WO2020087794A1 - Dérivé d'acide 5-aminolévulinique marqué par f-18, procédé de synthèse et application - Google Patents

Dérivé d'acide 5-aminolévulinique marqué par f-18, procédé de synthèse et application Download PDF

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WO2020087794A1
WO2020087794A1 PCT/CN2019/073553 CN2019073553W WO2020087794A1 WO 2020087794 A1 WO2020087794 A1 WO 2020087794A1 CN 2019073553 W CN2019073553 W CN 2019073553W WO 2020087794 A1 WO2020087794 A1 WO 2020087794A1
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reaction
aminolevulinic acid
ala
added
labeled
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庄晓青
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • 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
    • A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
    • A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
    • 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
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the embodiments of the present application relate to the technical field of organic compound synthesis, in particular to an F-18-labeled 5-aminolevulinic acid derivative, synthesis method, and application.
  • 5-Aminolevulinic acid is an endogenous precursor substance of heme metabolism in human body, which is catalyzed by glycine and succinyl CoA in 5-ALA synthase in mitochondria Under synthesis. It has no photosensitivity in itself, but it produces protoporphyrin IX (PpIX) with near infrared fluorescence and photosensitivity after being metabolized in the body. The formation process of protoporphyrin IX in normal cells is very slow, and under the action of ferrochelatase (Ferrochelatase) and Fe 2+ ions form heme with no photoactivity.
  • ferrochelatase Ferochelatase
  • protoporphyrin IX in malignant tumor cells is high and accumulated in large amounts, and emits near infrared fluorescence (Near Infrared, NIR).
  • NIR near infrared fluorescence
  • PpIX is a very effective photosensitizer. Under the irradiation of a certain wavelength of light, it undergoes a photochemical reaction to produce singlet oxygen and oxide, causing damage to cell membranes, mitochondria and nucleic acids, thereby causing cancer cells to die and wither. Death, play a therapeutic role. Therefore, 5-ALA is widely used in the diagnosis of various malignant tumors, photodynamic therapy for tumor treatment, and photodynamic diagnosis-oriented tumor resection surgery.
  • radionuclides have very ideal physical and chemical properties, but because the 5-ALA molecule is very small, it can only be labeled with a positron nuclide that does not have a significant impact on its molecular structure.
  • Suzuki et al. First reported that the precursor activated with Schiff base was subjected to 11 C methylation reaction at the 5 position to obtain 11 C-labeled radioactive probe 11 C-MALA. Then they initially evaluated the uptake of 11 C-MALA in various tumor cells and tumor models, and concluded that the uptake of 11 C-MALA is highly correlated with the aggregation of PpIX.
  • the ratio between the uptake of tumor brain tissue and the uptake of normal brain tissue at a 10-minute peak is only about 1.3, which is largely due to the 13 N
  • the half-life is only 9.96 minutes, and the biological half-life of 5-ALA in the body is about 1 hour, so it is difficult to achieve the desired effect.
  • its radioactive half-life should be greater than the half-life of the molecule's biological metabolism in the body, so that molecules in non-target organs have sufficient time for in vivo transport, metabolism, and excretion in vitro, resulting in high targets / Background ratio.
  • the purpose of the present application is to provide an F-18-labeled 5-aminolevulinic acid derivative, a synthesis method and an application to solve the problem of short half-life of radioactive probes in the prior art.
  • an F-18-labeled 5-aminolevulinic acid derivative including 18 F-ALA, whose chemical structure is:
  • n 1-6.
  • an F-18-labeled 5-aminolevulinic acid derivative including 18 FO-ALA, whose chemical structure is:
  • n 2-4.
  • a method for synthesizing an F-18-labeled 5-aminolevulinic acid derivative including:
  • the HBA was added to the dry pyridine, p-toluenesulfonyl chloride was added in portions under ice bath, and then gradually returned to room temperature, stirred overnight, after the reaction, the solution was concentrated, and the column was separated to obtain the precursor THBA;
  • the 18 F - ions from the accelerator were captured by the QMA column, and then eluted with aminopolyether / potassium carbonate to the reaction tube.
  • the acetonitrile was added to repeatedly remove the dry solvent.
  • the precursor THBA was added to the reaction tube and dissolved in dry acetonitrile.
  • the reaction was heated under reflux. After the reaction, the HCl solution was added to heat to remove the protecting group. After dilution with water, it was preliminarily purified with a solid phase extraction column. Finally, the column was separated by high performance liquid chromatography to obtain 18 F-ALA.
  • a method for synthesizing an F-18-labeled 5-aminolevulinic acid derivative including;
  • the HEBA was added to the dry pyridine, p-toluenesulfonyl chloride was added in portions under ice bath, and then gradually returned to room temperature, stirred overnight, after the reaction, the solution was concentrated, and the column was separated to obtain the precursor TEBA;
  • the 18 F - ions from the accelerator were captured by the QMA column, and then eluted with amino polyether / potassium carbonate to the reaction tube.
  • the solvent was repeatedly removed by adding acetonitrile.
  • the precursor TEBA was added to the reaction tube and dissolved in dry acetonitrile.
  • the reaction was heated under reflux.
  • the HCl solution was added to heat to remove the protective group.
  • the solid phase extraction column was used for preliminary purification. Finally, the column was separated by high performance liquid chromatography to obtain 18 FO-ALA.
  • an F-18-labeled 5-aminolevulinic acid derivative is provided for detecting tumors.
  • an F-18-labeled 5-aminolevulinic acid derivative is provided for tumor detection.
  • the embodiments of the present application provide an F-18-labeled 5-aminolevulinic acid derivative, a synthesis method, and an application.
  • the radioactive probe provided in the implementation of this application has a long radioactive half-life, and its stability and fat solubility are obviously higher than that of 5-ALA.
  • F-18-labeled 5-aminolevulinic acid derivatives can form higher concentrations in diseased tissues, while they are lower in normal tissues and less toxic. And because of its better fat solubility and stronger ability to penetrate the blood-brain barrier, it can accurately locate tumor tissues throughout the body and become a broad-spectrum tumor imaging agent.
