18F-labeled difluoromethyl selenide compound as well as synthesis method and application thereof

Abstract

The invention relates to the technical field of radioactive organic synthesis, in particular to an 18F-labeled difluoromethyl selenide compound as well as a synthesis method and application thereof. According to the [18F] difluoromethyl selenide compound provided by the invention, a series of novel radiolabeled compounds with potential PET imaging application value are designed and synthesized on the basis of the structure of the formula (I). According to the compounds, 18F-labeled difluoromethyl groups are accurately introduced to selenium atoms, anti-inflammatory, anti-tumor and anti-oxidation biological activities of an organic selenium parent structure are utilized, the compounds are endowed with in-vivo tracking ability, and the compounds can be used for early diagnosis, focus positioning and treatment effect evaluation of related diseases such as inflammatory diseases and tumors, and have wide application prospects. And a candidate entity with a novel structure is provided for research and development of PET molecular probes and transformation medical research.

Description

Technical Field

[0001] This invention relates to the field of radioactive organic synthesis technology, specifically to a... 18 F-labeled difluoromethyl selenide compounds, their synthesis methods, and applications. Background Technology

[0002] Positron emission tomography (PET) is a powerful and highly sensitive medical imaging technique capable of tracking biological processes in vivo. Therefore, this technology has important applications in clinical medicine (e.g., for disease diagnosis and staging) and drug development (which facilitates studies of biodistribution, receptor occupancy, and drug delivery). PET technology requires the use of molecules labeled with positron-emitting radionuclides; the most commonly used radionuclides include fluorine-18 (…). 18 F), Carbon-11 ( 11 C), Gallium-68 ( 68 Ga) or Zirconium-89 89 Zr). Fluorine-18 is valued for its excellent decay characteristics (half-life t). 1 / 2 =109.8 minutes, 97% β + Its decay (positron energy of 0.63 MeV) has made it a widely used radioactive isotope for PET.

[0003] Fluorinated molecules have had a significant impact on medicinal chemistry and drug development. Among them, difluoromethyl has become a highly valuable substituent due to its balanced lipophilicity, hydrogen bond donation capacity, and higher metabolic stability compared to methyl and monofluoromethyl analogs. Based on these advantages, fluorinated molecules... 18 Radioactive tracers of F-difluoromethyl are also of great value in the discovery of PET ligands.

[0004] Organoselenium compounds possess a variety of important biological functions, including anti-inflammatory, anti-tumor, and antioxidant effects. Therefore, the development of... 18 F-labeled difluoromethyl selenide ([ 18 The discovery of F]RSeCF2H) compounds and their synthetic strategies will provide technical support for the development of related PET probes. Summary of the Invention

[0005] In view of this, the present invention provides a 18 The discovery of F-labeled difluoromethyl selenide compounds, their synthesis methods, and applications provides technical support for the development of related PET probes and fills a technological gap.

[0006] On the one hand, the present invention provides a 18 F-labeled difluoromethyl selenide compounds have the structure shown in Formula III:

[0007] In formula (III), R 1 Selected from 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, and substituted or unsubstituted C1-C30 silyl. The substituents of the substituted C1-C30 alkyl, substituted C3-C30 cycloalkyl, substituted C2-C30 heterocycloalkyl, substituted C6-C30 aryl, substituted C3-C30 heteroaryl, and substituted C1-C30 silyl are selected from one or a combination of at least two of the following: 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, and C1-C30 silyl.

[0008] Preferably, the R 1 Selected from 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. The substituents of the substituted C1-C25 alkyl, substituted C3-C25 cycloalkyl, substituted C2-C25 heterocycloalkyl, substituted C6-C25 aryl, substituted C3-C25 heteroaryl, and substituted C1-C25 silyl are selected from one or a combination of at least two of the following: 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, and C1-C25 silyl.

[0009] Preferred, R 1 Selected from 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, and substituted or unsubstituted C1-C20 silyl. The substituents of the substituted C1-C20 alkyl, substituted C3-C20 cycloalkyl, substituted C2-C20 heterocycloalkyl, substituted C6-C20 aryl, substituted C3-C20 heteroaryl, and substituted C1-C20 silyl are selected from one or a combination of at least two of the following: 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, and C1-C20 silyl.

