WO2020017620A1 - 陽電子放出核種で標識された脂肪酸誘導体 - Google Patents

陽電子放出核種で標識された脂肪酸誘導体 Download PDF

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Publication number
WO2020017620A1
WO2020017620A1 PCT/JP2019/028380 JP2019028380W WO2020017620A1 WO 2020017620 A1 WO2020017620 A1 WO 2020017620A1 JP 2019028380 W JP2019028380 W JP 2019028380W WO 2020017620 A1 WO2020017620 A1 WO 2020017620A1
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Prior art keywords
fatty acid
salt
acid derivative
heart disease
compound
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English (en)
French (fr)
Japanese (ja)
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佳裕 村上
洋司 伏木
優史 藤田
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Astellas Pharma Inc
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Astellas Pharma Inc
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Priority to US17/261,328 priority Critical patent/US12029797B2/en
Priority to EP19837826.7A priority patent/EP3825302B1/en
Priority to KR1020217001389A priority patent/KR102718221B1/ko
Priority to CA3106903A priority patent/CA3106903A1/en
Priority to CN201980048149.8A priority patent/CN112638868B/zh
Priority to ES19837826T priority patent/ES3009015T3/es
Priority to AU2019304781A priority patent/AU2019304781B2/en
Priority to JP2020531374A priority patent/JP7375755B2/ja
Publication of WO2020017620A1 publication Critical patent/WO2020017620A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/54—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
    • G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
    • G01T1/16—Measuring radiation intensity
    • G01T1/161—Applications in the field of nuclear medicine, e.g. in vivo counting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to a fatty acid derivative or a salt thereof labeled with a positron emitting nuclide. Furthermore, the present invention relates to a diagnostic imaging composition containing the labeled fatty acid derivative or a salt thereof, and a kit for producing the same.
  • the heart requires large amounts of adenosine triphosphate (ATP) to send blood throughout the body, and most of it is produced by mitochondrial oxidative metabolism.
  • ATP adenosine triphosphate
  • various substrates such as fatty acids and glucose are metabolized, but when oxygen is distributed to the heart muscle, about 60 to 90% of the required ATP is produced by ⁇ -oxidation of fatty acids.
  • ATP adenosine triphosphate
  • the quantification of the fatty acid metabolic activity is performed by positron tomography (PET) or single photon tomography (SPECT) using a labeled long-chain fatty acid derivative as a radiolabeled tracer.
  • PET positron tomography
  • SPECT single photon tomography
  • the radiolabelled tracer used in SPECT represented by the following formula 15- (p- [123 I] iodophenyl) -3 (R, S) - methyl pentadecane acid (hereinafter abbreviated as [123 I] BMIPP.) (Non-Patent Document 1), which is actually used in the diagnosis of heart disease in clinical practice.
  • 16- [ 18 F] fluoro-4-thiahexadecanoic acid also referred to as 16- [ 18 F] fluoro-4-thiapalmitic acid represented by the following formula; 18 F] FTP
  • Patent Document 1 16- [ 18 F] fluoro-4-thiapalmitic acid represented by the following formula; 18 F] FTP
  • [ 123 I] BMIPP which is used as a tracer for diagnostic imaging by SPECT, has problems of low sensitivity and low resolution.
  • [ 18 F] BMIPP a tracer used for diagnostic imaging by PET, is an issue.
  • FTP and [ 18 F] FTO are also superior to SPECT using [ 123 I] BMIPP, but further improved sensitivity and resolution are required for more accurate diagnosis.
  • the present inventors have conducted intensive studies with the aim of creating a labeled fatty acid derivative in which the generation of [ 18 F] fluoride ion by metabolism is unlikely, and as a result, surprisingly, 3- ⁇ [(5Z) -tetradeca
  • the labeled fatty acid derivative represented by the formula (I) in which [ 18 F] fluorine is substituted on the carbon atom between the sulfur atom and the double bond of [5-5-en-1-yl] sulfanyl ⁇ propanoic acid is obtained by the conventional [ compared to 18 F] FTO, and finding that could cause [18 F] fluorine low accumulation of bone, selectively accumulates in the heart, radiolabelled tracers fatty acid metabolism in the myocardium can be sensitively imaging
  • the present invention has been completed.
