WO2018079882A1 - Composé pour une image en tomographie par émission de positrons de la plaque artérielle athéroscléreuse, et procédé de production de ce dernier - Google Patents

Composé pour une image en tomographie par émission de positrons de la plaque artérielle athéroscléreuse, et procédé de production de ce dernier Download PDF

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Publication number
WO2018079882A1
WO2018079882A1 PCT/KR2016/012238 KR2016012238W WO2018079882A1 WO 2018079882 A1 WO2018079882 A1 WO 2018079882A1 KR 2016012238 W KR2016012238 W KR 2016012238W WO 2018079882 A1 WO2018079882 A1 WO 2018079882A1
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WIPO (PCT)
Prior art keywords
compound
positron emission
emission tomography
arg
pro
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PCT/KR2016/012238
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English (en)
Korean (ko)
Inventor
지대윤
이병세
추소영
장기육
오주현
박효은
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서강대학교산학협력단
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Priority to PCT/KR2016/012238 priority Critical patent/WO2018079882A1/fr
Publication of WO2018079882A1 publication Critical patent/WO2018079882A1/fr

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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
    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins

Definitions

  • the present invention relates to a radioisotope-labeled compound for use in positron emission tomography (PET) for imaging atherosclerotic plaques, which is the cause of cardiovascular disease, and to a method and application thereof.
  • PET positron emission tomography
  • two to four peptides labeled by F-18 and capable of selectively targeting atherosclerotic plaques combine to provide a good positron emission monolayer for atherosclerotic plaques in arteries with fast blood flow in small amounts and in a short time.
  • the present invention relates to a compound capable of obtaining imaging images, a method of manufacturing the same, and a method of imaging atherosclerotic plaque using the same.
  • Cardiovascular diseases such as stroke and myocardial infarction are the world's No. 1 mortality rate and the second largest in Korea after cancer, mainly due to atherosclerotic plaques. Atherosclerotic plaques continue to form and develop with age, especially due to poor eating habits, overweight, and lack of exercise.
  • blood is ejected from the thinned vascular membrane and blood clots in the surrounding blood vessels. If this process is repeated, eventually the coagulated blood blocks the blood vessels and obstructs blood flow, and the coagulated blood bursts due to the elevated blood pressure, thereby causing a blood clot in the blood vessels.
  • the thrombus flows along the blood vessels and blocks the thin blood vessels.
  • the blood clots cause myocardial infarction in the coronary arteries and stroke in the brain.
  • Atherosclerotic plaques usually form in the coronary, carotid and cerebral arteries. The reason why these cardiovascular diseases are fatal is that they occur suddenly.
  • cerebrovascular diseases such as cerebral infarction and cerebral hemorrhage are characterized by no prior symptoms before onset.
  • Radiotracers targeting atherosclerotic plaques can be used as a drug for early diagnosis of cerebrovascular disease, but remain at the basic research stage using animals.
  • the present inventors have developed a compound capable of selectively binding to atherosclerotic plaques and labeled with radioactive isotopes for positron emission, thereby obtaining Positron Emission Tomography (PET) images of atherosclerotic plaques. Confirmed and completed the present invention
  • PET Positron Emission Tomography
  • Patent Document US Patent No. 8,436,140, Japanese Patent Application Publication No. 2012-82166
  • Another object of the present invention is to provide a method for preparing a compound for positron emission tomography imaging of atherosclerotic plaque.
  • Still another object of the present invention is to provide a radiopharmaceutical comprising a compound for positron emission tomography imaging of atherosclerosis as an active ingredient and a method for obtaining a positron emission tomography image for atherosclerosis using the same.
  • the present invention provides a compound for positron emission tomography imaging of atherosclerotic plaque represented by the following formula (1).
  • Peptides are peptides that specifically bind to atherosclerotic plaques
  • n 2 to 4
  • L 1, L 2 and L 3 are each independently a hydrocarbon group of C 1-50 containing at least one element selected from the group consisting of nitrogen, hydrogen, halogen and sulfur;
  • X is a radioisotope
  • n peptides may be the same or different from each other, HO 2 C-Arg-Pro-Pro-Arg-Gln-Cys-NH-, HO 2 C-Cys-Arg-Pro-Pro Cyclic both ends of -Arg-Gln-Cys-NH- or HO 2 C-Cys-Arg-Pro-Pro-Arg-Gln-Cys-NH- are bound by disulfide bonds (-SS-) It may be a peptide.
  • L 1 may be the same as or different from each other, and may include one or more triazole groups. Preferably L 1 is Can be.
  • L 2 may include one or more triazine groups, preferably L 2 Can be.
  • L 3 may comprise one or more ether groups, preferably L 3 is Can be.
  • the radioisotope X is F-18, Cu-64, Ga-68, Br-77, Zr-89, Y-90, Tc-99m, In-111, I-123, I-124, I-125, It may be selected from the group consisting of I-131 and Lu-177, most preferably using F-18.
  • Linker material (L 1 ) precursor Binding a linker material (L 1 ) precursor to a peptide that specifically binds to atherosclerotic plaque (S1);
  • L 1 , L 2 , L 3 and radioisotopes mentioned above are as defined above.
  • the step (S1) of binding the linker material (L 1 ) precursor to the peptide comprises: (1-a) Stirring the compound having an azido group dissolved in a solvent; (1-b) mixing acetic acid, trifluoroethanol, and dichloromethane with the material prepared in step (1-a), concentrating the filtrate and separating by column chromatography to obtain a compound from which resin has been removed; And (1-c) separating the peptide bound to the linker material (L 1 ) precursor from the material obtained through the step (1-b). 4-azido butanoic acid etc. can be used as a compound which has an azido group.
