanyl]propanoate was obtained in the same manner as in the third step of Example 1, except that t-butyl[(1-iodododecane-3-yl)oxy]diphenylsilane was used as the raw material.

[0080] Fourth step: Methyl 3-[(3-hydroxydodecyl)sulfanyl]propanoate was obtained in the same manner as in the fourth step of Example 1, except that methyl 3-[(3-{[t-butyl(diphenyl)silyl]oxy}dodecyl)sulfanyl]propanoate was used as the raw material.

[0081] Fifth step: Methyl 3-({3-[(4-methylbenzene-1-sulfonyl)oxy]dodecyl}sulfanyl)propanoate was obtained in the same manner as in the fifth step of Example 1, except that methyl 3-[(3-hydroxydodecyl)sulfanyl]propanoate was used as the raw material.

[0082] Sixth step: 3-[(3-[(4-methylbenzene-1-sulfonyl)oxy]dodecyl}sulfanyl)methyl propanoate was used as the raw material in the same manner as in the sixth step of Example 1, to obtain 3-[(3-[ 18 The formation of this compound was confirmed by the fact that the retention time in HPLC was consistent with that of the non-radiolabeled compound shown in Reference Example 2.

[0083] Example 3 The synthesis method of 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-[(2Z,5Z)-undeca-2,5-dien-1-yl]-4,8-dioxa-3,9-disilaundecane, which is the starting material in the first step, is shown in Reference Example 10.

[0084] First step: (5Z,8Z)-3-{[t-butyl(diphenyl)silyl]oxy}tetradeca-5,8-dien-1-ol was obtained in the same manner as in the first step of Example 1, except that 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-[(2Z,5Z)-undeca-2,5-dien-1-yl]-4,8-dioxa-3,9-disilaundecane was used as the raw material.

[0085] Second step: t-Butyl{[(5Z,8Z)-1-iodotetradeca-5,8-dien-3-yl]oxy}diphenylsilane was obtained in the same manner as in the second step of Example 1, except that (5Z,8Z)-3-{[t-butyl(diphenyl)silyl]oxy}tetradeca-5,8-dien-1-ol was used as the raw material.

[0086] Third step: Methyl 3-{[(5Z,8Z)-3-{[t-butyl(diphenyl)silyl]oxy}tetradec-5,8-dien-1-yl]sulfanyl}propanoate was obtained in the same manner as in the third step of Example 1, except that t-butyl{[(5Z,8Z)-1-iodotetradec-5,8-dien-3-yl]oxy}diphenylsilane was used as the raw material.

[0087] Fourth step: Methyl 3-{[(5Z,8Z)-3-{[t-butyl(diphenyl)silyl]oxy}tetradec-5,8-dien-1-yl]sulfanyl}propanoate was obtained in the same manner as in the fourth step of Example 1, except that methyl 3-{[(5Z,8Z)-3-hydroxytetradec-5,8-dien-1-yl]sulfanyl}propanoate was used as the raw material.

[0088] Fifth step: Methyl 3-({(5Z,8Z)-3-[(4-methylbenzene-1-sulfonyl)oxy]tetradec-5,8-dien-1-yl}sulfanyl)propanoate was obtained in the same manner as in the fifth step of Example 1, except that methyl 3-{[(5Z,8Z)-3-hydroxytetradec-5,8-dien-1-yl]sulfanyl}propanoate was used as the raw material.

[0089] Sixth step: 3-{[(5Z,8Z)-3-[(4-methylbenzene-1-sulfonyl)oxy]tetradeca-5,8-dien-1-yl}sulfanyl)methyl propanoate was used as the raw material in the same manner as in the sixth step of Example 1, to obtain 3-{[(5Z,8Z)-3-[ 18 F]fluorotetradec-5,8-dien-1-yl]sulfanyl}propanoic acid was obtained. The production of this compound was confirmed by the fact that the retention time in HPLC was consistent with that of the non-radiolabeled compound shown in Reference Example 3.

[0090] Example 4 The synthesis method of 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-undecyl-4,8-dioxa-3,9-disilaundecane, which is the starting material in the first step, is shown in Reference Example 11.

[0091] First step: 3-{[t-butyl(diphenyl)silyl]oxy}tetradecan-1-ol was obtained in the same manner as in the first step of Example 1, except that 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-undecyl-4,8-dioxa-3,9-disilaundecane was used as the raw material.