  • the present invention relates to a labeled fatty acid derivative represented by the formula (I) or a salt thereof.
  • a labeled fatty acid derivative represented by the formula (I) or a salt thereof In the formula, one of R 1 to R 3 is 18 F, and the other two are H.
  • the present invention (1) a composition for diagnostic imaging comprising the labeled fatty acid derivative of the formula (I) or a salt thereof and a pharmaceutically acceptable carrier, particularly a diagnostic imaging composition for heart disease; (2) use of the labeled fatty acid derivative of the formula (I) or a salt thereof for the production of a composition for diagnostic imaging of heart disease; (3) use of the labeled fatty acid derivative of the formula (I) or a salt thereof for diagnostic imaging of heart disease; (4) a labeled fatty acid derivative of the formula (I) or a salt thereof for use in diagnostic imaging of heart disease; (5) a method for diagnostic imaging of heart disease, comprising administering a detectable amount of a labeled fatty acid derivative of the formula (I) or a salt thereof to a subject; (6) an intermediate compound or a salt thereof which can be converted into a labeled fatty acid derivative of the formula (I) or a salt thereof; (7) A method for producing a labeled fatty acid derivative of the formula (I) or a salt thereof
  • the labeled fatty acid derivative represented by the formula (I) or a salt thereof according to the present invention has no increase in background value derived from accumulation in bone and has a higher myocardial activity than [ 18 F] FTO, which is a known labeled fatty acid. It has good accumulating properties for PET and enables imaging of fatty acid metabolism activity by PET. Therefore, the labeled fatty acid derivative represented by the formula (I) or a salt thereof of the present invention can be used as a radiolabeled tracer for the classification of patients with heart disease, the image diagnosis of the therapeutic effect of a therapeutic agent for heart disease, and the like.
  • FIG. 1 is a PET image obtained by administering the compound of Reference Example 4 ([ 18 F] FTO) and the compound of Example 1 (7- [ 18 F] FTO) to normal cynomolgus monkeys in Example 5. PET images 60 minutes and 240 minutes after administration of [ 18 F] FTO are shown in (A) and (B), respectively. PET images at 60 minutes and 240 minutes after administration of 7- [ 18 F] FTO are shown in (C) and (D), respectively.
  • FIG. 2 is a PET image obtained by administering the compound of Reference Example 4 ([ 18 F] FTO) and the compound of Example 1 (7- [ 18 F] FTO) to normal mice in Example 6.
  • FIG. 3 is a PET image obtained by administering the compound of Example 1 (7- [ 18 F] FTO) to normal and myocardial infarction model rats in Example 7.
  • (A) and (B) show cardiac PET cross-sectional images of normal and myocardial infarction model rats 20 minutes after administration of 7- [ 18 F] FTO, respectively.
  • One embodiment of the labeled fatty acid derivative represented by the formula (I) or a salt thereof according to the present invention is a labeled fatty acid derivative wherein R 1 is H or a salt thereof.
  • One embodiment of the labeled fatty acid derivative represented by the formula (I) or a salt thereof according to the present invention is a labeled fatty acid derivative selected from the following group, or a salt thereof.
  • R 2 is 18 F and R 1 and R 3 are H, that is, 3- ⁇ [(5Z) -3- [ 18 F] fluorotetradec-5-en-1-yl] Sulfanyl ⁇ propanoic acid (also referred to as 7- [ 18 F] fluoro-4-thiaoleic acid; hereinafter abbreviated as 7- [ 18 F] FTO)
  • the labeled fatty acid derivative represented by the formula (I) of the present invention or a salt thereof is used as a radiolabeled tracer for diagnostic imaging such as PET.
