A method for synthesizing aryl F-18 labeled sulfonyl chlorides and its application in labeling amine compounds
Aryl F-18 labeled sulfonyl chlorides were prepared by photocatalytic fluorination and oxidative chlorination reactions, which solved the problem of insufficient synthesis methods in the existing technology. This method achieved efficient preparation of aryl F-18 labeled sulfonyl chlorides and high conversion rate labeling of amine compounds, and is suitable for the development of various PET probes.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SICHUAN UNIV
- Filing Date
- 2026-04-17
- Publication Date
- 2026-08-04
AI Technical Summary
The lack of efficient methods for synthesizing aryl F-18 labeled sulfonyl chlorides in the existing technology limits their application in PET probe preparation and development.
Using thiophenol derivatives as labeling precursors, aryl F-18 labeled sulfonyl chlorides were prepared via photocatalytic fluorination and oxidative chlorination. These chlorides served as highly active intermediates for sulfonation reactions with amine compounds under mild conditions.
The efficient synthesis of aryl F-18 labeled sulfonyl chlorides was achieved with a radiochemical conversion rate of 92-95% and a conversion rate of up to 98% with sulfonation reactions with amine compounds. In particular, the labeling rate in the synthesis of AMPA receptor PET imaging agent [18F]2 was much higher than that of existing methods, and the conditions were milder.
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Figure CN122036563B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedical technology, specifically relating to a method for synthesizing aryl F-18 labeled sulfonyl chloride and its application in labeling amine compounds. Background Technology
[0002] Developing innovative and efficient F-18 labeling methods to label a broader range of bioactive molecules is crucial for advancing PET tracer development, the widespread clinical application of PET imaging, and precision disease diagnosis and treatment. Because aromatic carbon-fluorine bonds offer greater stability and are less prone to in vivo defluorination, and because many bioactive molecules and drugs contain aromatic structures, developing efficient labeling methods to achieve aryl F-18 labeling of bioactive molecules is particularly important.
[0003] Compared to direct aryl F-18 labeling, indirect labeling conditions are generally milder, enabling the labeling of many bioactive molecules that cannot be directly radiolabeled, especially compounds containing sensitive functional groups or complex structures. Furthermore, indirect labeling supports multi-step synthesis, offering greater flexibility in designing tracer synthetic routes. Therefore, indirect F-18 labeling plays an irreplaceable role in the development and clinical production of PET tracers due to its mild reaction conditions, high yield, and synthetic flexibility. The key to the success of indirect aryl F-18 labeling lies in the construction of the F-18-labeled reactive intermediate. Currently, important intermediates containing multiple functional groups, such as F-18-labeled benzaldehyde, benzoic acid, aniline, aryl halogens, and azide compounds, have been developed for the indirect labeling of probes. Sulfonyl chlorides exhibit high reactivity, rapidly undergoing sulfonation reactions with amino groups in bioactive molecules to generate a benzenesulfonamide skeleton, thereby achieving efficient labeling of amine compounds. However, due to the high reactivity of sulfonyl chlorides themselves, they are prone to hydrolysis under the commonly used heating alkaline labeling conditions.
[0004] Therefore, despite its great application potential, there are no reports on efficient synthetic methods for aryl F-18 labeled sulfonyl chlorides and their application in the preparation and development of PET probes. Summary of the Invention
[0005] The purpose of this invention is to provide a method for synthesizing aryl F-18-labeled sulfonyl chlorides and their application in amine labeling. Addressing the lack of efficient methods for synthesizing aryl F-18-labeled sulfonyl chlorides in existing technologies, this invention proposes a synthetic route using thiophenol derivatives as labeling precursors. This route involves obtaining an F-18-labeled thiophenol intermediate through photocatalytic fluorination of aryl F-18, followed by oxidative chlorination to obtain the aryl F-18-labeled sulfonyl chloride. The obtained aryl F-18-labeled sulfonyl chloride, as a highly reactive intermediate, can undergo sulfonation reactions with various amine compounds under mild conditions, enabling the efficient preparation of PET probes.