[0092] Second step: t-Butyl[(1-iodotetradecan-3-yl)oxy]diphenylsilane was obtained in the same manner as in the second step of Example 1, except that 3-{[t-butyl(diphenyl)silyl]oxy}tetradecan-1-ol was used as the raw material.

[0093] Third step: Methyl 3-[(3-{[t-butyl(diphenyl)silyl]oxy}tetradecyl)sulfanyl]propanoate was obtained in the same manner as in the third step of Example 1, except that t-butyl[(1-iodotetradecan-3-yl)oxy]diphenylsilane was used as the raw material.

[0094] Fourth step: Methyl 3-[(3-hydroxytetradecyl)sulfanyl]propanoate was obtained in the same manner as in the fourth step of Example 1, except that methyl 3-[(3-{[t-butyl(diphenyl)silyl]oxy}tetradecyl)sulfanyl]propanoate was used as the raw material.

[0095] Fifth step: Methyl 3-({3-[(4-methylbenzene-1-sulfonyl)oxy]tetradecyl}sulfanyl)propanoate was obtained in the same manner as in the fifth step of Example 1, except that methyl 3-[(3-hydroxytetradecyl)sulfanyl]propanoate was used as the raw material.

[0096] Sixth step: 3-({3-[(4-methylbenzene-1-sulfonyl)oxy]tetradecyl}sulfanyl)methyl propanoate was used as the raw material in the same manner as in the sixth step of Example 1, except that 3-[(3-[ 18 The formation of this compound was confirmed by the fact that its retention time in HPLC was consistent with that of the non-radiolabeled compound shown in Reference Example 4.

[0097] Example 5 The synthesis method of 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-[(2E)-undec-2-en-1-yl]-4,8-dioxa-3,9-disilaundecane, which is the starting material in the first step, is shown in Reference Example 12.

[0098] First step: (5E)-3-{[t-butyl(diphenyl)silyl]oxy}tetradec-5-en-1-ol was obtained in the same manner as in the first step of Example 1, except that 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-[(2E)-undec-2-en-1-yl]-4,8-dioxa-3,9-disilaundecane was used as the raw material.

[0099] Second step: t-butyl{[(5E)-1-iodotetradec-5-en-3-yl]oxy}diphenylsilane was obtained in the same manner as in the second step of Example 1, except that (5E)-3-{[t-butyl(diphenyl)silyl]oxy}tetradec-5-en-1-ol was used as the raw material.

[0100] Third step: Methyl 3-{[(5E)-3-{[t-butyl(diphenyl)silyl]oxy}tetradec-5-en-1-yl]sulfanyl}propanoate was obtained in the same manner as in the third step of Example 1, except that t-butyl{[(5E)-1-iodotetradec-5-en-3-yl]oxy}diphenylsilane was used as the raw material.

[0101] Fourth step: Methyl 3-{[(5E)-3-hydroxytetradec-5-en-1-yl]sulfanyl}propanoate was obtained in the same manner as in the fourth step of Example 1, except that methyl 3-{[(5E)-3-{[t-butyl(diphenyl)silyl]oxy}tetradec-5-en-1-yl]sulfanyl}propanoate was used as the raw material.

[0102] Fifth step: Methyl 3-({(5E)-3-[(4-methylbenzene-1-sulfonyl)oxy]tetradec-5-en-1-yl}sulfanyl)propanoate was obtained in the same manner as in the fifth step of Example 1, except that methyl 3-{[(5E)-3-hydroxytetradec-5-en-1-yl]sulfanyl}propanoate was used as the raw material.

[0103] Sixth step: 3-{[(5E)-3-[(4-methylbenzene-1-sulfonyl)oxy]tetradec-5-en-1-yl}sulfanyl)propanoic acid methyl ester was used as the raw material in the same manner as in the sixth step of Example 1, to obtain 3-{[(5E)-3-[ 18 F]fluorotetradec-5-en-1-yl]sulfanyl}propanoic acid was obtained. The production of this compound was confirmed by the fact that the retention time in HPLC was consistent with that of the non-radiolabeled compound shown in Reference Example 5.

[0104] Example 6 The synthesis method of 2,2,9,9,10,10-hexamethyl-5-[(2-octylcyclopropyl)methyl]-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane, which is the starting material in the first step, is shown in Reference Example 13.

