WO2020017557A1 - 新規化合物、および、その利用 - Google Patents

新規化合物、および、その利用 Download PDF

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WO2020017557A1
WO2020017557A1 PCT/JP2019/028110 JP2019028110W WO2020017557A1 WO 2020017557 A1 WO2020017557 A1 WO 2020017557A1 JP 2019028110 W JP2019028110 W JP 2019028110W WO 2020017557 A1 WO2020017557 A1 WO 2020017557A1
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Prior art keywords
compound
solution
trpv1 receptor
hydrogen
imaging
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English (en)
French (fr)
Japanese (ja)
Inventor
久志 土居
恭良 渡辺
宇貴秀 立石
大輔 加納
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Tokyo Medical and Dental University NUC
National Cancer Center Japan
RIKEN
National Cancer Center Korea
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Tokyo Medical and Dental University NUC
National Cancer Center Japan
RIKEN
National Cancer Center Korea
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Priority to JP2020531344A priority Critical patent/JP7373151B2/ja
Publication of WO2020017557A1 publication Critical patent/WO2020017557A1/ja
Anticipated expiration legal-status Critical
Priority to JP2023177000A priority patent/JP7679000B2/ja
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings

Definitions

  • the present invention relates to a novel compound and its use.
  • molecular imaging which is a technology for examining the target molecular behavior, has attracted attention. It is considered that molecular imaging is useful for early detection of various diseases and development of a drug which is effective and has few side effects in a short period of time.
  • PET Positron emission tomography
  • PET is well known as molecular imaging for obtaining information in a living body.
  • PET is a technique for capturing a tomographic image using gamma rays emitted when a positron collides with an electron.
  • a molecule labeled with a radionuclide that emits a positron (positron) is administered into a living body, and when a positron emitted when the radionuclide decays collides with a nearby electron, it reaches 511 KeV.
  • the PET method is widely used as a molecular imaging technique for diagnosing diseases and promoting drug discovery research.
  • Palliative care is the mainstream in pain treatment sites, and there is no root cure.
  • There are subjective indicators for the evaluation of analgesic effects there are no more accurate objective indicators and surrogate markers, and the evaluation of analgesic effects is limited to qualitative methods such as interviews, visual inspection, and palpation. I have.
  • One means for objectively evaluating the analgesic effect is image diagnosis. In recent years, among image diagnostics, an attempt has been made particularly to use PET for evaluating the analgesic effect. The reason is that PET has a good resolution, a variety of drugs can be used for PET, and function diagnosis can be performed by PET. If PET can be used to evaluate the analgesic effect, it will be possible to greatly improve medical techniques related to the diagnosis and / or treatment of pain without a root treatment.
  • TRPV1 Transient Receptor Potential Vanilloid 1 receptor
  • TRPV1 receptor antagonists are expected to lead to the development of analgesics, and pharmaceutical companies are developing candidate compounds for TRPV1 receptor antagonists.
  • application of a radioisotope-labeled TRPV1 receptor antagonist as a PET probe has been proposed.
  • Non-Patent Document 1 discloses an 11 C-labeled PET probe ([ 11 C] SB-366791) of a TRPV1 receptor antagonist SB-366791. ) Is disclosed.
  • An object of one embodiment of the present invention is to provide a compound suitable for imaging a TRPV1 receptor in the brain and use of the compound.
  • the compound according to one embodiment of the present invention, or a salt thereof is characterized in that it is a compound represented by the following formula (I) or a salt thereof, in order to solve the above problem:
  • R 1 is hydrogen or any organic group;
  • R 2 if R 1 is hydrogen is the number 2 or more organic groups carbon, if R 1 is other than hydrogen and any organic radical, R 1 and / or R 2 have a radioisotope].
  • the TRPV1 receptor imaging agent according to one embodiment of the present invention is characterized by containing, as an active ingredient, the compound according to one embodiment of the present invention, or a salt thereof, in order to solve the above problems.