[0010] Preferred, R 1 Selected from substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C2-C15 heterocycloalkyl, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C3-C15 heteroaryl, and substituted or unsubstituted C1-C15 silyl. The substituents of the substituted C1-C15 alkyl, substituted C3-C15 cycloalkyl, substituted C2-C15 heterocycloalkyl, substituted C6-C15 aryl, substituted C3-C15 heteroaryl, and substituted C1-C15 silyl are selected from one or a combination of at least two of the following: deuterium, halogen, cyano, amino, carboxyl, hydroxyl, ester, C1-C15 alkyl, C3-C15 cycloalkyl, C2-C15 heterocycloalkyl, C6-C15 aryl, C3-C15 heteroaryl, C1-C15 alkoxy, C1-C15 alkylthio, and C1-C15 silyl.

[0011] Preferably, the 18 F-labeled difluoromethylselenide compounds have any of the following structures: .

[0012] Secondly, the present invention provides the first aspect described above. 18 The method for synthesizing F-labeled difluoromethyl selenide compounds includes the following steps: S1、[¹ 8 F]KF / K 2.2.2 The complex reacted with compound I in the first reaction to obtain 18 F-labeled compound I was then oxidized with an oxidant and a catalyst to obtain intermediate II. S2, intermediate II, and compound B react in the presence of a photocatalyst, an organic base, and blue light to obtain the aforementioned product via a second reaction. 18 F-labeled difluoromethyl selenide compounds; Compound I, intermediate II, and compound B have the structures shown below: .

[0013] S1 includes the following steps: dissolving compound I in an organic solvent and then reacting it with [¹] 8 F]KF / K 2.2.2 Mixed, and obtained through the first reaction 18 F-labeled compound I was then added to an aqueous solution of oxidant and catalyst, followed by oxidation and HPLC separation to obtain a stock solution of intermediate II.

[0014] Preferably, the organic solvent is selected from at least one of acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0015] Preferably, the concentration of compound I in the organic solvent is 35 mmol / L-45 mmol / L.

[0016] Preferably, the temperature of the first reaction is 80℃-90℃, and the reaction time is 3min-8min.

[0017] Preferably, the oxidant includes NaIO4.

[0018] Preferably, the catalyst comprises RuCl3.

[0019] Preferably, the oxidation reaction temperature is 20℃-35℃, and the oxidation reaction time is 3min-8min.

[0020] Preferably, the radioactivity concentration of the stock solution of intermediate II is 180 MBq / mL-190 MBq / mL.

[0021] Preferably, the [¹] 8 F]KF / K 2.2.2 The preparation of the complex includes the following steps: […] 18 F] Fluoride ion target water was transferred to a solid-phase extraction column, eluted with eluent to obtain an eluent, and then dried under an inert atmosphere to obtain [ 18 F]KF / K 2.2.2 Complex.

[0022] Preferably, the eluent is composed of K 2.2.2 It is obtained by mixing acetonitrile solution with K2CO3 aqueous solution.

[0023] Preferably, the K 2.2.2 The concentration of the acetonitrile solution is 0.02 mol / L-0.03 mol / L.

[0024] Preferably, the concentration of the K2CO3 aqueous solution is 0.09 mol / L to 0.11 mol / L.

[0025] Preferably, the K 2.2.2 The volume ratio of acetonitrile solution to K2CO3 aqueous solution is (3.8-4.2):1.

[0026] Preferably, the drying method is azeotropic drying; the drying temperature is 100℃-110℃.

[0027] Preferably, the inert atmosphere is selected from at least one of nitrogen, helium, and argon.

[0028] Preferably, the [ 18 The radioactivity intensity of the fluoride ion target water is 10 GBq-12 GBq.

[0029] Preferably, the photocatalyst is selected from 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN), 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile (4DPAIPN), 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile (3DPAFIPN), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3DPA2FBN), Acid Red 87 (Eosin Y), Rose Bengal, Rhodamine 6G, and 9-mesine-10-methylacridine perchlorate ([Mes-Acr]). + ClO 4- Any one of perylene and N-phenylphenthiazine (PTH); preferably perylene. The photocatalyst has the following structure: .