[0105] First step: 3-{[t-butyl(diphenyl)silyl]oxy}-4-(2-octylcyclopropyl)butan-1-ol was obtained in the same manner as in the first step of Example 1, except that 2,2,9,9,10,10-hexamethyl-5-[(2-octylcyclopropyl)methyl]-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane was used as the raw material.

[0106] Second step: t-Butyl{[4-iodo-1-(2-octylcyclopropyl)butan-2-yl]oxy}diphenylsilane was obtained in the same manner as in the second step of Example 1, except that 3-{[t-butyl(diphenyl)silyl]oxy}-4-(2-octylcyclopropyl)butan-1-ol was used as the raw material.

[0107] Third step: Methyl 3-{[3-{[t-butyl(diphenyl)silyl]oxy}-4-(2-octylcyclopropyl)butyl]sulfanyl}propanoate was obtained in the same manner as in the third step of Example 1, except that t-butyl{[4-iodo-1-(2-octylcyclopropyl)butan-2-yl]oxy}diphenylsilane was used as the raw material.

[0108] Fourth step: Methyl 3-{[3-hydroxy-4-(2-octylcyclopropyl)butyl]sulfanyl}propanoate was obtained in the same manner as in the fourth step of Example 1, except that methyl 3-{[3-{[t-butyl(diphenyl)silyl]oxy}-4-(2-octylcyclopropyl)butyl]sulfanyl}propanoate was used as the raw material.

[0109] Fifth step: Methyl 3-({3-[(4-methylbenzene-1-sulfonyl)oxy]-4-(2-octylcyclopropyl)butyl}sulfanyl)propanoate was obtained in the same manner as in the fifth step of Example 1, except that methyl 3-{[3-hydroxy-4-(2-octylcyclopropyl)butyl]sulfanyl}propanoate was used as the raw material.

[0110] Sixth step: 3-{[3-[ 18 F]fluoro-4-(2-octylcyclopropyl)butyl]sulfanyl}propanoic acid was obtained. The formation of this compound was confirmed by the fact that the retention time in HPLC was consistent with that of the non-radiolabeled compound shown in Reference Example 6.

[0111] Example 7 The synthesis method of 2,2,9,9,10,10-hexamethyl-5-octyl-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane, which is the starting material in the first step, is shown in Reference Example 14.

[0112] First step: 3-{[t-butyl(diphenyl)silyl]oxy}undecan-1-ol was obtained in the same manner as in the first step of Example 1, except that 2,2,9,9,10,10-hexamethyl-5-octyl-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane was used as the raw material.

[0113] Second step: t-Butyl[(1-iodoundecan-3-yl)oxy]diphenylsilane was obtained in the same manner as in the second step of Example 1, except that 3-{[t-butyl(diphenyl)silyl]oxy}undecane-1-ol was used as the raw material.

[0114] Third step: Methyl 5-[(3-{[t-butyl(diphenyl)silyl]oxy}undecyl)sulfanyl]pentanoate was obtained in the same manner as in the third step of Example 1, except that t-butyl[(1-iodoundecan-3-yl)oxy]diphenylsilane was used as the raw material and methyl 5-sulfanylpentanoate was used instead of methyl 3-sulfanylpropionate.

[0115] Fourth step: Methyl 5-[(3-hydroxyundecyl)sulfanyl]pentanoate was obtained in the same manner as in the fourth step of Example 1, except that methyl 5-[(3-{[t-butyl(diphenyl)silyl]oxy}undecyl)sulfanyl]pentanoate was used as the raw material.

[0116] Fifth step: Methyl 5-({3-[(4-methylbenzene-1-sulfonyl)oxy]undecyl}sulfanyl)pentanoate was obtained in the same manner as in the fifth step of Example 1, except that methyl 5-[(3-hydroxyundecyl)sulfanyl]pentanoate was used as the raw material.

[0117] Sixth step: 5-({3-[(4-methylbenzene-1-sulfonyl)oxy]undecyl}sulfanyl)pentanoic acid methyl ester was used as the raw material in the same manner as in the sixth step of Example 1, to obtain 5-[(3-[ 18 F]fluoroundecyl)sulfanyl]pentanoic acid was obtained. The production of this compound was confirmed by the fact that the retention time in HPLC was consistent with that of the non-radiolabeled compound shown in Reference Example 7.