[0006] To achieve the above-mentioned objectives, the specific technical solution is as follows: A method for synthesizing aryl F-18 labeled sulfonyl chloride, the method comprising the following steps: Step a) Using a thiophenol derivative as a labeling precursor, an aryl F-18 labeled thiophenol derivative intermediate is obtained through an aryl F-18 fluorination reaction.
[0007] Step b) involves subjecting the aryl F-18 labeled thiophenol derivative intermediate to an oxidative chlorination reaction to obtain aryl F-18 labeled sulfonyl chloride.
[0008] The general formula of the labeled precursor of the thiophenol derivative is represented as follows: ;in, and Each is independently a phenylene; Selected from or ; Selected from , alkyl, Alkyl or aryl; Y is selected from C (=O) or is not present; when Y is C (=O), Selected from alkyl, cycloalkyl, aryl or Alkyl group; when Y is absent, Selected from aryl compounds.
[0009] The general formula of the aryl F-18 labeled thiophenol derivative intermediate is represented as follows: ;in, The aryl F-18 labeled sulfonyl chloride is 4-[ 18 F]Fluorobenzenesulfonyl chloride.
[0010] Furthermore, the aryl F-18 fluorination reaction is a photocatalytic aryl F-18 fluorination reaction, which occurs under photocatalyst and light irradiation conditions. 18 F Fluoride ions are used as the fluorine source, and the solvent used is selected from dichloromethane or 1,2-dichloroethane.
[0011] Furthermore, the photocatalyst is an acridine salt photocatalyst, including 9-mesinetrimethyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate.
[0012] Furthermore, the illumination conditions are as follows: illumination with an LED light source with a wavelength of 400–500 nm for 5–30 minutes; the preferred conditions are illumination with an LED light source with a wavelength of 456 nm for 15 minutes.
[0013] Furthermore, the oxidative chlorination reaction is carried out in an organic solvent under acidic conditions using N-chlorosuccinimide as the oxidative chlorination reagent; the acidic conditions are provided by hydrochloric acid, and the organic solvent is acetonitrile; the reaction temperature is room temperature, and the reaction time is 5–20 minutes, preferably 10 minutes.
[0014] Furthermore, when the labeled precursor of the thiophenol derivative has a general formula in which Y is C (=O), the labeled precursor of the thiophenol derivative is selected from one or more of the following compounds: 4,4'-bis(acetylthio)diphenyl ether, wherein 4,4'-Bis(cyclohexaneformylthio)diphenyl ether, wherein is methyl, X is O, R is H; It is cyclohexyl, X is O, R is H; 4,4'-bis(neovalerylthio)diphenyl ether, wherein It is tert-butyl, X is O, R is H; 4,4'-bis(benzoylthio)diphenyl ether, wherein It is a phenyl group, where X is O and R is H; 4,4'-bis(tert-butoxycarbonylthio)diphenyl ether, wherein It is a tert-butoxy group, where X is O and R is H.
[0015] Furthermore, when the general formula of the thiophenol derivative's labeled precursor does not contain Y, the thiophenol derivative's labeled precursor is selected from one or more of the following compounds: 4,4'-bis(phenylthio)diphenyl ether, wherein... 4,4'-bis(phenylthio)diphenyl sulfide, wherein X is O, R is H; X is phenyl, R is H; 4,4'-bis(4-methylphenylthio)diphenyl ether, wherein It is 4-methylphenyl, where X is O and R is H; 4,4'-bis(2-methylphenylthio)diphenyl ether, wherein It is 2-methylphenyl, where X is O and R is H; 4,4'-bis(4-methoxyphenylthio)diphenyl ether, wherein It is 4-methoxyphenyl, X is O, and R is H.
[0016] The present invention also provides the application of aryl F-18 labeled sulfonyl chloride in the labeling of amine compounds, wherein the aryl F-18 labeled sulfonyl chloride is prepared according to the method of the present invention and is used to prepare F-18 labeled PET probes.
[0017] The aryl F-18 labeled sulfonyl chloride is subjected to a sulfonylation reaction with an amine compound to obtain a radioactive tracer containing an aryl F-18 labeled sulfonamide group.