[0030] Preferably, the organic base is selected from at least one of triethylamine, N,N-dicyclohexylmethylamine, and N,N-diisopropylethylamine.

[0031] Preferably, the solvent for the second reaction is selected from at least one of acetonitrile, tetrahydrofuran, dichloromethane, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0032] Preferably, in S2, the molar ratio of compound B, organic base, and photocatalyst is 1.0:(1.0-2.0):(0.0001-0.05).

[0033] Preferably, the temperature of the second reaction is 30℃-50℃, and the reaction time is 15min-30min.

[0034] Thirdly, the present invention provides the first aspect described above. 18 The F-labeled difluoromethylselenoether compound or prepared by the synthetic method described in the second aspect. 18 Applications of F-labeled difluoromethyl selenide compounds in biodistribution studies, receptor occupancy studies, in vivo PET imaging studies, and drug delivery studies.

[0035] The technical solution of the present invention has the following advantages: 1. The present invention provides [ 18 Based on the structure of formula (I), a series of novel radiolabeled compounds with potential applications in PET imaging were designed and synthesized using [F] difluoromethyl selenide compounds. These compounds were created by precisely introducing [F] difluoromethyl selenide compounds onto selenium atoms. 18 The F-labeled difluoromethyl group utilizes the anti-inflammatory, antitumor, and antioxidant bioactivity of the organoselenium parent structure, and also endows it with in vivo tracking capabilities. It can be used for early diagnosis, lesion localization, and treatment efficacy evaluation of inflammatory diseases, tumors, and other related conditions, providing a novel candidate entity for the development of PET molecular probes and translational medicine research.

[0036] 2. The present invention provides [ 18 The synthesis method of F] difluoromethyl selenide compounds uses selenobenzenesulfonate compounds as the selenium source. These compounds are easy to prepare and store and have excellent reactivity. The method eliminates the need for unstable and highly toxic selenium-containing compounds, thus improving the safety of the chemical synthesis.

[0037] 3. The synthesis method of the present invention, on the one hand, does not require the use of precious metal photocatalysts, but only requires the use of inexpensive commercial organic non-metallic photocatalysts, thus avoiding trace metal residues in the compound and meeting the safety requirements of the drug; on the other hand, the synthesis method of the present invention has mild reaction conditions and can be carried out smoothly at room temperature without the need for high temperature conditions, which greatly reduces the difficulty of experimental operation. Attached Figure Description

[0038] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0039] Figure 1 Compound III-1 of Example 1 of this invention has not been [ 18HPLC chromatogram of the F-labeled standard; Figure 2 This is the radioactive HPLC chromatogram of compound III-1 from Example 1 of the present invention; Figure 3 Compound III-2 of Example 2 of this invention has not been [ 18 HPLC chromatogram of the F-labeled standard; Figure 4 This is the radioactive HPLC chromatogram of compound III-2 from Example 2 of the present invention; Figure 5 Example 3 of the present invention, compound III-3, without [ 18 HPLC chromatogram of the F-labeled standard; Figure 6 This is the radioactive HPLC chromatogram of compound III-3 in Example 3 of the present invention; Figure 7 Example 4 of this invention, compound III-4, was not [ 18 HPLC chromatogram of the F-labeled standard; Figure 8 Radioactive HPLC chromatogram of compound III-4 in Example 4 of this invention; Figure 9 Compound III-5 of Example 5 of this invention was not [ 18 HPLC chromatogram of the F-labeled standard; Figure 10 Radioactive HPLC chromatogram of compound III-5 in Example 5 of this invention; Figure 11 Compound III-6 of Example 6 of this invention was not [ 18 HPLC chromatogram of the F-labeled standard; Figure 12 Radioactive HPLC chromatogram of compound III-6 in Example 6 of this invention; Figure 13 Compound III-7 of Example 7 of this invention was not [ 18 HPLC chromatogram of the F-labeled standard; Figure 14 Radioactive HPLC chromatogram of compound III-7 in Example 7 of this invention; Figure 15 Compound III-8 of Example 8 of this invention was not [ 18 HPLC chromatogram of the F-labeled standard; Figure 16 Radioactive HPLC chromatogram of compound III-8 in Example 8 of this invention. Detailed Implementation

[0040] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0041] Unless otherwise specified, all experimental steps or conditions in the examples were performed according to conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0042] When it comes to material ratios, it refers to volume ratios.