  • the labeled fatty acid derivative of the present invention has an ability to accumulate in the myocardium in a living body, enables the imaging of its fatty acid metabolism activity by PET and similar imaging methods, and is useful for heart disease, particularly ischemic heart. It can be used for diagnostic imaging of diseases. In the small animal test, it can be used as an in-vivo image diagnostic means in addition to the small animal PET system, as well as the Planar Positron Imaging System (PPIS), which acquires planar integrated images instead of tomographic images. Furthermore, it can also be used for autoradiography, which is an image analysis means for a section of an isolated organ, or for evaluation of accumulation in an isolated organ using a gamma counter.
  • PPIS Planar Positron Imaging System
  • the positron emitting nuclide used in the labeled fatty acid derivative of the present invention is 18 F.
  • 18 F is produced by a device called a cyclotron.
  • the 18 F produced can be used to label the compound of formula (I).
  • a desired nuclide is obtained from a (ultra) small cyclotron installed in a facility or the like to be used, and the labeled fatty acid derivative of the formula (I) of the present invention or a salt thereof is produced by a method known in the art, and is used for diagnostic imaging.
  • a composition can be made.
  • the labeled fatty acid derivative represented by the formula (I) of the present invention or a salt thereof may have an asymmetric center, and an enantiomer (optical isomer) based on this may exist.
  • the compound of the formula (I) or a salt thereof includes any of the isolated individual enantiomers such as (R) -form and (S) -form, and mixtures thereof (including racemic mixtures or non-racemic mixtures).
  • the labeled fatty acid derivative of the formula (I) of the present invention may form a salt depending on conditions, and the present invention includes these salts.
  • the salt include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine; and various amino acids and amino acid derivatives such as acetylleucine. And ammonium salts.
  • the labeled fatty acid derivative of the formula (I) or a salt thereof of the present invention may be provided as a hydrate, a solvate or a polymorphic substance, and the present invention includes these.
  • the present invention includes an intermediate compound or a salt thereof which can be converted into a labeled fatty acid derivative of the formula (I) or a salt thereof.
  • the “intermediate compound that can be converted into the labeled fatty acid derivative of the formula (I) or a salt thereof” includes, for example, a compound represented by the following formula (1i).
  • Another embodiment includes a compound represented by the following formula (1h), which is a precursor of the compound represented by (1i). (Wherein, one of Y 1 to Y 3 is OH and the other two are H. Any one of R 11 to R 31 is a leaving group, and the other two are H. Further, R ′ is H or a lower alkyl group which may be substituted. The same shall apply hereinafter.)
  • intermediate compounds may be converted into labeled fatty acid derivative or a salt thereof of formula (I) or a salt thereof, comprising the step of reacting the [18 F] fluoride ions, labeling fatty of formula (I) Includes methods for producing derivatives or salts thereof.
  • the present invention includes a kit for preparing a diagnostic imaging composition, which comprises at least an intermediate compound or a salt thereof which can be converted into a labeled fatty acid derivative of the formula (I) or a salt thereof.
  • a kit for rapid synthesis of the labeled fatty acid derivative of the present invention includes an intermediate compound or a salt thereof which can be converted into a labeled fatty acid derivative of the formula (I) or a salt thereof, and a kit for producing an imaging diagnostic composition, which comprises a reagent for 18 F labeling.
  • the kit also includes a reaction vessel, an apparatus for transferring the isotope material to the reaction vessel, a pre-packed separation column for separating the product from excess reactants, a shield, as is known in the art. And the like.
  • the “reagent for 18 F labeling” is a reagent containing [ 18 F] fluoride ion, for example, [ 18 F] TBAF, [ 18 F] KF and the like.
  • “Lower alkyl” refers to straight-chain or branched alkyl having 1 to 6 carbon atoms (hereinafter, also referred to as C 1-6 ), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl and the like.
