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CN-122010810-A - The method comprises the following steps of18F-marked difluoromethyl seleno ether compound, and synthetic method and application thereof

CN122010810ACN 122010810 ACN122010810 ACN 122010810ACN-122010810-A

Abstract

The invention relates to the technical field of radioactive organic synthesis, in particular to 18 F-marked difluoromethyl seleno ether compounds, a synthesis method and application thereof. The [ 18 F ] difluoromethyl selenoethyl compound provided by the invention is based on the structure of a formula (I), and a series of novel radiolabeled compounds with potential PET imaging application value are designed and synthesized. By accurately introducing 18 F marked difluoromethyl groups on selenium atoms, the compounds utilize anti-inflammatory, anti-tumor and antioxidant biological activities of organic selenium parent structures, endow the organic selenium parent structures with in-vivo tracking capacity, can be used for early diagnosis, focus positioning and treatment effect evaluation of related diseases such as inflammatory diseases, tumors and the like, and provide candidate entities with novel structures for research and development of PET molecular probes and research of transformation medicine.

Inventors

  • FANG YI
  • LI JINGWEN
  • LIU CHUNYI
  • CHEN ZHENGPING

Assignees

  • 江苏省原子医学研究所

Dates

Publication Date
20260512
Application Date
20251222

Claims (10)