[0043] No examples provided 18 The F-labeled compound standards were all prepared according to existing techniques.

[0044] Synthesis of intermediate II:

[0045] will contain [ 18 The target water containing fluoride ions (12 GBq) was transferred to an activated Sep-Pak Light QMA column, followed by 1 mL of K+. 2.2.2 A solution of (20 μmol, 7.5 mg, dissolved in 800 μL acetonitrile) / K₂CO₃ (20 μmol, 2.8 mg, dissolved in 200 μL water) will [ 18 After elution with fluoride ions, the product was azeotropically dried at 105°C under a nitrogen atmosphere to obtain [ 18 F]KF / K 2.2.2 The complex was cooled to 30°C, and then a solution of compound I (11.1 mg, 40 μmol) in acetonitrile (1 mL) was transferred to a dry […]. 18 F]KF / K 2.2.2 The reaction in the complex was completed at 85°C for 5 minutes. 18 F mark.

[0046] After cooling the reaction solution to 30°C, an aqueous solution (1 mL) containing NaIO4 (240 μmol, 51.3 mg) and RuCl3·3H2O (8 μmol, 1.7 mg) was added, and the reaction was carried out at 25°C for 5 minutes. The reaction solution was diluted with 3 mL of water and then purified by semi-preparative HPLC (mobile phase: MeCN / H2O = 55 / 45 (v / v), 5 mL / min). The solution collected from the HPLC peak corresponding to compound II (retention time 7.5–8.5 min) was passed through a SepPak C18 short column and eluted with anhydrous dichloromethane to obtain a stock solution of intermediate II (185 MBq / mL).

[0047] Example 1 Preparation of compound III-1:

[0048] In a 2 mL EP tube, compound B-1 (20 μmol), perylene (0.01 μmol, dissolved in 25 μL dichloromethane), N,N-diisopropylethylamine (DIPEA, 40 μmol), stock solution of intermediate II (3.7 MBq, 20 μL), and dichloromethane (255 μL) were added sequentially. The tube was then irradiated for 25 minutes under a 20W blue LED lamp (1-2 cm away, with a cooling fan used to maintain the reaction system at room temperature). After the reaction was complete, the dichloromethane was dried with a nitrogen stream, and then acetonitrile (500 μL) was added to redissolve the reaction mixture. The reaction was performed in triplicate. A suitable sample was taken for high-performance liquid chromatography (HPLC) analysis for product identification and radiochemical conversion (RCC) calculation. The results are shown in Table 1. The radiometric HPLC chromatogram of compound III-1 is shown in Table 1. Figure 2 As shown, without [ 18 The UV-HPLC chromatogram of the compound standard labeled with F is shown below. Figure 1 As shown.

[0049] Example 2 Preparation of compound III-2:

[0050] In a 2 mL EP tube, compound B-2 (20 μmol), perylene (0.01 μmol, dissolved in 25 μL dichloromethane), N,N-diisopropylethylamine (DIPEA, 40 μmol), stock solution of intermediate II (3.7 MBq, 20 μL), and dichloromethane (255 μL) were added sequentially. The tube was then irradiated for 25 minutes under a 20W blue LED lamp (1-2 cm away, with a cooling fan used to maintain the reaction system at room temperature). After the reaction, the dichloromethane was dried with a nitrogen stream, and then acetonitrile (500 μL) was added to redissolve the reaction mixture. The reaction was performed in triplicate. A suitable sample was taken for high-performance liquid chromatography (HPLC) analysis for product identification and radiochemical conversion (RCC) calculation. The calculation results are shown in Table 1. The radiometric HPLC chromatogram of compound III-2 is shown in Table 1. Figure 4 As shown, without [ 18 The UV-HPLC chromatogram of the compound standard labeled with F is shown below. Figure 3 As shown.