[0018] The amine compounds are selected from one or more of the following types: aliphatic primary amines, aliphatic secondary amines, aromatic primary amines, aromatic secondary amines, ammonia, hydroxylamine, amine-containing bioactive molecules or amine-containing drug molecules; wherein, the amine-containing bioactive molecules include drug molecules containing primary or secondary amino groups, polypeptides, amino acid derivatives or receptor ligands.
[0019] The amine compound is an AMPA receptor ligand, and the resulting F-18-labeled PET probe is an AMPA receptor PET imaging agent. 18 F]2, used for PET imaging of AMPA receptors.
[0020] The synthesis mechanism of this invention is as follows: (1) Mechanism of Aryl F-18 Fluorination: This invention employs a photocatalytic aryl F-18 fluorination strategy. Under illumination, acridine salt photocatalysts (such as 9-mesinetrimethyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate) are excited to an excited state, generating a strongly oxidizing free radical cation. This free radical cation can abstract electrons from the thiophenol derivative precursor, forming an aryl free radical cation intermediate. Subsequently, the nucleophilic F-18 fluoride ion attacks this intermediate, introducing the F-18 atom into the aromatic ring through a nucleophilic aromatic substitution mechanism, while releasing a thioether leaving group. Since the thiophenol derivative precursor has a symmetrical structure containing two equivalent thioether groups as leaving groups, this design improves the selectivity and efficiency of F-18 labeling. This photocatalytic process is carried out at or near room temperature, avoiding the destruction of sensitive functional groups by traditional high-temperature labeling methods.
[0021] (2) Oxidative chlorination reaction mechanism: Under acidic conditions, the F-18-labeled thiophenol derivative intermediate is converted into sulfonyl chloride by the oxidative chlorination of N-chlorosuccinimide (NCS). In this reaction, NCS acts as both a chlorine source and an oxidant, first oxidizing the sulfur atom and simultaneously introducing a chlorine atom. In the acidic environment provided by hydrochloric acid, the sulfur atom undergoes a continuous oxidation process, from thioether (S) to sulfinic acid (SO) and then to a sulfonyl group (SO2), ultimately forming sulfonyl chloride (SO2Cl). This reaction proceeds rapidly at room temperature, completing in only 5-20 minutes, thus avoiding the hydrolytic decomposition of sulfonyl chloride under high-temperature conditions.
[0022] (3) Sulfonation reaction mechanism: The reaction of aryl F-18 labeled sulfonyl chlorides with amines follows a nucleophilic acyl substitution mechanism. The sulfur atom in the sulfonyl chloride has strong electrophilicity due to its connection with two strongly electron-withdrawing oxygen atoms and one chlorine atom. The nitrogen atom in the amine acts as a nucleophile, attacking the sulfur atom of the sulfonyl chloride to form a tetrahedral intermediate. Subsequently, the chloride ion leaves as a leaving group, and a proton is transferred, ultimately forming a stable sulfonamide product. This reaction can proceed efficiently at room temperature, with a conversion rate as high as 98%, indicating that aryl F-18 labeled sulfonyl chlorides have extremely high reactivity and can react with a variety of substrates, including aliphatic primary amines, aliphatic secondary amines, aromatic primary amines, aromatic secondary amines, ammonia, hydroxylamine, and bioactive molecules containing amine groups.
[0023] Compared with the prior art, the beneficial effects of this invention are: This invention represents the first efficient synthesis of aryl F-18-labeled sulfonyl chlorides, filling a gap in this field. Using a thiophenol derivative as a labeling precursor, a two-step method involving photocatalytic aryl F-18 fluorination and oxidative chlorination was successfully employed to prepare 4-[ 18 F]Fluorobenzenesulfonyl chloride has a radiochemical conversion rate of 92-95%.
[0024] The aryl F-18 labeled sulfonyl chloride prepared in this invention, as an active intermediate, exhibits a radiochemical conversion rate of up to 98% in its sulfonation reaction with amine compounds, significantly superior to existing labeled methods. Particularly in the synthesis of the AMPA receptor PET imaging agent [18F]2, the labeling rate of the method in this invention (96%) is far higher than the heating method reported in the literature (13%, 180°C), and the reaction conditions are milder.