  • One embodiment is C 1-4 alkyl, one embodiment is methyl, ethyl or t-butyl, and one embodiment is methyl.
  • Leaving group means a substituent that is eliminated by a nucleophilic substitution reaction, and includes, but is not limited to, for example, a sulfonyl group and a halogen.
  • the sulfonyl group include a p-toluenesulfonyloxy group, a p-nitrobenzenesulfonyloxy group, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group. It is a sulfonyloxy group.
  • halogen include Cl, Br and I, and one embodiment is Br.
  • Specific examples of the present invention include the following.
  • (1-1) A labeled fatty acid derivative represented by the formula (I) or a salt thereof.
  • (1-2) The labeled fatty acid derivative or a salt thereof according to (1-1), wherein R 1 is H.
  • (2) A diagnostic imaging composition comprising the labeled fatty acid derivative or a salt thereof described in any of the above (1-1) to (1-4), and a pharmaceutically acceptable carrier.
  • the composition for diagnostic imaging according to (2) which is a composition for diagnostic imaging of heart disease.
  • the labeled fatty acid derivative of the formula (I) or a salt thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic structure or the type of the substituent. At that time, depending on the type of the functional group, it is effective in production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at a stage from the raw material to the intermediate. There are cases. Examples of such a protecting group include the protecting groups described in ⁇ Greene's Protective Groups in Organic Synthesis (5th edition, 2014) '' by PGM Wuts, and according to these reaction conditions. May be appropriately selected and used. In such a method, a desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group as necessary.
  • AlkylFluor TM 1,3-bis (2,6-diisopropylphenyl) -2-fluoroimidazolium tetrafluoroborate
  • DBU 1,8-diazabicyclo [5.4.0] -7-undecene
  • EtOAc ethyl acetate
  • HMPA hexamethylphosphoric triamide
  • MeCN acetonitrile
  • MeOH methanol
  • Nos p-nitrobenzenesulfonyl
  • Ph phenyl
  • TBAF tetra-n-butylammonium fluoride
  • TBDMS t-butyldimethylsilyl
  • TBDPS t -Butyldiphenylsilyl
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • THP tetrahydropyran-2-yl
  • Tstetrahydropyran-2-yl 1,3-
  • any one of X 1 , X 2 , and X 3 is OPg 2 , and the other two are H.
  • Pg 1 and Pg 2 each represent a protecting group. Is, for example, TBDMS, TBDPS, trimethylsilyl, triethylsilyl, triisopropylsilyl, methoxymethyl, 1-ethoxyethyl, [2- (trimethylsilyl) ethoxy] methyl, THP, p-methoxybenzyl. TBDMS, TBDPS, and THP. The same applies hereinafter.)
  • Compound (1c) can be produced from compound (1a) and compound (1b). This reaction is stirred in a solvent inert to the reaction in the presence of a base at -78 ° C to room temperature, usually for 0.1 hour to 3 days.
  • a solvent include THF, 1,4-dioxane, HMPA and the like, and a mixture thereof.
  • the base include potassium hexamethyldisilazide, potassium-t-butoxide and the like.
  • Compound (1d) can be prepared by deprotecting the protecting group Pg 1 of compound (1c). Deprotection can be performed using a method well known to those skilled in the art. For example, 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 hour to 3 days It can be performed by stirring.
  • a fluorine reagent include TBAF, pyridine hydrofluoric acid, and the like.
  • acetic acid may be added. Examples of the acid include hydrochloric acid, p-toluenesulfonic acid and the like.
  • Compound (1e) can be produced by converting the hydroxyl group of compound (1d) to iodine by an iodination reaction.
  • the iodination reaction is carried out by stirring the compound (1d) 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 hour to 3 days.
  • the base include imidazole and triethylamine.
  • the solvent include dichloromethane, THF and the like.
  • Compound (1g) can be produced from compound (1e) and compound (1f). This reaction is carried out by stirring compound (1e) and compound (1f) in an inert solvent in the presence of a base at ice-cooling to room temperature for 0.1 hour to 3 days.