  • a TRPV1 receptor imaging kit which comprises a compound represented by the following formula (I) or a salt thereof: [In the formula (I), R 1 is hydrogen or any organic group; R 2, if R 1 is hydrogen is the number 2 or more organic groups carbon, if R 1 is other than hydrogen and any organic radical, R 1 and / or R 2 have a radioisotope].
  • TRPV1 receptor in the brain can be imaged.
  • FIG. 2 shows images of the brain (A) and the whole body (B) by PET measurement when the compound (15) according to one embodiment of the present invention is used.
  • FIG. 2 shows images of the brain (A) and the whole body (B) by PET measurement when the compound (16) according to one embodiment of the present invention is used.
  • FIG. 8 shows images of the brain (A) and the whole body (B) by PET measurement when the compound (17) according to one embodiment of the present invention is used.
  • FIG. 8 shows images of the brain (A) and the whole body (B) by PET measurement when the compound (18) according to one embodiment of the present invention is used.
  • FIG. 8 shows images of the brain (A) and the whole body (B) by PET measurement when the compound (19) according to one embodiment of the present invention is used.
  • 5 is a graph showing changes in SUV over time in brain PET measurement when a compound according to one embodiment of the present invention and a compound according to the related art are used.
  • 4 is a graph showing a change in SUV over time in a PET measurement of a body surface when a compound according to one embodiment of the present invention and a compound according to a conventional technique are used.
  • the compound according to the present embodiment or a salt thereof is a compound represented by the following formula (I) or a salt thereof: [In the formula (I), R 1 is hydrogen or any organic group; R 2, if R 1 is hydrogen is the number 2 or more organic groups carbon, if R 1 is other than hydrogen and any organic radical, R 1 and / or R 2 have a radioisotope].
  • the compound represented by the formula (I) or a salt thereof has a partial structure in SB-366791, which has a partial structure necessary for binding of SB-366791 to a TRPV1 receptor. Therefore, the compounds show a selective affinity for the TRPV1 receptor. Further, the compound has a radioisotope (for example, a short-lived radioisotope) at a metabolically stable site. Therefore, the compound can not only visualize the distribution of the TRPV1 receptor but also accurately quantify the TRPV1 receptor. Further, the compound has high metabolic stability in a living body. Therefore, the compounds are suitable for administration to living organisms. Further, the compound easily accumulates in the brain. Therefore, the compounds are suitable for imaging the central nervous system, including the brain.
  • a radioisotope for example, a short-lived radioisotope
  • R 1 in the formula (I) is hydrogen or any organic group
  • R 2 in the formula (I) is an organic group having 2 or more carbon atoms when R 1 is hydrogen.
  • 1 is other than hydrogen, it is any organic group.
  • a substituent consisting only of hydrogen is not included in the “organic group”.
  • the organic group for R 1 and / or R 2 is not particularly limited, and examples thereof include an aryl group, a heterocyclic group, an alkyl group, a fluoroalkyl group, an alkenyl group, a fluoroalkenyl group, an alkynyl group, and a fluoroalkynyl group. , An alkoxyl group, a fluoroalkoxyl group, an acetyl group, a carboxyalkyl group, and an alkylamide group.
  • the organic group for R 1 is preferably an alkyl group, particularly preferably those having 20 or less carbon atoms, more preferably those having 10 or less carbon atoms, and more preferably those having 5 or less carbon atoms, Those having 3 or less carbon atoms are more preferred, and a methyl group is particularly preferred.
  • R 1 is such an organic group, in the compound represented by the formula (I) and a salt thereof, the structure is stabilized and the metabolic stability in a living body is improved.
  • the organic group for R 2 is preferably an alkyl group, among which those having 20 or less carbon atoms are preferred, those having 10 or less carbon atoms are more preferred, those having 5 or less carbon atoms are more preferred, Those having 3 or less carbon atoms are more preferred.
  • the organic group for R 2 is preferably a fluoroalkyl group, and specific examples thereof include a fluoroethyl group, a fluoropropyl group, and a fluorobutyl group.
  • R 1 is hydrogen
  • R 2 may be a methyl group. If R 2 is such an organic group, the structure of the compound represented by the formula (I) and a salt thereof is stabilized, and metabolic stability in a living body is improved.