[0025] The substrates of this invention have a wide range of applications. The prepared aryl F-18 labeled sulfonyl chloride can react with a variety of amine compounds, including aliphatic primary amines, aliphatic secondary amines, aromatic primary amines, aromatic secondary amines, ammonia, hydroxylamine, and bioactive molecules containing amine groups, providing a universal labeling platform for the development of various PET probes. Attached Figure Description
[0026] Figure 1 This is a flowchart of the synthesis method of aryl F-18 labeled sulfonyl chloride according to the present invention; Figure 2 This invention provides a probe for synthesizing AMPA using F-18-labeled sulfonyl chloride. 18 The route of F]2. Detailed Implementation
[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention are described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of this invention, not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.
[0028] Example 1 like Figure 1 The diagram shown is a flowchart of the synthesis method of aryl F-18 labeled sulfonyl chloride according to the present invention, which includes the following steps: Step a) Using a thiophenol derivative as a labeling precursor, an aryl F-18 labeled thiophenol derivative intermediate is obtained through an aryl F-18 fluorination reaction.
[0029] Step b) involves subjecting the aryl F-18 labeled thiophenol derivative intermediate to an oxidative chlorination reaction to obtain aryl F-18 labeled sulfonyl chloride.
[0030] The general formula of the labeled precursor of the thiophenol derivative is represented as follows: ;in, and Each is independently a phenylene; Selected from or ; Selected from , alkyl, Alkyl or aryl; Y is selected from C (=O) or is not present; when Y is C (=O), Selected from alkyl, cycloalkyl, aryl or Alkyl group; when Y is absent, Selected from aryl; The general formula of the aryl F-18 labeled thiophenol derivative intermediate is represented as follows: ;in, The aryl F-18 labeled sulfonyl chloride is 4-[ 18 F]Fluorobenzenesulfonyl chloride.
[0031] The aryl F-18 fluorination reaction is a photocatalytic aryl F-18 fluorination reaction, which occurs under photocatalyst and light irradiation conditions. 18 The process uses F-fluoride ions as the fluorine source, and the solvent used is selected from dichloromethane or 1,2-dichloroethane.
[0032] The photocatalyst is an acridine salt photocatalyst, including 9-mesinetrimethyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate.
[0033] The illumination conditions are as follows: LED light source with a wavelength of 400–500 nm is used for illumination, and the illumination time is 5–30 minutes.
[0034] The oxidative chlorination reaction is carried out in an organic solvent under acidic conditions using N-chlorosuccinimide as the oxidative chlorination reagent; the acid is hydrochloric acid and the organic solvent is acetonitrile; the reaction temperature is room temperature and the reaction time is 5–20 minutes.
[0035] When the labeled precursor of a thiophenol derivative has a general formula in which Y is C (=O), the labeled precursor of the thiophenol derivative is selected from one or more of the following compounds: 4,4'-bis(acetylthio)diphenyl ether, wherein 4,4'-Bis(cyclohexaneformylthio)diphenyl ether, wherein is methyl, X is O, R is H; It is cyclohexyl, X is O, R is H; 4,4'-bis(neovalerylthio)diphenyl ether, wherein It is tert-butyl, X is O, R is H; 4,4'-bis(benzoylthio)diphenyl ether, wherein It is a phenyl group, where X is O and R is H; 4,4'-bis(tert-butoxycarbonylthio)diphenyl ether, wherein It is a tert-butoxy group, where X is O and R is H.
[0036] When the general formula Y is absent in the labeled precursor of the thiophenol derivative, the labeled precursor of the thiophenol derivative is selected from one or more of the following compounds: 4,4'-bis(phenylthio)diphenyl ether, wherein 4,4'-bis(phenylthio)diphenyl sulfide, wherein X is O, R is H; X is phenyl, R is H; 4,4'-bis(4-methylphenylthio)diphenyl ether, wherein It is 4-methylphenyl, where X is O and R is H; 4,4'-bis(2-methylphenylthio)diphenyl ether, wherein It is 2-methylphenyl, where X is O and R is H; 4,4'-bis(4-methoxyphenylthio)diphenyl ether, wherein It is 4-methoxyphenyl, X is O, and R is H.