[0118] The chemical structures and physicochemical data of the compounds obtained in each step are shown in Tables 1 to 6.

[0119] [Table 1]

[0120] [Table 2]

[0121] [Table 3]

[0122] [Table 4]

[0123] [Table 5]

[0124] [Table 6]

[0125] Reference example 1 3-{[(5Z,8Z,11Z)-3-fluorotetradec-5,8,11-trien-1-yl]sulfanyl}propanoic acid was synthesized to be used as a standard in Example 1. The steps are shown below. Methyl 3-{[(5Z,8Z,11Z)-3-hydroxytetradec-5,8,11-trien-1-yl]sulfanyl}propanoate (180 mg) was dissolved in toluene (1.8 mL) under a nitrogen stream, and PyFluor (98 mg) and DBU (registered trademark) (165 μL) were added at room temperature and stirred for 70 hours. The supernatant was purified using silica gel column chromatography (EtOAc / n-hexane). The resulting residue was dissolved in THF (1.8 mL) and MeOH (1.8 mL), and then an aqueous solution of sodium hydroxide (1 M, 1.8 mL) was added at room temperature and stirred for 1 hour. An aqueous solution of hydrochloric acid (1 M) was added to neutralize the mixture, and then chloroform and saturated saline were added, followed by extraction with chloroform to separate the organic layer. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 3-{[(5Z,8Z,11Z)-3-fluorotetradec-5,8,11-trien-1-yl]sulfanyl}propanoic acid (50 mg) as an oily substance.

[0126] Reference example 2 3-[(3-fluorododecyl)sulfanyl]propanoic acid used as a standard in Example 2 was synthesized in the same manner as in Reference Example 1, except that methyl 3-[(3-hydroxydodecyl)sulfanyl]propanoate was used as a raw material.

[0127] Reference example 3 3-{[(5Z,8Z)-3-fluorotetradec-5,8-dien-1-yl]sulfanyl}propanoic acid used as a standard in Example 3 was synthesized in the same manner as in Reference Example 1, except that methyl 3-{[(5Z,8Z)-3-hydroxytetradec-5,8-dien-1-yl]sulfanyl}propanoate was used as a raw material.

[0128] Reference example 4 3-[(3-fluorotetradecyl)sulfanyl]propanoic acid used as a standard in Example 4 was synthesized in the same manner as in Reference Example 1, except that methyl 3-[(3-hydroxytetradecyl)sulfanyl]propanoate was used as a raw material.

[0129] Reference example 5 3-{[(5E)-3-fluorotetradec-5-en-1-yl]sulfanyl}propanoic acid used as a standard in Example 5 was synthesized in the same manner as in Reference Example 1, except that methyl 3-{[(5E)-3-hydroxytetradec-5-en-1-yl]sulfanyl}propanoate was used as the raw material.

[0130] Reference example 6 3-{[3-fluoro-4-(2-octylcyclopropyl)butyl]sulfanyl}propanoic acid used as a standard in Example 6 was synthesized in the same manner as in Reference Example 1, except that methyl 3-{[3-hydroxy-4-(2-octylcyclopropyl)butyl]sulfanyl}propanoate was used as the raw material.

[0131] Reference example 7 5-[(3-fluoroundecyl)sulfanyl]pentanoic acid used as a standard in Example 7 was synthesized in the same manner as in Reference Example 1, except that methyl 5-[(3-hydroxyundecyl)sulfanyl]pentanoate was used as a raw material.

[0132] Reference example 8 2,2,9,9,10,10-Hexamethyl-3,3-diphenyl-5-[(2Z,5Z,8Z)-undeca-2,5,8-trien-1-yl]-4,8-dioxa-3,9-disilaundecane was synthesized as the raw material of Example 1. The steps are shown below.

[0133] Under a nitrogen stream, 4-methylbenzene-1-sulfonic acid [(3Z,6Z)-nona-3,6-dien-1-yl](triphenyl)phosphanium (3.99 g) was dissolved in a mixture of THF (100 mL) and HMPA (6 mL) and cooled to -78°C. Potassium hexamethyldisilazide (1 M THF solution, 7.2 mL) was added dropwise, and the mixture was stirred for 1 hour under ice cooling. The reaction solution was cooled to -78°C, and then a solution of 5-{[t-butyl(dimethyl)silyl]oxy}-3-{[t-butyl(diphenyl)silyl]oxy}pentanal (2.00 g) in THF (10 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. After stirring at room temperature for 2 hours, water was added. Ethyl acetate, n-hexane and water were added, and the organic layer was separated, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / n-hexane) to give 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-[(2Z,5Z,8Z)-undeca-2,5,8-trien-1-yl]-4,8-dioxa-3,9-disilaundecane (2.27 g) as an oily substance.