  • an F-18-labeled 5-aminolevulinic acid derivative including 18 F-ALA, and its chemical structure is:
  • n 1-6.
  • an F-18-labeled 5-aminolevulinic acid derivative including 18 FO-ALA, and its chemical structure is:
  • n 2-4.
  • a method for synthesizing an F-18-labeled 5-aminolevulinic acid derivative including:
  • the HBA was added to the dry pyridine, p-toluenesulfonyl chloride was added in portions under ice bath, and then gradually returned to room temperature, and stirred overnight. After the reaction, the solution was concentrated and separated by the column to obtain the precursor THBA (6- (tosyloxy) hexyl5 -((tert-butoxycarbonyl) amino) -4-oxopentanoate);
  • the 18 F - ions from the accelerator were captured by the QMA column, and then eluted with aminopolyether / potassium carbonate to the reaction tube.
  • the acetonitrile was added to repeatedly remove the dry solvent.
  • the precursor THBA was added to the reaction tube and dissolved in dry acetonitrile.
  • the reaction was heated under reflux. After the reaction, the HCl solution was added to heat to remove the protecting group. After dilution with water, it was preliminarily purified with a solid phase extraction column. Finally, the column was separated by high performance liquid chromatography to obtain 18 F-ALA.
  • the synthetic route of 18 F-ALA is as follows.
  • Boc-5-ALA, dimethylaminopyridine (DMAP), and 1,6-dihexanol are added at a molar ratio of 1: 1: 1 in an ice bath and added with the same molar amount of carbodiimide as Boc-5-ALA.
  • TsCl p-toluenesulfonyl chloride
  • the 18 F - ions from the accelerator were captured by the QMA column, then eluted with K222 / K 2 CO 3 to the reaction tube, and the solvent was removed repeatedly by adding acetonitrile. Then add 5-20 mg of HBA to the reaction tube and dissolve it in 1 mL of dry acetonitrile. Reflux and heat to react. After the reaction, 2M HCl solution was added to remove the protecting group by heating, then diluted with water, and then preliminarily purified with a solid phase extraction column. Finally, the column was separated by HPLC, and finally the radiochemical purity of 18 F-ALA-3 was obtained> 95%.
  • a method for synthesizing an F-18-labeled 5-aminolevulinic acid derivative including;
  • the HEBA was added to the dry pyridine, p-toluenesulfonyl chloride was added in portions under ice bath, and then gradually returned to room temperature, and stirred overnight, after the reaction, the solution was concentrated, and the column was separated to obtain the precursor TEBA (2- (2- (tosyloxy ) ethoxy) ethyl 5-((tert-butoxycarbonyl) amino) -4-oxopentanoate);
  • the 18 F - ions from the accelerator were captured by the QMA column, and then eluted with amino polyether / potassium carbonate to the reaction tube.
  • the solvent was repeatedly removed by adding acetonitrile.
  • the precursor TEBA was added to the reaction tube and dissolved in dry acetonitrile.
  • the reaction was heated under reflux.
  • the HCl solution was added to heat to remove the protective group.
  • the solid phase extraction column was used for preliminary purification. Finally, the column was separated by high performance liquid chromatography to obtain 18 FO-ALA.
  • HEBA p-toluenesulfonyl chloride
  • the 18 F - ions from the accelerator were captured by the QMA column, then eluted with K222 / K 2 CO 3 to the reaction tube, and the solvent was removed repeatedly by adding acetonitrile. Then add 5-20 mg of TEBA to the reaction tube and dissolve it in 1 mL of dry acetonitrile, and heat under reflux to carry out the reaction. After the reaction, 2M HCl solution was added to remove the protecting group by heating, then diluted with water, and then preliminarily purified with a solid phase extraction column. Finally, the column was separated by HPLC, and finally the radiochemical purity of 18 FO-ALA-2 was obtained> 95%.
  • the 5-aminolevulinic acid derivatives include 18 F-ALA for detecting tumors.
  • Nude mice were used to make tumor models, tumor-bearing mice were anesthetized and placed on animal PET / CT, then 0.1-0.5mCi 18 F-ALA solution was injected from the tail vein, and metabolized in the body for 0.5-2 hours for PET / CT imaging. image.
  • AsPC-1 cells were used to construct a tumor model, and 0.1-0.5mCi of 18 F-ALA-3 probe was injected from the tail vein.
  • the ⁇ count of each organ in the tumor mice was detected 10 minutes, 1 hour and 2 hours after injection. Value, that is, the amount of radiopharmaceutical 18F-ALA-3, and the ratio of tumor to muscle, the experimental results are shown in Table 1.
  • the distribution data of 18 F-ALA-3 in tumor mice indicates that 18 F-ALA-3 has a higher uptake in the tumor, and the ratio of tumor to muscle is higher, which can be used as a target for tumor Like agent.
  • the 5-aminolevulinic acid derivatives include 18 FO-ALA for detecting tumors.
  • the embodiments of the present application provide an F-18-labeled 5-aminolevulinic acid derivative, a synthesis method, and an application.
  • the radioactive probe provided in the implementation of this application has a long radioactive half-life, and its stability and fat solubility are obviously higher than that of 5-ALA.
  • F-18-labeled 5-aminolevulinic acid derivatives can form higher concentrations in diseased tissues, but lower concentrations in normal tissues and less toxicity. And because of its better fat solubility and stronger ability to penetrate the blood-brain barrier, it can accurately locate tumor tissues throughout the body and become a broad-spectrum tumor imaging agent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un dérivé d'acide 5-aminolévulinique marqué par F-18, son procédé de synthèse et son application. Une sonde radioactive fournie dans une mise en œuvre de la présente invention présente une longue demi-vie radioactive, ainsi qu'une stabilité et une solubilité dans la graisse nettement supérieures à celles de l'acide 5-aminolévulinique. Par comparaison avec l'acide 5-aminolévulinique, le dérivé d'acide 5-aminolévulinique marqué par F-18 peut former des concentrations plus élevées dans des tissus malades, tout en ayant des concentrations et une toxicité inférieures dans des tissus normaux. En outre, le dérivé ayant une meilleure solubilité dans la graisse, il présente une capacité améliorée à pénétrer la barrière hémato-encéphalique, peut localiser avec précision des tissus tumoraux dans tout le corps, et peut potentiellement constituer un agent d'imagerie de tumeur à large spectre.
PCT/CN2019/073553 2018-10-29 2019-01-29 Dérivé d'acide 5-aminolévulinique marqué par f-18, procédé de synthèse et application Ceased WO2020087794A1 (fr)