[0037] The following provides detailed experimental methods for the synthesis of labeled precursor thiophenol derivatives, the synthesis of thiophenol derivatives labeled with aryl F-18, and the synthesis of aryl F-18 labeled sulfonyl chlorides.
[0038] Synthesis of the labeled precursor S1 (4,4'-bis(acetylthio)diphenyl ether): Under nitrogen protection, 4,4'-dimercaptodiphenyl ether (100 mg, 0.43 mmol, 1.0 eq) and pyridine (69 μL, 0.86 mmol, 2.0 eq) were dissolved in anhydrous tetrahydrofuran (5 mL). After stirring in an ice bath for 20 min, acetyl chloride (85 mg, 1.08 mmol, 2.5 eq) was added dropwise, and the mixture was then stirred at room temperature for 1.5 h. After the reaction was monitored by TLC to be complete, the reaction was quenched with cold water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (100% DCM) to give 120 mg of white solid, with a yield of 88.3%.
[0039] The chemical reaction formula for the labeled precursor S1 is: .
[0040] The labeled precursors S2-S4 and S6-S10 were synthesized using the same steps as S1, employing the corresponding acyl chlorides or thiophenols: S2 yield 18.1%, S3 yield 17.5%, S4 yield 18.6%, S6 yield 84.5%, S7 yield 15.4%, S8 yield 41.0%, S9 yield 47.4%, and S10 yield 27.5%. The labeled precursor S5 was synthesized using Boc anhydride and DMAP, with a yield of 27.7%.
[0041] The synthesis of the labeled precursor S5 was carried out under nitrogen protection. 4,4'-dimercaptodiphenyl ether (300.0 mg, 1.28 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by the sequential addition of Boc anhydride (1.12 g, 5.12 mmol, 4.0 eq) and 4-dimethylaminopyridine (DMAP) (782.0 mg, 6.40 mmol, 5.0 eq). The mixture was stirred at room temperature for 6 hours. After the reaction was confirmed to be complete by TLC (PE:EA = 10:1), the reaction was quenched with cold water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 8:1) to give 154 mg of a colorless oil, with a yield of 27.7%.
[0042] The labeled precursor S11 was prepared under nitrogen protection by dissolving 4,4'-dimercaptodiphenyl ether (150 mg, 0.64 mmol, 1.0 eq) in anhydrous tetrahydrofuran (5 mL). After cooling the reaction solution to 0 °C, sodium hydride (129 mg, 3.20 mmol, 5.0 eq) dispersed in 60% mineral oil was added in portions. The mixture was stirred in an ice bath for 30 min, followed by dropwise addition of dimethylcarbamoyl chloride (177 μL, 1.92 mmol, 3.0 eq), and then stirred at room temperature for 3 h. After the reaction was monitored by TLC until complete, the reaction was carefully quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was then purified by silica gel column chromatography (DCM:MeOH = 30:1) to give 175.0 mg of a white solid, in a yield of 72.6%. S12 was synthesized with reference to S11, with a difference rate of 66%.
[0043] The reaction formula for labeling the precursor S2-S12 is as follows:
[0044]
[0045]
[0046]
[0047]
[0048]
[0049]
[0050]
[0051]
[0052]
[0053]
[0054] The synthesis of aryl F-18 labeled thiophenol derivatives involves placing 0.01 mmol of the labeled precursor compound, 2 mg of the catalyst 9-mesethyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate, in a V-type reaction flask, adding 0.5 mL of dichloromethane or 1,2-dichloroethane, and then adding a pretreated 18F-fluoride ion solution.