[0134] Reference example 9 2,2,9,9,10,10-Hexamethyl-5-nonyl-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane was synthesized as the raw material of Example 2. The steps are shown below.

[0135] First step: Magnesium (170 mg) was suspended in diethyl ether (10 mL) under nitrogen flow, and iodine (10 mg) was added and stirred. A small amount of a solution of 1-bromononane (1.3 mL) in diethyl ether (5 mL) was added dropwise, and the reaction solution was heated until the brown color disappeared, and the remaining solution was added dropwise to the end. After stirring at room temperature for 15 minutes, it was cooled in an ice bath and a solution of 3-{[t-butyl(dimethyl)silyl]oxy}propanal (1.0 g) in diethyl ether (5 mL) was added dropwise. After stirring at the same temperature for 30 minutes, a saturated aqueous ammonium chloride solution was added. Ethyl acetate and water were added to perform a liquid separation operation, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain 1-{[t-butyl(dimethyl)silyl]oxy}dodecan-3-ol (1.27 g) as an oily substance.

[0136] Second step: 1-{[t-butyl(dimethyl)silyl]oxy}dodecan-3-ol (1.27 g) was dissolved in DMF (2.5 mL) under a nitrogen stream, and imidazole (0.82 g) and t-butyldiphenylchlorosilane (1.45 mL) were added and stirred at room temperature for 70 hours. Ethyl acetate and water were added to separate the liquid, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain 2,2,9,9,10,10-hexamethyl-5-nonyl-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane (2.08 g) as an oily substance.

[0137] Reference example 10 2,2,9,9,10,10-Hexamethyl-3,3-diphenyl-5-[(2Z,5Z)-undeca-2,5-dien-1-yl]-4,8-dioxa-3,9-disilaundecane used as a raw material in Example 3 was synthesized in the same manner as in Reference Example 8, except that 4-methylbenzene-1-sulfonic acid [(3Z,6Z)-nona-3,6-dien-1-yl] (triphenyl) phosphanium was used instead of the raw material 4-methylbenzene-1-sulfonic acid [(3Z)-nona-3-en-1-yl] (triphenyl) phosphanium.

[0138] Reference example 11 2,2,9,9,10,10-Hexamethyl-3,3-diphenyl-5-undecyl-4,8-dioxa-3,9-disilaundecane used as a raw material in Example 4 was synthesized in the same manner as in Reference Example 9, except that 1-bromoundecane was used instead of the raw material 1-bromononane.

[0139] Reference example 12 2,2,9,9,10,10-Hexamethyl-3,3-diphenyl-5-[(2E)-undec-2-en-1-yl]-4,8-dioxa-3,9-disilaundecane was synthesized as the raw material of Example 5. The steps are shown below. Lithium bromide (0.55 g) was placed in a reaction vessel, and the mixture was heated in a 150°C oil bath while being depressurized with a vacuum pump, and dried for 1 hour. After cooling, THF (15 mL) was added, followed by nonyl(triphenyl)phosphonium bromide (1.5 g) and stirring at room temperature for 10 minutes. The mixture was cooled to -78°C, and phenyllithium (2.0 M dibutyl ether solution, 1.6 mL) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was cooled again to -78°C. A THF (7.5 mL) solution of 5-{[t-butyl(dimethyl)silyl]oxy}-3-{[t-butyl(diphenyl)silyl]oxy}pentanal (1.5 g) was added dropwise, followed by phenyllithium (2.0 M dibutyl ether solution, 1.6 mL) and stirring at -78°C for 30 minutes. The bath was removed and the mixture was stirred for another 30 minutes. The mixture was cooled to -78°C again, and hydrogen chloride (1 M in diethyl ether, 3.19 mL) was added. Potassium t-butoxide (0.40 g) was added, the bath was removed, and the mixture was stirred for 1.5 hours. Water was added to the reaction solution, and then ethyl acetate was added to separate the mixture. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-[(2E)-undec-2-en-1-yl]-4,8-dioxa-3,9-disilaundecane (1.37 g) as an oily substance.