[0051] Example 3 Preparation of compound III-3:

[0052] In a 2 mL EP tube, compound B-3 (20 μmol), perylene (0.01 μmol, dissolved in 25 μL dichloromethane), N,N-diisopropylethylamine (DIPEA, 40 μmol), stock solution of intermediate II (3.7 MBq, 20 μL), and dichloromethane (255 μL) were added sequentially. The tube was then irradiated for 25 minutes under a 20W blue LED lamp (1-2 cm away, with a cooling fan used to maintain the reaction system at room temperature). After the reaction, the dichloromethane was dried with a nitrogen stream, and then acetonitrile (500 μL) was added to redissolve the reaction mixture. The reaction was performed in triplicate. A suitable sample was taken for high-performance liquid chromatography (HPLC) analysis for product identification and radiochemical conversion (RCC) calculation. The calculation results are shown in Table 1. The radiometric HPLC chromatogram of compound III-3 is shown in Table 1. Figure 6 As shown, without [ 18 The UV-HPLC chromatogram of the compound standard labeled with F is shown below. Figure 5 As shown.

[0053] Example 4 Preparation of compound III-4:

[0054] In a 2 mL EP tube, compound B-4 (20 μmol), perylene (0.01 μmol, dissolved in 25 μL dichloromethane), N,N-diisopropylethylamine (DIPEA, 40 μmol), stock solution of intermediate II (3.7 MBq, 20 μL), and dichloromethane (255 μL) were added sequentially. The tube was then irradiated for 25 minutes under a 20W blue LED lamp (1-2 cm away, with a cooling fan used to maintain the reaction system at room temperature). After the reaction was complete, the dichloromethane was dried with a nitrogen stream, and then acetonitrile (500 μL) was added to redissolve the reaction mixture. The reaction was performed in triplicate. A suitable sample was taken for high-performance liquid chromatography (HPLC) analysis for product identification and radiochemical conversion (RCC) calculation. The results are shown in Table 1. The radiometric HPLC chromatogram of compound III-4 is shown in Table 1. Figure 8 The UV-HPLC chromatogram of the unlabeled compound standard is shown below. Figure 7 As shown.

[0055] Example 5 Preparation of compound III-5:

[0056] In a 2 mL EP tube, compound B-5 (20 μmol), perylene (0.01 μmol, dissolved in 25 μL dichloromethane), N,N-diisopropylethylamine (DIPEA, 40 μmol), stock solution of intermediate II (3.7 MBq, 20 μL), and dichloromethane (255 μL) were added sequentially. The tube was then irradiated for 25 minutes under a 20W blue LED lamp (1-2 cm away, with a cooling fan used to maintain the reaction system at room temperature). After the reaction was complete, the dichloromethane was dried with a nitrogen stream, and then acetonitrile (500 μL) was added to redissolve the reaction mixture. The reaction was performed in triplicate. A suitable sample was taken for high-performance liquid chromatography (HPLC) analysis for product identification and radiochemical conversion (RCC) calculation. The calculation results are shown in Table 1. The radiometric HPLC chromatogram of compound III-5 is shown in Table 1. Figure 10 As shown, without [ 18 The UV-HPLC chromatogram of the compound standard labeled with F is shown below. Figure 9 As shown.

[0057] Example 6 Preparation of compound III-6:

[0058] In a 2 mL EP tube, compound B-6 (20 μmol), perylene (0.01 μmol, dissolved in 25 μL dichloromethane), N,N-diisopropylethylamine (DIPEA, 40 μmol), stock solution of intermediate II (3.7 MBq, 20 μL), and dichloromethane (255 μL) were added sequentially. The tube was then irradiated for 25 minutes under a 20W blue LED lamp (1-2 cm away, with a cooling fan used to maintain the reaction system at room temperature). After the reaction was complete, the dichloromethane was dried with a nitrogen stream, and then acetonitrile (500 μL) was added to redissolve the reaction mixture. The reaction was performed in triplicate. A suitable sample was taken for high-performance liquid chromatography (HPLC) analysis for product identification and radiochemical conversion (RCC) calculation. The calculation results are shown in Table 1. The radiometric HPLC chromatogram of compound III-6 is shown in Table 1. Figure 12 As shown, without [ 18 The UV-HPLC chromatogram of the compound standard labeled with F is shown below. Figure 11 As shown.