  • any atom may be a radioisotope.
  • the radioisotope is not particularly limited, but a short-lived radioisotope is preferable.
  • Examples of the short-lived radioactive isotope include a radioactive isotope of carbon and a radioactive isotope of fluorine. Among them, 11 C and 18 F are preferable.
  • As a long-lived radioisotope 14 C is preferable.
  • 11 C half-life: 20.4 minutes
  • 18 F half-life: 109.8 minutes
  • the exposure of the patient is slightly increased, but the time from the synthesis of the compound having 18 F to its use is reduced. A reasonable margin can be obtained. Since the compound according to the present embodiment cannot always be prepared for use at the place where it is used, the compound having 18 F is synthesized at a synthesis facility or the like, and then used at a place where the compound is used. It is excellent in that it can be used after being ordered.
  • the salt of the compound represented by the above formula (I) is not particularly limited, and may be any salt.
  • the salt include metal salts (sodium salt, magnesium salt, calcium salt, and potassium salt).
  • the TRPV1 receptor imaging agent according to the present embodiment contains the compound or a salt thereof according to the first embodiment of the present invention as an active ingredient.
  • the imaging agent for the TRPV1 receptor according to the present embodiment may be used for visualizing the brain (for example, visualizing a specific region of the brain) independently of the TRPV1 receptor.
  • the TRPV1 receptor imaging agent according to the present embodiment may be a brain imaging agent.
  • the imaging agent according to the present embodiment can be used for evaluating a disease state that affects the expression level of the TRPV1 receptor (in other words, has a correlation with the expression level of the TRPV1 receptor).
  • the condition include pain, cancer, osteoarthritis, postherpetic neuralgia, lung disease (for example, cough attack and bronchial asthma), inflammatory bowel disease, and irritable bowel syndrome, and the like.
  • lung disease for example, cough attack and bronchial asthma
  • inflammatory bowel disease for example, cough attack and bronchial asthma
  • irritable bowel syndrome and the like.
  • the present invention is not limited to these, and includes any painful condition.
  • the cancer includes all solid and hematological cancers. Such cancers include cancers arising in the bone, such as osteosarcoma and metastatic bone cancer, as particularly painful examples.
  • the imaging agent according to the present embodiment can quantitatively image the TRPV1 receptor. Therefore, with the imaging agent according to the present embodiment, it is possible to quantitatively diagnose the severity of the pathological condition.
  • PET is suitable as a method for evaluating the above-mentioned pathological condition, but is not limited thereto.
  • SPECT Single photon emission computed tomography
  • the compound or its salt is a 13 C-labeled compound
  • the metabolite analysis by LC-MS Liquid chromatography-mass spectrometry
  • the compound or its salt is a 14 C-labeled compound.
  • AMS Accelelerator mass spectrometry
  • the imaging agent according to the present embodiment can be used for PET imaging.
  • a small amount of the imaging agent may be administered to the subject, so that the pharmacological action (removal of pain, induction of burn sensation, etc.) due to inhibition of the TRPV1 receptor does not appear in the subject. Is safe. Further, with the imaging agent according to the present embodiment, exposure to radioisotopes can be minimized.
  • the method of administering the imaging agent is not particularly limited.
  • examples of the administration method include injection administration (for example, intravenous administration and transarterial administration), oral administration, nasal administration, oral mucosal administration, and transdermal administration.
  • the imaging agent for the TRPV1 receptor according to the present embodiment may be an injection, an oral medicine, a nasal medicine, or an external medicine.
  • the imaging agent may be prepared as a liquid formulation, either a solution or a suspension, or may be prepared as a solid formulation suitable for dissolving or suspending in a liquid (eg, a buffer). Good.
  • TRPV1 receptor is known as a target molecule such as an analgesic because it functions as a pain receptor. Therefore, the imaging agent can be used for screening a drug targeting the TRPV1 receptor.
  • the screening method for example, a method is conceivable in which the TRPV1 receptor is visualized with the imaging agent, and a drug candidate substance whose expression level of the TRPV1 receptor changes upon administration is screened as a pharmaceutical.