[0140] Reference example 13 2,2,9,9,10,10-Hexamethyl-5-[(2-octylcyclopropyl)methyl]-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane was synthesized as the raw material for Example 6. The steps are shown below. First step: 2-[2-(4-methoxyphenyl)-1,3-dioxane-4-yl]ethan-1-ol (3.76 g) was dissolved in dichloromethane (40 mL) under a nitrogen stream, and imidazole (1.50 g) and t-butyldimethylsilyl chloride (2.62 g) were added at room temperature and stirred for 30 minutes. After adding sodium bicarbonate water, water was added and the mixture was extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain t-butyl{2-[2-(4-methoxyphenyl)-1,3-dioxane-4-yl]ethoxy}dimethylsilane (5.44 g) as an oily substance.

[0141] Second step: Under a nitrogen stream, t-butyl{2-[2-(4-methoxyphenyl)-1,3-dioxan-4-yl]ethoxy}dimethylsilane (5.44 g) was dissolved in toluene (20 mL) and cooled on ice. Diisobutylaluminum hydride (1M toluene solution, 18.5 mL) was added dropwise, and the mixture was stirred for 3 hours while warming to room temperature. The mixture was cooled on ice again, and diisobutylaluminum hydride (1M toluene solution, 9 mL) was added and stirred for another 3 hours. Water was added, and then an aqueous solution of sodium potassium tartrate was added until the mixture could be stirred. Ethyl acetate was added to separate the layers, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain 5-{[t-butyl(dimethyl)silyl]oxy}-3-[(4-methoxyphenyl)methoxy]pentan-1-ol (1.88 g) as an oily substance.

[0142] Third step: 5-{[t-butyl(dimethyl)silyl]oxy}-3-[(4-methoxyphenyl)methoxy]pentan-1-ol (1.88 g) was dissolved in dichloromethane (40 mL) and cooled with ice. Dess-Martin reagent (2.25 g) was added little by little and stirred at the same temperature for 1 hour. Aqueous sodium thiosulfate solution and aqueous sodium bicarbonate solution were added, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain 5-{[t-butyl(dimethyl)silyl]oxy}-3-[(4-methoxyphenyl)methoxy]pentanal (1.61 g) as an oily substance.

[0143] Fourth step: t-Butyl({(5Z)-3-[(4-methoxyphenyl)methoxy]tetradec-5-en-1-yl}oxy)dimethylsilane was synthesized in the same manner as in Reference Example 8, except that nonyl(triphenyl)phosphanium bromide was used instead of the raw material 4-methylbenzene-1-sulfonic acid [(3Z,6Z)-nona-3,6-dien-1-yl](triphenyl)phosphanium, and 5-{[t-butyl(dimethyl)silyl]oxy}-3-{[t-butyl(diphenyl)silyl]oxy}pentanal was used instead of 5-{[t-butyl(dimethyl)silyl]oxy}-3-[(4-methoxyphenyl)methoxy]pentanal.

[0144] Fifth step: t-Butyl({(5Z)-3-[(4-methoxyphenyl)methoxy]tetradec-5-en-1-yl}oxy)dimethylsilane (1.95 g) was dissolved in dichloromethane (59 mL), water (3.3 mL) was added and stirred, then DDQ (1.24 g) was added at room temperature and stirred at the same temperature for 30 minutes. n-Hexane was added and the solid was filtered off, water was added to the filtrate and extracted with chloroform, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain (5Z)-1-{[t-butyl(dimethyl)silyl]oxy}tetradec-5-en-3-ol (1.31 g) as an oily substance.

[0145] Sixth step: (5Z)-1-{[t-butyl(dimethyl)silyl]oxy}tetradec-5-en-3-ol (1.31 g) was dissolved in dichloromethane (65 mL) under a nitrogen stream and cooled on ice. Diethylzinc (1M n-hexane solution, 19 mL) was added, and the mixture was stirred at the same temperature for 5 minutes, followed by addition of diiodomethane (1.54 mL). After stirring at the same temperature for 30 minutes, the mixture was allowed to naturally warm up and stirred at room temperature for 1 hour. The mixture was cooled on ice again, and a saturated aqueous ammonium chloride solution was added, extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain 4-{[t-butyl(dimethyl)silyl]oxy}-1-(2-octylcyclopropyl)butan-2-ol (1.33 g) as an oily substance.

