Dopamine D3 receptor radioactive tracer and preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and provides a dopamine D3 receptor radioactive tracer and a preparation method and application thereof. According to the dopamine D3 receptor radiotracer (11C-YQA14) disclosed by the invention, a structure as shown in a formula 1 is used as a precursor compound, and gaseous 11C-CH3I is introduced under a closed condition to obtain the 11C-YQA14. The dopamine D3 receptor radioactive tracer has ideal affinity to a dopamine D3 receptor and has low affinity to a dopamine D2 receptor, so that the dopamine D3 receptor radioactive tracer can selectively recognize the dopamine D3 receptor and has low recognizability to the dopamine D2 receptor.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, and in particular to a dopamine D3 receptor radiotracer, its preparation method, and its application. Background Technology

[0002] Radioactive tracers (often simply called tracers, also known as radioligands or ligands) are compounds labeled with radioactive isotopes that have high affinity and selectivity for target receptors. After injection, when the tracer interacts with the target receptor in the body, the gamma rays emitted by the isotope are detected by positron emission tomography (PET). This data is then processed into quantitatively studyable data, enabling quantitative monitoring of target receptors in the living brain. Furthermore, through modeling and calculation, precise changes in dopamine system levels in the brain can be obtained, and results such as blood flow, metabolism, or recent synaptic density can also be measured. This provides a direct and intuitive key experimental basis for the precise regulation of the dopamine system in the body's physiological and pathological states. It offers ideal, visualized, and quantitative scientific evidence for the diagnosis and treatment of numerous neuropsychiatric diseases, becoming an important approach to the study of neurological disorders.

[0003] In 1990, Sokoloff et al. discovered the dopamine D3 receptor (D3R) and found that it shares 75% amino acid sequence homology with the dopamine D2 receptor (D2R), further clarifying the specific subtypes of dopamine receptors. D3R is mainly concentrated in the limbic system, such as the nucleus accumbens, Callejia's islet, and olfactory tubercle, and is also expressed in the cortex, striatum, and amygdala, participating in neural activities such as learning, memory, emotion, and reward. In the peripheral nervous system, D3R is mainly distributed in organs such as the intestines, pancreas, and adrenal glands, participating in physiological processes such as digestion, insulin secretion, and adrenaline secretion. Therefore, D3R is closely related to various major neuropsychiatric disorders caused by dopamine system dysfunction, such as schizophrenia, Parkinson's disease, drug dependence (or addiction), various forms of mental stress, anxiety, and sleep disorders. Furthermore, due to the peripheral distribution of D3R expression, studies have found that it also plays an important role in the regulation of physiological functions such as renal function protection and immune regulation. Therefore, in-depth research on the expression, distribution, and function of D3R will help reveal the pathogenesis of these diseases and provide new therapeutic targets.

[0004] Despite the important specific role of D3R mentioned above, developing a suitable tracer has taken several years. In particular, due to its significant structural homogeneity with D2R, developing a selective D3R radiotracer has been a challenge for many years.

[0005] To date, the most common dopamine tracer used in various studies is [ 11C]Raclopride, [ 18 F]Fallypride,[ 11 C]FLB457 and [ 11 [C]PHNO. Because these tracers have significant affinity for both D2R and D3R, results are usually reported as D2 / 3R binding. [ 11 C]Raclopride, [ 18 F]Fallypride,[ 11 [C]FLB457 is a D3R antagonist with a higher affinity for D2R. Although [ 11 C]PHNO is currently the best radioactive tracer for D3R, but it is not completely selective and its affinity for D2R is region-dependent. Therefore, developing new selective tracers for D3R remains important. Summary of the Invention

[0006] In view of this, the object of the present invention is to provide a dopamine D3 receptor radiotracer, its preparation method, and its application. The dopamine D3 receptor radiotracer provided by the present invention can selectively recognize dopamine D3 receptors and has low affinity for dopamine D2 receptors.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a dopamine D3 receptor radiotracer having the structure shown in Formula I: [Name not provided] 11 C-YQA14: Formula I.

[0008] This invention also provides a method for preparing the dopamine D3 receptor radiotracer described in the above technical solution, comprising the following steps: Dissolve tris(2-tolyl)phosphine and tris(dibenzylene-baseacetone)dipalladium to obtain a tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution; Dissolve the precursor compound shown in Formula 1 to obtain a precursor compound solution; Dissolve CuCl and CsF to obtain a CuCl-CsF solution; gaseous 11 C-CH3I was introduced into the tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution, and the process was terminated after the radioactivity reading stabilized. 11 The C-CH3I was introduced; and the precursor compound solution and CuCl-CsF solution were added sequentially to the resulting system. Radioactive element labeling was performed under sealed conditions to obtain the dopamine D3 receptor radiotracer. Formula 1.

[0009] Preferably, the mass ratio of the precursor compound shown in Formula 1, tris(2-tolyl)phosphine, tris(dibenzyl-baseacetone)palladium, CuCl, and CsF is 2~3.5:10~15:1~2:1.5~2.5:1~2; The radioactive element labeling temperature is 50~100℃, and the time is 5~10min.