  • the drug candidate substance and the drug include, but are not limited to, low molecular compounds, nucleic acids, peptides, and proteins such as antibodies.
  • the screening can be performed in a test tube or in a living body.
  • the amount of the active ingredient in the imaging agent of the present embodiment is not particularly limited, and may be, for example, 0.001% by weight to 100% by weight, or 0.01% by weight to 100% by weight with respect to the imaging agent. %, 0.1% to 100% by weight, 0.1% to 95% by weight, 0.1% to 90% by weight 0.1% to 80% by weight, 0.1% to 70% by weight, 0.1% to 60% by weight, and 0.1% to 80% by weight. % To 50% by weight, 0.1% to 40% by weight, 0.1% to 30% by weight, 0.1% to 20% by weight %, Or 0.1% to 10% by weight.
  • the imaging agent of the present embodiment may contain a component (a pharmaceutically acceptable carrier) other than the active ingredient.
  • Components other than the active ingredient include excipients, lubricants, binders and disintegrants when the imaging agent of the present embodiment is provided as a solid preparation.
  • the agent When the agent is provided as a liquid formulation, it may include solvents, solubilizing agents, suspending agents, isotonic agents, buffers and soothing agents.
  • preservatives, antioxidants and stabilizers can also be mentioned as components other than the active ingredients.
  • Excipient examples include, but are not limited to, lactose, sucrose, D-mannitol, xylitol, sorbitol, erythritol, starch and crystalline cellulose.
  • lubricants include, but are not limited to, magnesium stearate, calcium stearate, wax, talc and colloidal silica.
  • binder examples include, but are not limited to, pregelatinized starch, methylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include, but are not limited to, starch, carboxymethylcellulose, low-substituted hydroxypropylcellulose, calcium carboxymethylcellulose, croscarmellose sodium and sodium carboxymethyl starch.
  • solvent examples include, but are not limited to, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and tricaprylin.
  • dissolution aid examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. It is not limited to these.
  • surfactants eg, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • hydrophilicity-enhancing agents eg, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
  • Molecules include, but are not limited to.
  • tonicity agent examples include, but are not limited to, sodium chloride, glycerin and D-mannitol.
  • buffer examples include, but are not limited to, phosphates, acetates, carbonates and citrates.
  • oothing agent examples include, but are not limited to, benzyl alcohol.
  • preservatives include, but are not limited to, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • antioxidant examples include, but are not limited to, sulfites and ascorbic acid.
  • the “stabilizer” is not particularly limited as long as it is generally used in the pharmaceutical field.
  • the amount of components other than the active ingredient in the imaging agent of the present embodiment is not particularly limited, and may be, for example, 0% by weight to 99.999% by weight, or 0% by weight to 99% by weight based on the imaging agent. 0.99% by weight, 0% to 99.9% by weight, 5% to 99.9% by weight, 10% to 99.9% by weight. 20% to 99.9% by weight, 30% to 99.9% by weight, 40% to 99.9% by weight, 50 wt% to 99.9 wt%, 60 wt% to 99.9 wt%, 70 wt% to 99.9 wt%, 80 wt% to 99 wt% 9.9% by weight, or 90% to 99.9% by weight.
  • the TRPV1 receptor imaging kit according to the present embodiment includes the compound described in [Embodiment 1] or a salt thereof.
  • the TRPV1 receptor imaging kit according to the present embodiment may be used for visualizing the brain (for example, visualizing a specific region of the brain) independently of the TRPV1 receptor.
  • the imaging kit for TRPV1 receptor according to the present embodiment may be a brain imaging kit.
  • the TRPV1 receptor imaging agent can be easily adjusted and / or the TRPV1 receptor imaging agent can be easily administered to a subject.
  • the imaging kit may have a configuration other than the compound described in the above [Embodiment 1], or a salt thereof (in other words, an active ingredient in an imaging agent for TRPV1 receptor).
  • the above-mentioned configuration includes, for example, excipients, lubricants, binders and disintegrants.