  1. 1. 18 F marked difluoromethyl seleno ether compound is characterized by having a structure shown in the following formula III: In the formula (III) of the present invention, R 1 is selected from the group consisting of substituted or unsubstituted C1-C30 alkyl, substituted or unsubstituted C3-C30 cycloalkyl, substituted or unsubstituted C2-C30 heterocycloalkyl, substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C3-C30 heteroaryl, substituted or unsubstituted C1-C30 methyl; Wherein the substituted C1-C30 alkyl, substituted C3-C30 cycloalkyl, substituted C2-C30 heterocycloalkyl, substituted C6-C30 aryl, substituted C3-C30 heteroaryl, substituted C1-C30 silicon-based substituents are selected from one or a combination of at least two of deuterium, halogen, cyano, amino, carboxyl, hydroxyl, ester, C1-C30 alkyl, C3-C30 cycloalkyl, C2-C30 heterocycloalkyl, C6-C30 aryl, C3-C30 heteroaryl, C1-C30 alkoxy, C1-C30 alkylthio, C1-C30 silicon-based.
  2. 2. The 18 F-labeled difluoromethyl selenoxide compound of claim 1, wherein R 1 is selected from the group consisting of substituted or unsubstituted C1-C25 alkyl, substituted or unsubstituted C3-C25 cycloalkyl, substituted or unsubstituted C2-C25 heterocycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted C3-C25 heteroaryl, and substituted or unsubstituted C1-C25 silyl; Wherein the substituted C1-C25 alkyl, substituted C3-C25 cycloalkyl, substituted C2-C25 heterocycloalkyl, substituted C6-C25 aryl, substituted C3-C25 heteroaryl, substituted C1-C25 silicon-based substituents are selected from one or a combination of at least two of deuterium, halogen, cyano, amino, carboxyl, hydroxyl, ester, C1-C25 alkyl, C3-C25 cycloalkyl, C2-C25 heterocycloalkyl, C6-C25 aryl, C3-C25 heteroaryl, C1-C25 alkoxy, C1-C25 alkylthio, C1-C25 silicon-based; preferably, R 1 is selected from the group consisting of substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C2-C20 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C1-C20 silyl; Wherein the substituted C1-C20 alkyl, substituted C3-C20 cycloalkyl, substituted C2-C20 heterocycloalkyl, substituted C6-C20 aryl, substituted C3-C20 heteroaryl, substituted C1-C20 silicon-based substituents are selected from one or a combination of at least two of deuterium, halogen, cyano, amino, carboxyl, hydroxyl, ester, C1-C20 alkyl, C3-C20 cycloalkyl, C2-C20 heterocycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, C1-C20 alkoxy, C1-C20 alkylthio, C1-C20 silicon-based.
  3. 3. The 18 F-labeled difluoromethyl seleno ether compound according to claim 1 or 2, having any of the following structures: 。
  4. 4. a method for synthesizing 18 F-labeled difluoromethyl seleno-ether compound as defined in any one of claims 1-3, comprising the steps of: S1, carrying out a first reaction on the [1 8 F]KF/K 2.2.2 ] compound and a compound I to obtain a 18 F marked compound I, then adding an oxidant and a catalyst, and carrying out an oxidation reaction to obtain an intermediate II; S2, the intermediate II and the compound B are subjected to a second reaction in the presence of a photocatalyst, organic alkali and blue light to obtain the 18 F marked difluoromethyl seleno ether compound; wherein, the compound I, the intermediate II and the compound B have the structures shown in the specification: 。
  5. 5. The method according to claim 4, wherein S1 comprises the steps of dissolving compound I in an organic solvent, mixing with [1 8 F]KF/K 2.2.2 ], subjecting to a first reaction to obtain 18 F-labeled compound I, adding an aqueous solution of an oxidant and a catalyst, and subjecting to an oxidation reaction and HPLC separation to obtain a stock solution of intermediate II.
  6. 6. The synthetic method according to claim 4 or 5, wherein the organic solvent is at least one selected from acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide; Preferably, the concentration of the compound I in the organic solvent is 35mmol/L-45mmol/L; Preferably, the temperature of the first reaction is 80-90 ℃, and the time of the first reaction is 3-8 min; preferably, the oxidizing agent comprises NaIO 4 ; Preferably, the catalyst comprises RuCl 3 ; Preferably, the temperature of the oxidation reaction is 20-35 ℃, and the time of the oxidation reaction is 3-8 min; preferably, the radioactive concentration of the stock solution of the intermediate II is 180MBq/mL-190MBq/mL.
  7. 7. The method of any one of claims 4-6, wherein the preparation of the [1 8 F]KF/K 2.2.2 ] complex comprises transferring the [ 18 F ] fluoride ion-containing target water to a solid phase extraction cartridge, eluting with an eluent to obtain an eluent, and drying the eluent under an inert atmosphere to obtain the [ 18 F]KF/K 2.2.2 complex.
  8. 8. The method of claim 7, wherein the eluent is obtained by mixing K 2.2.2 in acetonitrile with K 2 CO 3 in water; Preferably, the concentration of the acetonitrile solution of the K 2.2.2 is 0.02mol/L to 0.03mol/L; Preferably, the concentration of the K 2 CO 3 aqueous solution is 0.09mol/L to 0.11mol/L; Preferably, the volume ratio of the acetonitrile solution of the K 2.2.2 to the aqueous solution of the K 2 CO 3 is (3.8-4.2): 1; preferably, the drying mode is azeotropic drying, and the drying temperature is 100-110 ℃; Preferably, the inert atmosphere is selected from at least one of nitrogen, helium and argon; Preferably, the radioactivity of the [ 18 F ] fluoride ion target water is 10GBq-12GBq.
  9. 9. The synthetic method according to claim 4, wherein the photocatalyst is at least one selected from the group consisting of 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile, 2,4,5, 6-tetra (diphenylamino) -isophthalonitrile, 2,4, 6-tris (diphenylamino) -5-fluoro isophthalonitrile, 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile, acid red 87, rose bengal, rhodamine 6G, 9-mesitylene-10-methylacridine perchlorate, perylene, and N-phenylphenothiazine; and/or the organic base is at least one selected from triethylamine, N-dicyclohexylmethyl amine and N, N-diisopropylethylamine; And/or the solvent of the second reaction is at least one selected from acetonitrile, tetrahydrofuran, dichloromethane, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; And/or in S2, the molar ratio of the compound B to the organic base to the photocatalyst is 1.0 (1.0-2.0): 0.0001-0.05); And/or the temperature of the second reaction is 30-50 ℃, and the time of the second reaction is 15-30 min.
  10. 10. Use of 18 F-labeled difluoromethyl seleno-ethers according to any one of claims 1-3 or 18 F-labeled difluoromethyl seleno-ethers prepared by a synthetic method according to any one of claims 4-9 in biodistribution studies, receptor occupancy studies, in vivo PET imaging studies and drug administration studies.