  • the (2-a) cyanuric chloride is dissolved in a solvent, alcohol and triethylamine are mixed and stirred, and then the solvent is removed and separated by column chromatography. And (2-b) dissolving the compound obtained through the step (2-a) in a solvent, adding triethylamine and propanediamine to react, removing the solvent, and separating by column chromatography.
  • step (S3) of preparing a compound labeled with a radioisotope by binding the radioisotope anion to a linker material (L 3 ) precursor (3-a) the aqueous solution of radioisotope anion is passed through the Cryptofix-Potassium carbonate solution. To elute the radioisotope anion, and (3-b) mixing and stirring the linker material (L 3 ) precursor to the solution prepared from (3-a).
  • the compound for positron emission tomography imaging of atherosclerotic plaques has two to four peptides capable of selectively targeting atherosclerotic plaques, thereby better binding to atherosclerotic plaques in the arteries with rapid blood flow.
  • the radioactive isotopes that emit positrons are labeled to obtain excellent positron emission tomography images of atherosclerotic plaques.
  • Figure 1 is a comparison of the conventional micro PET / CT image when applying the compound for positron emission tomography imaging according to the present invention.
  • Figure 2 is a comparison of the conventional technique with the autoradiography image in the arterial vessel 2 hours after the injection of the compound for positron emission tomography imaging according to the present invention.
  • Cyanuric chloride (2.0 g, 10.8 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 ° C., and then propazyl alcohol (0.94 mL, 16.2 mmol) and triethylamine (3.0 mL, 21.6 mmol) were added. After 5 minutes, the temperature was raised to room temperature, the mixture was stirred for 3 hours, and then dichloromethane was removed by concentration under reduced pressure, followed by column chromatography (10% ethyl acetate / hexane) to obtain target compound 2 (0.6 g, 25%). .
  • diisopropylethylamine (0.24 mL, 1.38 mmol) was added thereto, followed by stirring for 3 hours using vortex at room temperature.
  • the resin was transferred to a syringe with polyethylene frit and washed with dimethylformamide, methanol and dichloromethane to obtain resin 6.
  • Aqueous [ 18 F] fluoride anion aqueous solution (103 mCi) produced from cyclotron was captured by passing through chromafix ® , washed with ethanol (1.0 mL), and then purified by Cryptofix-Potassium (Kryptofix [2.2.2]. ] -K 2 CO 3 ) was passed through ethanol (1.0 mL) in which [ 18 F] fluoride anion was eluted into a vial vessel. The solution was stirred well at 100 ° C. and blown with nitrogen to remove the ethanol solvent.
  • Example 2 The acetonitrile solution containing Compound [ 18 F] 13 obtained in Example 1 was placed in a vial vessel containing Compound 11 (1.0 mg) and stirred at 40 ° C. for 30 minutes. Distilled water (1 mL) was added to the reaction mixture, followed by injection into a high performance liquid chromatography to separate [ 18 F] 1a. [ 18 F] 1a of distilled water (10 mL) was added to the solution, which was then passed through a C-18 SePak ® cartridge, captured, washed with distilled water (3.0 mL) and blown with nitrogen into the C-18 SePak ® cartridge. Drained off.
  • Ethanol (1.0 mL) was passed through a C-18 SePak ® cartridge to elute compound [ 18 F] 1a and blow nitrogen to remove ethanol as much as possible.
  • the final compound [ 18 F] 1a obtained was 1.45 mCi (2.6%), and diluted with an appropriate amount of saline solution for animal experiments using mice.
  • Example 3 Compound [ 18 F] 1a Atherosclerotic Plaque Micro PET / CT Imaging
  • the F-18 labeling compound [ 18 F] 1a (0.300-500 mCi) prepared in Example 2 was intravenously injected into ApoE ( ⁇ / ⁇ ) mice, and the image was then obtained through a micro PET / CT scanner for 90 minutes.
  • [ 18 F] FDG (0.500mCi) was intravenously injected into ApoE (-/-) mice and images were obtained for 90 minutes using a micro PET / CT scanner.
  • FIG. 1 is a micro PET / CT image of an ApoE ( ⁇ / ⁇ ) mouse injected with [ 18 F] FDG and [ 18 F] 1a of the present invention, respectively, with arrows showing atherosclerotic plaques.
  • [ 18 F] FDG the intake of the heart and other organs is high
  • [ 18 F] 1a of the present invention the intake of organs and tissues other than the atherosclerotic plaque is almost absent.
  • FIG. 2 is an autoradiography image obtained by injecting [ 18 F] FDG and [ 18 F] 1a of the present invention into ApoE ( ⁇ / ⁇ ) mice, respectively, and detaching the arterial tube 2 hours later. It can be seen that a lot of intake occurred in the portion of the aortic arch (aortic arch) is formed a lot.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un composé marqué avec un isotope radioactif, utilisé pour la tomographie par émission de positrons (TEP) pour l'imagerie de la plaque artérielle athéroscléreuse, qui est une cause de maladies cardiovasculaires; et un procédé de production et une application de ce dernier. Plus spécifiquement, la présente invention concerne un composé, son procédé de production, et un procédé d'imagerie de la plaque artérielle athéroscléreuse utilisant ce dernier, le composé étant marqué par un isotope radioactif et couplé avec 2 à 4 peptides susceptibles de cibler de manière sélective la plaque artérielle athéroscléreuse, ce procédé permettant d'obtenir, rapidement et avec une faible quantité du composé, une excellente image TEP d'une plaque d'athérosclérose dans une artère où le flux sanguin est rapide.
PCT/KR2016/012238 2016-10-28 2016-10-28 Composé pour une image en tomographie par émission de positrons de la plaque artérielle athéroscléreuse, et procédé de production de ce dernier WO2018079882A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2016/012238 WO2018079882A1 (fr) 2016-10-28 2016-10-28 Composé pour une image en tomographie par émission de positrons de la plaque artérielle athéroscléreuse, et procédé de production de ce dernier