  • an imaging agent for the TRPV1 receptor as a solid preparation can be easily prepared.
  • examples of the constitution include a solvent, a solubilizing agent, a suspending agent, a tonicity agent, a buffering agent, and a soothing agent.
  • the imaging agent of the TRPV1 receptor which is a liquid preparation, can be easily prepared using the imaging kit of the present embodiment.
  • the composition may include a preservative, an antioxidant, and a stabilizer. In this case, a TRPV1 receptor imaging agent that can be stored for a long period of time can be easily prepared using the imaging kit of the present embodiment.
  • the imaging agent of the TRPV1 receptor can be easily administered to the subject using the imaging kit of the present embodiment.
  • the compound according to one embodiment of the present invention, or a salt thereof is characterized in that it is a compound represented by the following formula (I) or a salt thereof, in order to solve the above problem:
  • R 1 is hydrogen or any organic group;
  • R 2 if R 1 is hydrogen is the number 2 or more organic groups carbon, if R 1 is other than hydrogen and any organic radical, R 1 and / or R 2 have a radioisotope].
  • the TRPV1 receptor imaging agent according to one embodiment of the present invention is characterized by containing, as an active ingredient, the compound according to one embodiment of the present invention, or a salt thereof, in order to solve the above problems.
  • the TRPV1 receptor imaging agent according to one embodiment of the present invention is preferably used for PET imaging or for evaluating a disease state that affects the expression level of the TRPV1 receptor.
  • the condition may be pain, cancer, osteoarthritis, postherpetic neuralgia, lung disease, inflammatory bowel disease, or irritable bowel syndrome. preferable.
  • a TRPV1 receptor imaging kit which comprises a compound represented by the following formula (I) or a salt thereof: [In the formula (I), R 1 is hydrogen or any organic group; R 2, if R 1 is hydrogen is the number 2 or more organic groups carbon, if R 1 is other than hydrogen and any organic radical, R 1 and / or R 2 have a radioisotope].
  • the extract was washed with purified water and saturated saline, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product.
  • the crude product was recrystallized from ethyl acetate: n-hexane to obtain a compound (1) (2.8 g, 61%).
  • reaction mixture was washed with dilute hydrochloric acid (0.1 mol / L), purified water, and saturated saline, and dried using anhydrous MgSO 4 .
  • This solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: AcOEt: n-hexane) to obtain a light brown oily compound (9) (1.8 g, 80%).
  • the compound (9) obtained by this method could be used for the next step (O-alkylation reaction) without further purification.
  • the extract was washed with purified water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a paste-like crude product.
  • the crude product was subjected to silica gel column chromatography (eluent: ethyl acetate: n-hexane) to obtain Compound (12) (120 mg, 68%). At the same time, 19 mg of unreacted raw material was recovered.
  • reaction mixture was allowed to cool, poured into purified water, and extracted with ethyl acetate.
  • the extract was washed with purified water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a paste-like crude product.
  • the crude product was subjected to silica gel column chromatography (eluent; ethyl acetate: n-hexane) to obtain compound (13) (104 mg, 43%). At the same time, 59 mg of unreacted raw material was recovered.
  • 11 CH 3 I is synthesized by converting materials in the order of 11 CO 2 , 11 CH 3 OH, and 11 CH 3 I in the first reaction vessel. did. A phenol precursor (0.4 mg, 1.5 ⁇ mol), cesium carbonate (Cs 2 CO 3 ) (4.0 mg, 12.3 ⁇ mol), and DMF (300 ⁇ L) were previously placed in the second reaction vessel, and then 11 CH 3 I synthesized in the first reaction vessel was transferred by distillation into the second reaction vessel. Subsequently, the solution in the second reaction vessel was heated at 90 ° C. for 4 minutes to perform a reaction.
  • the second reaction vessel was cooled to room temperature, and the reaction product was subjected to HPLC (High performance liquid chromatography).
  • HPLC High performance liquid chromatography
  • the solution was diluted and passed through a membrane filter to collect the target compound (14) (424 MBq, 62 GBq / ⁇ mol) in a vial.