[0055]
[0056] The F-18-labeled product was obtained by irradiation under a 456 nm LED lamp for 15 minutes. The radiochemical conversion rates (RCC) of different labeled precursors were as follows: S1 59.2% in DCM, S2 6.5% in DCM, S3 60.5% in DCE, S4 30.7% in DCE, S5 49.9% / 52.3% in DCM / DCE, S6 74.3% / 65.6% in DCM / DCE, S7 24.1% in DCM, S8 71.5% / 56.4% in DCM / DCE, S9 25.5% / 9.7% in DCM / DCE, S10 18.5% in DCE, S11 16.8% in DCM, and S12 16.3% in DCM. The radiochemical conversion rates of aryl F-18 labeling of different labeled precursors are shown in Table 1. Table 1 Radiochemical conversion rates of aryl F-18 labeled precursors (S1-S10)
[0057] Aryl F-18 labeled sulfonyl chloride (4-[ 18 Synthesis of [F]fluorobenzenesulfonyl chloride:
[0058] The F-18-labeled intermediate was dissolved in 0.5 mL of acetonitrile solution, followed by the addition of 100 μL of 2N hydrochloric acid solution and 5 mg of N-chlorosuccinimide (NCS). The mixture was stirred at room temperature for 10 minutes. After the reaction was complete, 10 mL of water was added, and the mixture was enriched using a C18 column. Finally, elution with 500 μL yielded a solution of aryl F-18-labeled benzenesulfonyl chloride.
[0059] from 18 F-1 preparation of 4-[ 18 The radiochemical conversion rate of F]fluorobenzenesulfonyl chloride is 92%, from 18 The radiochemical conversion rate of F-2 was 95%.
[0060] Example 2 An application of aryl F-18 labeled sulfonyl chloride in the labeling of amine compounds, used to prepare F-18 labeled PET probes, characterized in that the aryl F-18 labeled sulfonyl chloride is subjected to a sulfonation reaction with an amine compound to obtain a radioactive tracer containing aryl F-18 labeled sulfonamide groups.
[0061]
[0062] The amine compounds are selected from one or more of the following types: aliphatic primary amines, aliphatic secondary amines, aromatic primary amines, aromatic secondary amines, ammonia, hydroxylamine, amine-containing bioactive molecules or amine-containing drug molecules; wherein, the amine-containing bioactive molecules include drug molecules containing primary or secondary amino groups, polypeptides, amino acid derivatives or receptor ligands.
[0063] The amine compound is an AMPA receptor ligand, and the resulting F-18-labeled PET probe is an AMPA receptor PET imaging agent. 18 F]2, used for PET imaging of AMPA receptors.
[0064] A 50 μL solution of acetonitrile containing aryl F-18 labeled sulfonyl chloride was mixed with 0.01 mmol of an amine compound and reacted at room temperature for 10 minutes. The reaction was then detected by radio-HPLC. The radiochemical conversion rates of the sulfonation reactions of various amine compounds were as follows: ammonia 90%, hydroxylamine 65%, benzylamine 96%, n-butylamine 95%, tert-butylamine 82%, cyclohexylamine 90%, piperidine 97%, morpholine 87%, diethylamine 83%, 4-methoxybenzylamine 82%, phenethylamine 86%, n-hexylamine 98%, 4-fluoroaniline 76%, aniline 95%, p-toluidine 95%, 4-trifluoromethylaniline 98%, 3,5-dimethylaniline 85%, AMPA acceptor ligand 96%, 4-chloroaniline 67%, 4-methoxyaniline 90%, 3-methylaniline 96%, 2-methylaniline 97%, and 4-iodoaniline 91%. Table 2 shows the statistical results of the radiochemical conversion rates of different amine compounds.
[0065] Table 2. Statistical table of radiochemical conversion rates of different amine compounds.
[0066]
[0067] Experimental results show that the aryl F-18 labeled sulfonyl chloride prepared in this invention can react efficiently with a variety of amine compounds, such as aliphatic primary amines, aliphatic secondary amines, aromatic primary amines, aromatic secondary amines, ammonia, hydroxylamine, and bioactive molecules containing amine groups, at room temperature, with a radiochemical conversion rate of 65-98%.