  • a base examples include sodium hydride, potassium-t-butoxide and the like.
  • Compound (1h) can be prepared by deprotecting the protecting group Pg 2 of the compound (1 g). Deprotection can be performed in the same manner as in the second step.
  • Compound (1i) can be produced by converting a hydroxyl group of compound (1h) to a leaving group.
  • the leaving group is a sulfonyl group
  • the reaction is performed by stirring the compound (1h) and the sulfonylating agent in an inert solvent in the presence of a base at ice-cooling to room temperature, usually for 0.1 hour to 3 days.
  • the sulfonylating agent include (p-toluenesulfonyl) chloride, (p-nitrobenzenesulfonyl) chloride, (methanesulfonyl) chloride, and trifluoromethanesulfonic anhydride.
  • the solvent include dichloromethane, THF and the like.
  • the base include triethylamine, diisopropylethylamine and the like. At this time, trimethylamine hydrochloride may be added.
  • the reaction is carried out in a solvent inert to the reaction in the presence of triphenylphosphine in the presence of compound (1h) and a halogenating agent at ice-cooling to room temperature, usually for 0.1 hour to 3 hours. Stir for days.
  • a halogenating agent include carbon tetrabromide and iodine.
  • the solvent include carbon tetrachloride, dichloromethane, THF and the like.
  • a base such as imidazole or triethylamine may be added.
  • Compound (1j) may be, for example, the compound (1i), a reagent containing a well-known positron emission 18 F which was produced from the cyclotron by methods familiar to those skilled in the art, [18 F] fluoride ion solution, [18 It can be produced by reacting [F] tetra-n-butylammonium fluoride ([ 18 F] TBAF), [ 18 F] KF and the like under heating.
  • Compound (I) can be produced from compound (1j) by a method well known to those skilled in the art. For example, in a solvent inert to the reaction, in the presence of an aqueous base, at ice-cold to 110 ° C., usually It can be performed by stirring for 0.1 hour to 3 days. Examples of the base include sodium hydroxide, potassium hydroxide and the like. When R ′ is H, the seventh step-2 is omitted.
  • Isolation and purification of the compound of the formula (I) or a salt thereof produced in this manner can be carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. Done.
  • Various isomers can be produced by selecting an appropriate starting compound, or can be separated by utilizing a difference in physicochemical properties between the isomers.
  • an optical isomer can be obtained by a general optical resolution method of a racemate (for example, fractional crystallization leading to a diastereomer salt with an optically active base or acid, chromatography using a chiral column or the like).
  • it can be produced from a suitable optically active starting compound.
  • the diagnostic imaging composition of the present invention can be produced by combining the labeled fatty acid derivative with at least one pharmaceutically acceptable carrier.
  • the composition for diagnostic imaging 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 a sterile aqueous or non-aqueous solution, suspension, and emulsion.
  • Aqueous solvents include, for example, distilled water for injection and physiological saline.
  • the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
  • compositions may further include a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, and a solubilizing agent.
  • a tonicity agent sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation.
  • these can be used by preparing a sterile solid composition, dissolving and suspending in sterile water or a sterile injection solvent before use.
  • the diagnostic imaging composition of the present invention is an injection for intravenous administration.
  • Another embodiment is an aqueous solution.
  • the composition for diagnostic imaging of the present invention can be used after adjusting the dose according to the imaging method (PET etc.) to be 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 needs to include a detectable amount of the labeled fatty acid derivative, it is necessary to pay close attention to the amount of exposure of the patient.
  • the radioactivity of the diagnostic imaging composition of the present invention labeled with 18 F is about 1.85 to 740 megabecquerel (MBq), and in one embodiment, about 1.85 to 37 MBq, and In one embodiment, it is about 37-740 MBq. This may be administered once or in multiple doses, or may be administered by continuous infusion.