  • the second reaction vessel was cooled to room temperature and the reaction was submitted for HPLC.
  • the fractionated solution was concentrated by an evaporator, and after diluting the solution, the target compound (15) (2.04 GBq, 317 GBq / ⁇ mol) was collected in a vial through a membrane filter.
  • the second reaction vessel was cooled to room temperature and the reaction was submitted for HPLC.
  • the fractionated solution was concentrated by an evaporator, and after diluting the solution, the solution was passed through a membrane filter to collect the target compound (16) (1.18 GBq, 247 GBq / ⁇ mol) in a vial.
  • 11 CH 3 I was synthesized by converting materials in the order of 11 CO 2 , 11 CH 3 OH, and 11 CH 3 I in the first reaction vessel.
  • a phenol precursor (0.86 mg, 3.0 ⁇ mol), cesium carbonate (Cs 2 CO 3 ) (2.0 mg, 6.1 ⁇ mol), and DMF (300 ⁇ L) were previously placed in the second reaction vessel, and then The 11 CH 3 I synthesized in the first reaction vessel was transferred by distillation into the second reaction vessel. Subsequently, the solution in the second reaction vessel was heated at 90 ° C. for 4 minutes to perform a reaction. After the heating reaction, the second reaction vessel was cooled to room temperature, and the reaction product was subjected to HPLC.
  • the second reaction vessel was cooled to room temperature and the reaction was submitted for HPLC.
  • the fractionated solution was concentrated by an evaporator, and after diluting the solution, the target compound (18) (2.81 GBq, 669 GBq / ⁇ mol) was collected in a vial through a membrane filter.
  • the second reaction vessel was cooled to room temperature and the reaction was submitted for HPLC.
  • the fractionated solution was concentrated by an evaporator, and after diluting the solution, the solution was passed through a membrane filter to collect the target compound (19) (1.93 GBq, 410 GBq / ⁇ mol) in a vial.
  • PET measurement was performed using 9-week-old male SD rats.
  • the device used was (microPET F220, manufactured by Siemens).
  • any one of the test substances of the compounds (14) to (19) was injected into the tail vein by intravenous injection, and scanning was performed for 90 minutes.
  • Table 1 shows the administration conditions of each compound. Accumulation of each compound in the brain was evaluated by using a MAP (Maximum a posterior) with an integrated image of 3 to 20 minutes. The accumulation of each compound in the whole body was evaluated by MIP (Minimum intensity projection) using integrated images of 0 to 90 minutes.
  • FIGS. 1 to 6 show the control labeled compound [ 11 C] SB36691 (Compound (14)), Compound (15), Compound (16), Compound (17), Compound (18) and Compound (18) according to the prior art, respectively.
  • 19 is an image showing the result of PET measurement using (19). More specifically, (A) of each figure is an image showing the result of PET measurement in the brain, and (B) of each figure is an image showing the result of PET measurement in the whole body.
  • compounds (15) to (19) were found to accumulate on the surface of the body and accumulate in sites that are sensitive to touch, such as the neck, axilla, and thigh. Since these sites are considered to be high expression sites of the TRPV1 receptor, it is considered that they are the result of accurate imaging of the TRPV1 receptor.
  • FIG. 7 and FIG. 8 show the results of calculating SUV (Standard uptake alue) in the brain and skin for the compounds (14) to (19) and drawing time radioactivity curves.
  • the TRPV1 receptor not only can the distribution of the TRPV1 receptor be visualized, but also the TRPV1 receptor can be accurately quantified.
  • ADVANTAGE OF THE INVENTION By this invention, the imaging and quantification of TRPV1 receptor with high precision which the accumulation
  • the present invention can be used for imaging of the TRPV1 receptor.

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CN115057906A (zh) * 2022-07-28 2022-09-16 中节能万润股份有限公司 利用去氢表雄酮合成胆固醇的方法
CN115057906B (zh) * 2022-07-28 2022-12-02 中节能万润股份有限公司 利用去氢表雄酮合成胆固醇的方法

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