[0146] Seventh step: 2,2,9,9,10,10-hexamethyl-5-[(2-octylcyclopropyl)methyl]-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane was synthesized in the same manner as in the second step of Reference Example 9, except that 4-{[t-butyl(dimethyl)silyl]oxy}-1-(2-octylcyclopropyl)butan-2-ol was used instead of the raw material 1-{[t-butyl(dimethyl)silyl]oxy}dodecan-3-ol.

[0147] Reference example 14 2,2,9,9,10,10-Hexamethyl-5-octyl-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane was synthesized as the raw material for Example 7. The steps are shown below. First step: Under a nitrogen atmosphere, diethyl ether (10 mL) was added to 3-{[t-butyl(dimethyl)silyl]oxy}propanal (1.16 g) and cooled in an ice bath, and octylmagnesium bromide (2 M diethyl ether solution, 3.4 mL) was added dropwise and stirred at the same temperature for 90 minutes. Saturated ammonium chloride solution and water were added to the reaction solution, and then ethyl acetate was added to perform a liquid separation operation. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc / n-hexane) to obtain 1-{[t-butyl(dimethyl)silyl]oxy}undecan-3-ol (0.72 g) as an oily substance.

[0148] Second step: 2,2,9,9,10,10-hexamethyl-5-octyl-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane was synthesized in the same manner as in the second step of Reference Example 9, except that 1-{[t-butyl(dimethyl)silyl]oxy}undecane-3-ol was used instead of the raw material 1-{[t-butyl(dimethyl)silyl]oxy}dodecan-3-ol.

[0149] Reference example 15 Using a method similar to that described in J. Nucl. Med., 2010, 51(8), 1310-1317, 18 F]FTO was obtained and made into a liquid formulation in the same manner as in the sixth step of Example 1.

[0150] The chemical structures and physicochemical data of the compounds obtained in Reference Examples 1 to 15 are shown in Tables 7 to 9.

[0151] [Table 7]

[0152] [Table 8]

[0153] [Table 9]

[0154] Example 8 PET study using normal cynomolgus monkeys (Experimental Method) Using normal cynomolgus monkeys, Examples 1 to 7 and Reference Example 15 ([ 18 A cardiac PET study was performed using solutions containing each compound prepared in a fluoroscopy (F]FTO). To perform non-invasive PET imaging, male cynomolgus monkeys were anesthetized with isoflurane and placed in a supine position on a PET camera SHR17000 (Hamamatsu Photonics). A solution containing each compound (approximately 300 MBq) was administered via the leg vein, and continuous imaging was performed for more than 180 minutes after administration. PET images were reconstructed using DRAMA (dynamic row-action maximum likelihood algorithm), and average images were obtained for each time interval from 0 to 180 minutes after administration in 20-minute intervals. Regions of interest (ROIs) were set in the myocardial region or bone (near the spine), and the accumulation of each compound (Standardized Uptake Value (SUV)) was calculated as {radioactivity counts in ROI (MBq / cc) / [administered dose (MBq) / body weight (g)]}.

[0155] (result) The SUV values ​​quantified by setting ROIs in the myocardium and bone for each compound are shown in Tables 10 and 11 as SUV (myocardium) and SUV (bone). In the tables, Examples 1 to 7 show the value of one case, and Reference Example 15 shows the average ± standard error of three cases, and when the target organ could not be confirmed on the image and ROI setting was impossible, it is shown as nd. The times in the tables represent the end points of each time segment, and for example, "20 min" represents the SUV value after 0 to 20 min, and "180 min" represents the SUV value after 160 to 180 min. In addition, in Reference Example 15 ([ 18 FIG. 1 shows MIP (Maximum Intensity Projection) PET images taken 60 minutes and 180 minutes after administration of [F]FTO and the compound of Example 6.

[0156] [Table 10]

[0157] [Table 11]

[0158] From the results of Tables 10 and 11, Reference Example 15 ([ 18 As compared with [F]FTO), it was shown that the ratio of accumulation in the myocardium to non-specific accumulation in the bone was improved in Examples 1 to 7. In particular, in Example 6, no non-specific accumulation in the bone was detected at all, and it was shown that good PET imaging of the heart is possible as shown in FIG. From these results, 18 It was confirmed that the Example compounds of the present invention in which F was substituted showed higher accumulation in the heart compared to non-specific accumulation in the bone. [Industrial Applicability]

[0159] The labeled fatty acid derivative of the present invention can be used as a radiolabeled tracer for rapid and non-invasive identification of patients with heart disease, diagnosis of the therapeutic effect of an agent for treating heart disease, and the like.