[0068] Example 3 This invention also discloses an AMPA receptor PET probe. 18 The synthesis of F]2, such as Figure 2 As shown, 4-[ 18[F]Fluorobenzenesulfonyl chloride undergoes sulfonation with AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor ligand, with a radiochemical conversion rate of up to 96% after 10 minutes at room temperature. This is significantly higher than the method reported in the literature (Nuclear Medicine and Biology 110-111 (2022) 47-58, which requires heating at 180℃ and has a labeling rate of only 13%).
[0069] The method of this invention has significant advantages: the reaction conditions are milder (room temperature), the radiochemical conversion rate is increased by more than 7 times, and the obtained AMPA receptor PET imaging agent [ 18 F]2 can be used for PET imaging studies of AMPA receptors.
[0070] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A method for synthesizing aryl F-18 labeled sulfonyl chloride, characterized in that, The method includes the following steps: Step a) Using a thiophenol derivative as a labeling precursor, an aryl F-18 labeled thiophenol derivative intermediate is obtained through an aryl F-18 fluorination reaction; Step b) involves subjecting the aryl F-18 labeled thiophenol derivative intermediate to an oxidative chlorination reaction to obtain aryl F-18 labeled sulfonyl chloride; The general formula structure of the labeled precursor of the thiophenol derivative is represented as follows: ;in, and Each is independently a phenylene; for ; for Y is C (=O), Selected from alkyl, cycloalkyl, aryl or Alkoxy; The general formula of the aryl F-18 labeled thiophenol derivative intermediate is represented as follows: ;in, It is a phenylene. for Y is C (=O), Selected from alkyl, cycloalkyl, aryl or alkoxy, wherein the aryl F-18 labeled sulfonyl chloride is 4-[ 18 F]Fluorobenzenesulfonyl chloride.
2. The method according to claim 1, characterized in that, The aryl F-18 fluorination reaction is a photocatalytic aryl F-18 fluorination reaction, which occurs under photocatalyst and light irradiation conditions. 18 F Fluoride ions are used as the fluorine source, and the solvent used is selected from dichloromethane or 1,2-dichloroethane.
3. The method according to claim 2, characterized in that, The photocatalyst is an acridine salt photocatalyst: 9-mesinetrimethyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate.
4. The method according to claim 2 or 3, characterized in that, The illumination conditions are as follows: LED light source with a wavelength of 400–500 nm is used for illumination, and the illumination time is 5–30 minutes.
5. The method according to claim 4, characterized in that, The oxidative chlorination reaction was carried out in an organic solvent under acidic conditions using N-chlorosuccinimide as the oxidative chlorination reagent; the acidic conditions were provided by hydrochloric acid, and the organic solvent was acetonitrile; the reaction temperature was room temperature, and the reaction time was 5–20 minutes.
6. The method according to claim 1, characterized in that, The labeled precursors of thiophenol derivatives are selected from one or more of the following compounds: 4,4'-bis(acetylthio)diphenyl ether, 4,4'-bis(cyclohexanecarboxylthio)diphenyl ether, 4,4'-bis(neopentylthio)diphenyl ether, 4,4'-bis(benzoylthio)diphenyl ether, 4,4'-bis(tert-butoxycarbonylthio)diphenyl ether.
7. The application of an aryl F-18 labeled sulfonyl chloride in the labeling of amine compounds, wherein the aryl F-18 labeled sulfonyl chloride is prepared according to any one of claims 1-6 and is used to prepare an F-18 labeled PET probe, characterized in that, The aryl F-18 labeled sulfonyl chloride is subjected to a sulfonylation reaction with an amine compound to obtain a radioactive tracer containing an aryl F-18 labeled sulfonamide group.
8. The application according to claim 7, characterized in that, The amine compound is selected from one or more of the following types: aliphatic primary amines, aliphatic secondary amines, aromatic primary amines, aromatic secondary amines, ammonia, and hydroxylamine.
9. The application according to claim 7, characterized in that, The amine compound is an AMPA receptor ligand, and the resulting F-18-labeled PET probe is an AMPA receptor PET imaging agent used for AMPA receptor PET imaging.