  • Example number the branch number indicates the number of the step in the example in which the compound was obtained.
  • the compound having the example number of Ex1-3 was obtained in the third step of Example 1)
  • Ref Reference example number
  • Str Chemical structural formula
  • DAT Physicochemical data
  • ESI + m / z value in mass spectrometry (ionization method ESI, unless otherwise noted [ M + H] + )
  • ESI- m / z value in mass spectrometry (ionization method ESI, unless otherwise noted [MH] - )
  • APCI / ESI + ionization method APCI and ESI performed simultaneously, unless otherwise noted [ M + H] +
  • CI + m / z value in mass spectrometry (ionization method CI, [M + H] + unless otherwise noted)
  • NMR ⁇ value (ppm) of signal in 1H-NMR in
  • concentration mol / L is expressed as M.
  • a 1 M aqueous sodium hydroxide solution means a 1 mol / L aqueous sodium hydroxide solution.
  • Example 1 First step: Under a nitrogen stream, nonyltriphenylphosphonium bromide (7.39 g) was dissolved in a mixture of THF (190 mL) and HMPA (7.4 mL) and cooled to -78 ° C. After potassium hexamethyldisilazide (15.7 mL of a 1 M THF solution) was added dropwise, the mixture was stirred for 1 hour under ice cooling.
  • Second step 2,2,9,9,10,10-hexamethyl-3,3-diphenyl-5-[(2Z) -undec-2-en-1-yl] -4,8-dioxa-3, 9-disilaundecane (2.94 mg) was dissolved in a mixture of THF (30 mL) and water (1.5 mL), p-toluenesulfonic acid monohydrate (96 mg) was added at room temperature, and the same temperature was maintained for 20 hours. Stirred. Aqueous sodium bicarbonate and ethyl acetate were added, the organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Triphenylphosphine (2.57 g) was dissolved in dichloromethane (120 mL) under a nitrogen stream, and iodine (2.49 g) and imidazole (0.83 g) were added, followed by stirring at room temperature for 10 minutes.
  • a solution of (5Z) -3- ⁇ [t-butyl (diphenyl) silyl] oxy ⁇ tetradec-5-en-1-ol (2.29 g) in dichloromethane (20 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • MeCN 0.8 mL of methyl 3-( ⁇ (5Z) -3-[(4-methylbenzene-1-sulfonyl) oxy] tetradec-5-en-1-yl ⁇ sulfanyl
  • the solution was added and heated at 130 ° C. for 10 minutes.
  • a 0.2 M aqueous solution of potassium hydroxide 0.2 mL was added to the reaction solution, and the mixture was heated at 110 ° C. for 4 minutes.
  • Example 2 shows a method for synthesizing 5- ⁇ [t-butyl (dimethyl) silyl] oxy ⁇ -4- ⁇ [t-butyl (diphenyl) silyl] oxy ⁇ pentanal as a starting material in the first step.
  • Third step In the same manner as in the third step of Example 1, except that (5Z) -2- ⁇ [t-butyl (diphenyl) silyl] oxy ⁇ tetradec-5-en-1-ol is used as a raw material, t -Butyl ⁇ [(5Z) -1-iodotetradec-5-en-2-yl] oxy ⁇ diphenylsilane was obtained.
  • Example 3 7- [ 18 F] FTO can also be obtained using methyl 3- ⁇ [(5Z) -3-bromotetradec-5-en-1-yl] sulfanyl ⁇ propanoate as an intermediate. The steps are shown below.
  • Second step Except that methyl 3- ⁇ [(5Z) -3-bromotetradec-5-en-1-yl] sulfanyl ⁇ propanoate is used as a starting material, the same procedure as in the seventh step of Example 1 is carried out. -I got [ 18 F] FTO.
  • Example 4 7- [ 18 F] FTO uses methyl 3-( ⁇ (5Z) -3-[(4-nitrobenzene-1-sulfonyl) oxy] tetradec-5-en-1-yl ⁇ sulfanyl) propanoate as an intermediate It can also be obtained by using. The steps are shown below.