[0059] Example 7 Preparation of compound III-7:

[0060] In a 2 mL EP tube, compound B-7 (20 μmol), perylene (0.01 μmol, dissolved in 25 μL dichloromethane), N,N-diisopropylethylamine (DIPEA, 40 μmol), stock solution of intermediate II (3.7 MBq, 20 μL), and dichloromethane (255 μL) were added sequentially. The tube was then irradiated for 25 minutes under a 20W blue LED lamp (1-2 cm away, with a cooling fan used to maintain the reaction system at room temperature). After the reaction was complete, the dichloromethane was dried with a nitrogen stream, and then acetonitrile (500 μL) was added to redissolve the reaction mixture. The reaction was performed in triplicate. A suitable sample was taken for high-performance liquid chromatography (HPLC) analysis for product identification and radiochemical conversion (RCC) calculation. The calculation results are shown in Table 1. The radiometric HPLC chromatogram of compound III-7 is shown in Table 1. Figure 14 As shown, without [ 18 The UV-HPLC chromatogram of the compound standard labeled with F is shown below. Figure 13 As shown.

[0061] Example 8 Preparation of compound III-8:

[0062] In a 2 mL EP tube, compound B-8 (20 μmol), perylene (0.01 μmol, dissolved in 25 μL dichloromethane), N,N-diisopropylethylamine (DIPEA, 40 μmol), stock solution of intermediate II (3.7 MBq, 20 μL), and dichloromethane (255 μL) were added sequentially. The tube was then irradiated for 25 minutes under a 20W blue LED lamp (1-2 cm away, with a cooling fan used to maintain the reaction system at room temperature). After the reaction was complete, the dichloromethane was dried with a nitrogen stream, and then acetonitrile (500 μL) was added to redissolve the reaction mixture. The reaction was performed in triplicate. A suitable sample was taken for high-performance liquid chromatography (HPLC) analysis for product identification and radiochemical conversion (RCC) calculation. The results are shown in Table 1. The radiometric HPLC chromatogram of compound III-8 is shown in Table 1. Figure 16 As shown, without [ 18 The UV-HPLC chromatogram of the compound standard labeled with F is shown below. Figure 15 As shown.

[0063] Table 1

[0064] As shown in Table 1, this synthetic method has excellent substrate universality, is compatible with functional groups and structures such as cyano, hydroxyl, and heteroaromatic rings, and has excellent radiochemical conversion efficiency, making it promising for subsequent labeling and modification of complex drug active molecules.

[0065] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A kind 18 F-labeled difluoromethyl selenide compounds, characterized in that, It has the structure shown in Equation III: In formula (III), R 1 Selected from 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, and substituted or unsubstituted C1-C30 methyl. The substituents of the substituted C1-C30 alkyl, substituted C3-C30 cycloalkyl, substituted C2-C30 heterocycloalkyl, substituted C6-C30 aryl, substituted C3-C30 heteroaryl, and substituted C1-C30 silyl are selected from one or a combination of at least two of the following: 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, and C1-C30 silyl.

2. As described in claim 1 18 F-labeled difluoromethyl selenide compounds, characterized in that, The R 1 Selected from 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. The substituents of the substituted C1-C25 alkyl, substituted C3-C25 cycloalkyl, substituted C2-C25 heterocycloalkyl, substituted C6-C25 aryl, substituted C3-C25 heteroaryl, and substituted C1-C25 silyl are selected from one or a combination of at least two of the following: 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, and C1-C25 silyl. Preferred, R 1 Selected from 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, and substituted or unsubstituted C1-C20 silyl. The substituents of the substituted C1-C20 alkyl, substituted C3-C20 cycloalkyl, substituted C2-C20 heterocycloalkyl, substituted C6-C20 aryl, substituted C3-C20 heteroaryl, and substituted C1-C20 silyl are selected from one or a combination of at least two of the following: 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, and C1-C20 silyl.