Claims

1. A labeled fatty acid derivative represented by formula (I) or a salt thereof. 【Chemistry 1】 (In the formula, L is C 2-4 is alkylene, R is C 6-14 is an alkyl group, 6-14 The alkyl group may have 1 to 3 double bonds, and the C 6-14 Three consecutive carbon atoms in the alkyl may be joined together to form a cyclopropane ring; However, this does not include the case where R is a (2Z)-undec-2-en-1-yl group.

2. The labeled fatty acid derivative or a salt thereof according to claim 1, wherein L is ethylene.

3. R is C 6-14 Alkyl, 6-14 The labeled fatty acid derivative or a salt thereof according to claim 2, wherein three consecutive carbon atoms of the alkyl are combined to form a cyclopropane ring.

4. Labeled fatty acid derivatives 3-{[(5Z,8Z,11Z)-3-[ 18 F]fluorotetradeca-5,8,11-trien-1-yl]sulfanyl}propanoic acid, 3-[(3-[ 18 F]fluorododecyl)sulfanyl]propanoic acid, 3-{[(5Z,8Z)-3-[ 18 F]fluorotetradec-5,8-dien-1-yl]sulfanyl}propanoic acid, 3-[(3-[ 18 F]fluorotetradecyl)sulfanyl]propanoic acid, 3-{[(5E)-3-[ 18 F]fluorotetradec-5-en-1-yl]sulfanyl}propanoic acid, 3-{[3-[ 18 F]fluoro-4-(2-octylcyclopropyl)butyl]sulfanyl}propanoic acid, and 5-[(3-[ 18 F]fluoroundecyl)sulfanyl]pentanoic acid The labeled fatty acid derivative or its salt according to claim 1, which is a labeled fatty acid derivative selected from the group consisting of:

5. A composition for diagnostic imaging, comprising the labeled fatty acid derivative or a salt thereof according to any one of claims 1 to 4, and a pharma- ceutically acceptable carrier.

6. The diagnostic imaging composition according to claim 5 , wherein the diagnostic imaging composition is a diagnostic imaging composition for cardiac disease.

7. The diagnostic imaging composition according to claim 6, wherein the heart disease is ischemic heart disease.

8. Use of the labeled fatty acid derivative or a salt thereof according to any one of claims 1 to 4 for the production of a composition for diagnostic imaging of heart disease.

9. 9. Use of the labeled fatty acid derivative or a salt thereof according to claim 8, wherein the heart disease is ischemic heart disease.

10. The labeled fatty acid derivative or a salt thereof according to any one of claims 1 to 4, for use in diagnostic imaging of heart disease.

11. The labeled fatty acid derivative or a salt thereof according to claim 10, wherein the heart disease is ischemic heart disease.

12. A compound represented by formula (1g) or a salt thereof. 【Chemistry 2】 (In the formula, L is C 2-4 is alkylene, R is C 6-14 is an alkyl group, 6-14 The alkyl group may have 1 to 3 double bonds, and the C 6-14 Three consecutive carbon atoms in the alkyl may be joined together to form a cyclopropane ring; R' is H or a lower alkyl group; X is a sulfonyloxy group or a halogen; However, this does not include the case where R is a (2Z)-undec-2-en-1-yl group.

13. 13. The compound or salt thereof according to claim 12, wherein R' is lower alkyl.

14. 14. The compound or salt thereof according to claim 13, wherein L is ethylene.

15. R is C 6-14 Alkyl, 6-14 The compound or a salt thereof according to claim 14, wherein three consecutive carbon atoms of the alkyl are joined together to form a cyclopropane ring.

16. The compound or salt thereof according to claim 12, 18 A method for producing a labeled fatty acid derivative or a salt thereof according to any one of claims 1 to 4, comprising a step of reacting a [F] fluoride ion with the fatty acid derivative or a salt thereof.

17. A kit for producing the composition for diagnostic imaging according to claim 5, comprising the compound or a salt thereof according to any one of claims 12 to 15.

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