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CN201811264446.XA CN109369433B (zh) 2018-10-29 2018-10-29 一种f-18标记的5-氨基乙酰丙酸衍生物、合成方法及应用
CN201811264446.X 2018-10-29

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CN109369433B (zh) * 2018-10-29 2020-01-17 庄晓青 一种f-18标记的5-氨基乙酰丙酸衍生物、合成方法及应用
CN118084701B (zh) * 2024-02-19 2026-01-27 暨南大学附属第一医院（广州华侨医院） 酪氨酸衍生物及其制备方法、制备原料和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856566A (en) * 1997-09-02 1999-01-05 Dusa Pharmaceuticals, Inc. Sterilized 5-aminolevulinic acid
CN101723850A (zh) * 2008-10-10 2010-06-09 北京师范大学 新型18f标记芳香氨基酸及其制备方法和肿瘤显像应用
CN109369433A (zh) * 2018-10-29 2019-02-22 庄晓青 一种f-18标记的5-氨基乙酰丙酸衍生物、合成方法及应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856566A (en) * 1997-09-02 1999-01-05 Dusa Pharmaceuticals, Inc. Sterilized 5-aminolevulinic acid
CN101723850A (zh) * 2008-10-10 2010-06-09 北京师范大学 新型18f标记芳香氨基酸及其制备方法和肿瘤显像应用
CN109369433A (zh) * 2018-10-29 2019-02-22 庄晓青 一种f-18标记的5-氨基乙酰丙酸衍生物、合成方法及应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PIPPIN, ADAM B. ET AL.: "Radiochemical Synthesis and Evaluation of 13N-Labeled 5-Aminolevulinic Acid for PET Imaging of Gliomas", ACS MEDICINAL CHEMISTRY LETTERS, vol. 8, no. 12, 15 November 2017 (2017-11-15), pages 1236 - 1240, XP055699334, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.7b00311 *

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