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PCT/KR2016/012238 WO2018079882A1 (fr) 2016-10-28 2016-10-28 Composé pour une image en tomographie par émission de positrons de la plaque artérielle athéroscléreuse, et procédé de production de ce dernier

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022100696A1 (fr) * 2020-11-13 2022-05-19 北京大学 Lieur bioconjugué multi-spécifique et son procédé de synthèse

Citations (4)

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KR20100028167A (ko) * 2008-09-04 2010-03-12 경북대학교 산학협력단 활성화 내피세포 및 동맥경화 표적용 펩티드 및 이의 용도
KR20120136034A (ko) * 2011-06-08 2012-12-18 연세대학교 산학협력단 동시 진단 또는 치료용 융합 바이오 소재
KR20130124270A (ko) * 2013-10-25 2013-11-13 성균관대학교산학협력단 동맥경화반 특이적 엠알 조영제 및 이의 제조방법
KR20170025337A (ko) * 2015-08-28 2017-03-08 서강대학교산학협력단 죽상 동맥경화반의 양전자방출 단층촬영술 영상용 화합물 및 이의 제조방법

Patent Citations (4)

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KR20100028167A (ko) * 2008-09-04 2010-03-12 경북대학교 산학협력단 활성화 내피세포 및 동맥경화 표적용 펩티드 및 이의 용도
KR20120136034A (ko) * 2011-06-08 2012-12-18 연세대학교 산학협력단 동시 진단 또는 치료용 융합 바이오 소재
KR20130124270A (ko) * 2013-10-25 2013-11-13 성균관대학교산학협력단 동맥경화반 특이적 엠알 조영제 및 이의 제조방법
KR20170025337A (ko) * 2015-08-28 2017-03-08 서강대학교산학협력단 죽상 동맥경화반의 양전자방출 단층촬영술 영상용 화합물 및 이의 제조방법

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Title
LI, H.: "Triazine-Based Tool Box for Developing Peptidic PET Imaging Probes: Syntheses , Microfluidic Radiolabeling, and Structure-Activity Evaluation", BIOCONJUGATE CHEMISTRY, 24 March 2014 (2014-03-24), pages 761 - 772, XP055606330 *
SEO, J. W.: "64Cu-Labeled LyP-1-Dendrimer for PET-CT Imaging of Atherosclerotic Plaque", BIOCONJUGATE CHEMISTRY, 16 January 2014 (2014-01-16), pages 231 - 239, XP055306875 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022100696A1 (fr) * 2020-11-13 2022-05-19 北京大学 Lieur bioconjugué multi-spécifique et son procédé de synthèse

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