Description

18 F marked difluoromethyl seleno ether compound and synthetic method and application thereof Technical Field The invention relates to the technical field of radioactive organic synthesis, in particular to 18 F-marked difluoromethyl seleno ether compounds, a synthesis method and application thereof. Background Positron Emission Tomography (PET) is a powerful and highly sensitive medical imaging technique that enables in vivo tracking of biological processes. Thus, this technique finds important application in clinical medicine (e.g., for diagnosis and staging of diseases) and drug development (which facilitates biodistribution studies, receptor occupancy studies, and drug administration studies). PET technology requires the use of molecules labeled with positron-emitting radionuclides, the most commonly used radionuclides including fluorine-18 (18 F), carbon-11 (11 C), gallium-68 (68 Ga) or zirconium-89 (89 Zr). Fluorine-18 is a widely used PET radioisotope because of its excellent decay characteristics (half-life t 1/2 =109.8 minutes, 97% β + decay, positron energy of 0.63 MeV). Fluorinated molecules have had a significant impact in the areas of pharmaceutical chemistry and drug development. Among them, difluoromethyl gene has been a very valuable substituent, its balanced lipophilicity, hydrogen bond donating ability and higher metabolic stability compared to methyl and monofluoromethyl analogues. Based on these advantages, the 18 F-difluoromethyl containing radiotracer is also of great value in PET ligand discovery. The organic selenium compound has a plurality of important biological functions of anti-inflammatory, anti-tumor, anti-oxidation and the like. Therefore, developing 18 F-labeled difluoromethyl selenoether ([ 18F]RSeCF2 H) compound and its synthesis strategy will provide technical support for the development of related PET probes. Disclosure of Invention In view of the above, the invention provides 18 F-marked difluoromethyl seleno ether compound, and a synthesis method and application thereof, which provide technical support for the development of related PET probes and fill the blank of related technologies. On the one hand, the invention provides 18 F marked difluoromethyl seleno ether compound, which has the structure shown in the following formula III: In the formula (III) of the present invention, R 1 is selected from the group consisting of substituted or unsubstituted C1-C30 alkyl, substituted or unsubstituted C3-C30 cycloalkyl, substituted or unsubstituted C2-C30 heterocycloalkyl, substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C3-C30 heteroaryl, substituted or unsubstituted C1-C30 silyl; Wherein the substituted C1-C30 alkyl, substituted C3-C30 cycloalkyl, substituted C2-C30 heterocycloalkyl, substituted C6-C30 aryl, substituted C3-C30 heteroaryl, substituted C1-C30 silicon-based substituents are selected from one or a combination of at least two of deuterium, halogen, cyano, amino, carboxyl, hydroxyl, ester, C1-C30 alkyl, C3-C30 cycloalkyl, C2-C30 heterocycloalkyl, C6-C30 aryl, C3-C30 heteroaryl, C1-C30 alkoxy, C1-C30 alkylthio, C1-C30 silicon-based. Preferably, R 1 is selected from the group consisting of substituted or unsubstituted C1-C25 alkyl, substituted or unsubstituted C3-C25 cycloalkyl, substituted or unsubstituted C2-C25 heterocycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted C3-C25 heteroaryl, and substituted or unsubstituted C1-C25 silyl; Wherein the substituted C1-C25 alkyl, substituted C3-C25 cycloalkyl, substituted C2-C25 heterocycloalkyl, substituted C6-C25 aryl, substituted C3-C25 heteroaryl, substituted C1-C25 silicon-based substituents are selected from one or a combination of at least two of deuterium, halogen, cyano, amino, carboxyl, hydroxyl, ester, C1-C25 alkyl, C3-C25 cycloalkyl, C2-C25 heterocycloalkyl, C6-C25 aryl, C3-C25 heteroaryl, C1-C25 alkoxy, C1-C25 alkylthio, C1-C25 silicon-based. Preferably, R 1 is selected from the group consisting of substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C2-C20 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C1-C20 silyl; Wherein the substituted C1-C20 alkyl, substituted C3-C20 cycloalkyl, substituted C2-C20 heterocycloalkyl, substituted C6-C20 aryl, substituted C3-C20 heteroaryl, substituted C1-C20 silicon-based substituents are selected from one or a combination of at least two of deuterium, halogen, cyano, amino, carboxyl, hydroxyl, ester, C1-C20 alkyl, C3-C20 cycloalkyl, C2-C20 heterocycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, C1-C20 alkoxy, C1-C20 alkylthio, C1-C20 silicon-based. Preferably, R 1 is selected from the group consisting of substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C2-C15 heterocycloalkyl, substituted or un