3. As described in claim 1 or 2 18 F-labeled difluoromethyl selenide compounds, characterized in that, It has any of the following structures: 。 4. The claim 1-3 18 A method for synthesizing F-labeled difluoromethyl selenide compounds, characterized in that, Includes the following steps: S1、[¹ 8 F]KF / K 2.2.2 The complex reacted with compound I in the first reaction to obtain 18 F-labeled compound I was then oxidized with an oxidant and a catalyst to obtain intermediate II. S2, intermediate II, and compound B react in the presence of a photocatalyst, an organic base, and blue light to obtain the aforementioned product via a second reaction. 18 F-labeled difluoromethyl selenide compounds; Compound I, intermediate II, and compound B have the structures shown below: 。 5. The synthesis method according to claim 4, characterized in that, S1 includes the following steps: After dissolving compound I in an organic solvent, it is combined with [¹] 8 F]KF / K 2.2.2 Mixed, and obtained through the first reaction 18 F-labeled compound I was then added to an aqueous solution of oxidant and catalyst, followed by oxidation and HPLC separation to obtain a stock solution of intermediate II.

6. The synthesis method according to claim 4 or 5, characterized in that, The organic solvent is selected from at least one of acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; Preferably, the concentration of compound I in the organic solvent is 35 mmol / L-45 mmol / L; Preferably, the temperature of the first reaction is 80℃-90℃, and the reaction time is 3min-8min; Preferably, the oxidant includes NaIO4; Preferably, the catalyst comprises RuCl3; Preferably, the oxidation reaction temperature is 20℃-35℃, and the oxidation reaction time is 3min-8min; Preferably, the radioactivity concentration of the stock solution of intermediate II is 180 MBq / mL-190 MBq / mL.

7. The synthesis method according to any one of claims 4-6, characterized in that, The [¹ 8 F]KF / K 2.2.2 The preparation of the complex includes the following steps: […] 18 F] Fluoride ion target water was transferred to a solid-phase extraction column, eluted with eluent to obtain an eluent, and then dried under an inert atmosphere to obtain [ 18 F]KF / K 2.2.2 Complex.

8. The synthesis method according to claim 7, characterized in that, The eluent is composed of K 2.2.2 It is obtained by mixing acetonitrile solution with K2CO3 aqueous solution; Preferably, the K 2.2.2 The concentration of the acetonitrile solution is 0.02 mol / L - 0.03 mol / L; Preferably, the concentration of the K2CO3 aqueous solution is 0.09 mol / L-0.11 mol / L; Preferably, the K 2.2.2 The volume ratio of acetonitrile solution to K2CO3 aqueous solution is (3.8-4.2):1; Preferably, the drying method is azeotropic drying; the drying temperature is 100℃-110℃; Preferably, the inert atmosphere is selected from at least one of nitrogen, helium, and argon; Preferably, the [ 18 The radioactivity intensity of the fluoride ion target water is 10 GBq-12 GBq.

9. The synthesis method according to claim 4, characterized in that, The photocatalyst is selected from at least one of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile, 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile, 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile, Acid Red 87, Bengal Rose Red, Rhodamine 6G, 9-trimethylmethyl-10-methylacridinium perchlorate, perylene, and N-phenylphenthiazide; And / or, the organic base is selected from at least one of triethylamine, N,N-dicyclohexylmethylamine, and N,N-diisopropylethylamine; And / or, the solvent for the second reaction is selected from at least one of acetonitrile, tetrahydrofuran, dichloromethane, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; And / or, in S2, the molar ratio of compound B, organic base, and 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 15min-30min.

10. The claim 1-3 18 F-labeled difluoromethylselenoether compounds or prepared by the synthetic method according to any one of claims 4-9 18 Applications of F-labeled difluoromethyl selenide compounds in biodistribution studies, receptor occupancy studies, in vivo PET imaging studies, and drug delivery studies.

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