  • First step The same as in the sixth step of Example 1, except that (p-nitrobenzenesulfonyl) chloride is used as a sulfonylating agent, trimethylamine hydrochloride is not used, and 3-( ⁇ (5Z) -3- [ Methyl (4-nitrobenzene-1-sulfonyl) oxy] tetradec-5-en-1-yl ⁇ sulfanyl) propanoate was obtained.
  • Second step Example 1 except that methyl 3-( ⁇ (5Z) -3-[(4-nitrobenzene-1-sulfonyl) oxy] tetradec-5-en-1-yl ⁇ sulfanyl) propanoate was used as a raw material seventh step and in the same, to obtain a 7- [18 F] FTO.
  • Tables 1 to 3 show the chemical structural formulas and physicochemical data of the compounds obtained in each step.
  • Example 1 3- ⁇ [(5Z) -3-fluorotetradec-5-en-1-yl] sulfanyl ⁇ propanoic acid used as a preparation of Example 1 was synthesized. The steps are shown below. Cesium fluoride (69 mg) was heated to 150 ° C. under reduced pressure, allowed to stand for 2 hours, allowed to cool, replaced with nitrogen, added with AlkylFluor (trademark) (55 mg), and allowed to stand at 120 ° C. under reduced pressure for 1 hour. . After allowing to cool, toluene (1 mL) was added, and the mixture was stirred at 100 ° C for 2 hours.
  • Reference example 2 3- ⁇ [(5Z) -2-fluorotetradec-5-en-1-yl] sulfanyl ⁇ propanoic acid used as a preparation of Example 2 was synthesized. The steps are shown below. Dissolve methyl 3- ⁇ [(5Z) -2-hydroxytetradec-5-en-1-yl] sulfanyl ⁇ propanoate (50 mg) in toluene (0.5 mL) and add pyridine-2-sulfonyl fluoride at room temperature. (29 mg) and DBU (45 ⁇ L) were added, and the mixture was stirred at room temperature overnight. The reaction solution was directly purified using silica gel column chromatography (EtOAc / n-hexane).
  • the obtained residue was dissolved by adding THF (0.5 mL) and MeOH (0.5 mL), and an aqueous sodium hydroxide solution (1 M, 0.5 mL) was added, followed by stirring at room temperature for 30 minutes. After neutralization with an aqueous hydrochloric acid solution (1 M), the mixture was extracted with ethyl acetate and saturated saline. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
  • the obtained residue was dissolved in water / MeCN solution (20:80, 1 mL) and purified by HPLC (0.005% TFA aqueous solution / MeCN (20:80), column: YMC-Pack Pro C18, 10 ⁇ 250 mm) , S-5 ⁇ m, flow rate: 6 mL / min).
  • the obtained fraction of the desired product was concentrated under reduced pressure to reduce the liquid volume, and chloroform and saturated saline were added thereto to separate an organic layer.
  • the obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and 3- ⁇ [(5Z) -2-fluorotetradec-5-en-1-yl] sulfanyl ⁇ propanoic acid (6.1 mg) was used as an oil. Obtained.
  • Second step 9-bromononan-4-ol (10.2 g) was dissolved in dichloromethane (200 mL), and 3,4-dihydro-2H-pyran (4.35 mL) and pyridinium p-toluenesulfonate (1.15 g) were added. The mixture was stirred at room temperature for 24 hours. 3,4-Dihydro-2H-pyran (3 mL) was added, and the mixture was stirred at room temperature for 16 hours.
  • Reference example 6 First step: The same as in the third step of Reference Example 5, except that 2-[(9-bromononan-2-yl) oxy] oxane is used as a raw material, and bromide ⁇ 8-[(oxan-2- Yl) oxy] nonyl ⁇ triphenylphosphanium was obtained.
  • Second step t-butyldimethyl ( ⁇ (5Z) -13-[(oxan-2-yl) oxy] tetradec-5-en-1-yl ⁇ oxy) in the same manner as in the first step of Example 1.
  • the silane was obtained.
  • Example 5 PET test using normal cynomolgus monkeys (experimental method) With normal cynomolgus monkeys Example 1 (7- [18 F] FTO ), Example 2 (6- [18 F] FTO ), Reference Example 4 ([18 F] FTO) , Reference Example 5 (15 [ Cardiac angiography PET tests were performed using the liquid preparations containing each compound prepared in [ 18 F] FTO) and Reference Example 6 (17- [ 18 F] FTO).
  • PET images were reconstructed using a dynamic row-action maximum likelihood algorithm (DRAMA) to obtain an average image every 20 minutes, and then a region of interest (ROI) was set in the myocardial region or bone (near the spine), and each compound (Standardized Uptake Value (SUV)) was calculated as ⁇ radioactivity count in ROI (MBq / cc) / [dose (MBq) / body weight (g)] ⁇ .
  • DRAMA dynamic row-action maximum likelihood algorithm
  • Tables 6 and 7 show the SUV values determined by setting the ROI on the myocardium and bone of each compound as SUV (heart muscle) and SUV (bone).
  • Example 1 shows the average of two cases
  • Reference Example 4 shows the average ⁇ standard error of three cases
  • Examples 2, 5, and 6 show the values of one example, respectively.
  • nd is shown, and when not measured, nt is shown.
  • MIP Maximum Intensity Projection
  • Example 6 PET test using normal mice (experimental method) Using a DBA2 mouse, a whole-body contrast PET test was performed using a solution containing the compound of Example 1 (7- [ 18 F] FTO) or Reference Example 4 ([ 18 F] FTO).
  • a solution containing the compound of Example 1 (7- [ 18 F] FTO) or Reference Example 4 ([ 18 F] FTO) For non-invasive PET imaging, male DBA2 mice were anesthetized with the inhaled anesthetic isoflurane, held in a supine position on a PET camera Inveon (manufactured by Siemens), and a solution containing each compound (about 10 MBq) was administered via the tail vein, and PET imaging was performed for 5 minutes 90 minutes after the administration. PET images were reconstructed and then imaged.
  • the heart and the femur were isolated, and the radioactivity was measured using a gamma counter 2480 WIZARD 2 (manufactured by PerkinElmer).
  • the accumulation (SUV) of each compound was calculated as ⁇ radioactivity count in target organ (MBq / cc) / [dose (MBq) / body weight (g)] ⁇ .
  • Example 7 PET test using myocardial infarction model rat by coronary artery ligation (experimental method) A myocardial infarction model was created by coronary artery ligation treatment using SD rats, and a thoracic contrast-enhanced PET test was performed using a solution containing the compound of Example 1 (7- [ 18 F] FTO).
  • Using male SD rats untreated rats or myocardial infarction model rats were anesthetized with the inhalation anesthetic isoflurane and held in a supine position on a PET camera Inveon (manufactured by Siemens). 10 MBq) was administered from the tail vein, and PET imaging was performed for 5 minutes 20 minutes after the administration. PET images were reconstructed and then imaged.
  • FIG. 3 shows a coronal PET image near the center of the heart of the compound in an untreated or myocardial infarction model rat.
  • an untreated rat (A) depicts an oval heart in a coronal cross-sectional image
  • a myocardial infarction model rat (B) lacks a signal in a part of the oval heart. It was confirmed that. This signal loss is considered to indicate that myocardial metabolic dysfunction has occurred due to myocardial infarction due to coronary artery ligation, suggesting that this compound is effective for diagnosis of heart disease represented by myocardial infarction.
  • the labeled fatty acid derivative of the present invention can be used as a radiolabeled tracer for rapid and non-invasive classification of heart disease patients, diagnosis of therapeutic effects by therapeutic agents for heart disease, and the like.

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