[0010] Preferably, the method for preparing the precursor compound shown in Formula 1 includes the following steps: 4-Chloro-2-fluoro-1-iodobenzene, piperazine, potassium carbonate and organic solvent are mixed and subjected to a first reaction to obtain the first intermediate shown in Formula 2; Formula 2; The first intermediate, triethylamine, N-(4-bromobutyl)phthalimide and an organic solvent were mixed and subjected to a second reaction to obtain the second intermediate shown in Formula 3. Formula 3; The second intermediate, hexa-n-butyltin, the first catalyst, tri-tert-butylphosphine tetrafluoroborate, lithium chloride and organic solvent are mixed and a third reaction is carried out to obtain the third intermediate shown in Formula 4. Equation 4; The third intermediate, hydrazine hydrate, and alcohol solvent were mixed to carry out a fourth reaction, yielding the fourth intermediate shown in Formula 5. Formula 5; Benzooxazolin-2-one-5-carboxylic acid, thionyl chloride and organic solvent were mixed and subjected to the fifth reaction to obtain a system containing the fifth intermediate shown in Formula 6. Formula 6; The system containing the fifth intermediate, the fourth intermediate, potassium carbonate, and an organic solvent are mixed and subjected to a sixth reaction to obtain the precursor compound shown in Formula 1.

[0011] Preferably, in the first reaction, the molar ratio of 4-chloro-2-fluoro-1-iodobenzene to piperazine is 1:1~3, and the molar ratio of 4-chloro-2-fluoro-1-iodobenzene to potassium carbonate is 1:0.5~2. The temperature of the first reaction is 100~150℃, and the time is 12~36h.

[0012] Preferably, in the second reaction, the molar ratio of the first intermediate to triethylamine is 1:1~3, and the molar ratio of the first intermediate to N-(4-bromobutyl)phthalimide is 1:1~2; The temperature of the second reaction is 70~100℃, and the time is 12~36h.

[0013] Preferably, in the third reaction process, the molar ratio of the second intermediate to hexa-n-butyltin is 1:1~2; the molar ratio of the second intermediate to the first catalyst is 1:0.01~0.5; the molar ratio of the second intermediate to tri-n-butylphosphine tetrafluoroborate is 1:0.1~1; and the molar ratio of the second intermediate to lithium chloride is 1:1~10. The temperature of the third reaction is 25~100℃, and the time is 12~48h.

[0014] Preferably, during the fourth reaction, the mass concentration of hydrazine hydrate is 69-85%, and the molar ratio of the third intermediate to hydrazine hydrate is 1:1-5; the fourth reaction is carried out under reflux conditions, and the reaction time is 3-12 hours.

[0015] Preferably, in the fifth reaction, the molar ratio of benzoxazolin-2-one-5-carboxylic acid to sulfoxide is 1:1~3; the temperature of the fifth reaction is 25~90℃, and the time is 3~24h. In the sixth reaction, the molar ratio of the fourth intermediate to potassium carbonate is 1:1 to 3, the molar ratio of the fourth intermediate to benzoxazolin-2-one-5-carboxylic acid is 1:1 to 2, and the reaction time is 12 to 36 hours.

[0016] The present invention also provides the application of the dopamine D3 receptor radiotracer described in the above technical solution in PET imaging.

[0017] This invention provides a dopamine D3 receptor radiotracer.

[0018] The dopamine D3 receptor radiotracer of the present invention uses the structure shown in Formula I as a precursor compound. This precursor compound has an ideal affinity for the dopamine D3 receptor and only one affinity site for the dopamine D2 receptor. Therefore, the dopamine D3 receptor radiotracer of the present invention can selectively recognize the dopamine D3 receptor and has low recognition of the dopamine D2 receptor. Attached Figure Description

[0019] Figure 1 The mass spectrum of the first intermediate prepared in Example 1; Figure 2 The mass spectrum of the second intermediate prepared in Example 1; Figure 3 The mass spectrum of the third intermediate prepared in Example 1; Figure 4 The mass spectrum of the fourth intermediate prepared in Example 1; Figure 5 Mass spectrum of the precursor compound prepared in Example 1; Figure 6 The HPLC spectrum of the precursor compound prepared in Example 1 is shown. Detailed Implementation

[0020] This invention provides a dopamine D3 receptor radiotracer having the structure shown in Formula I, and its name is [missing information]. 11 C-YQA14: Formula I.

[0021] The dopamine D3 receptor radiotracer of the present invention uses the structure shown in Formula 1 as a precursor compound. This dopamine D3 receptor radiotracer has an ideal affinity for the dopamine D3 receptor and only one affinity site for the dopamine D2 receptor. Therefore, the dopamine D3 receptor radiotracer of the present invention can selectively recognize the dopamine D3 receptor.

[0022] This invention also provides a method for preparing the dopamine D3 receptor radiotracer described in the above technical solution, comprising the following steps: Dissolve tris(2-tolyl)phosphine and tris(dibenzylene-baseacetone)dipalladium to obtain a tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution; Dissolve the precursor compound shown in Formula 1 to obtain a precursor compound solution; Dissolve CuCl and CsF to obtain a CuCl-CsF solution; gaseous 11 C-CH3I was introduced into the tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution, and the process was terminated after the radioactivity reading stabilized. 11 The C-CH3I was introduced; and the precursor compound solution and CuCl-CsF solution were added sequentially to the resulting system. Radioactive element labeling was performed under sealed conditions to obtain the dopamine D3 receptor radiotracer. Formula 1.

[0023] In this invention, tris(2-tolyl)phosphine and tris(dibenzylene-baseacetone)dipalladium are dissolved to obtain a tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution. In this invention, the dissolving agent is preferably N-methylpyrrolidone (NMP).

[0024] In this invention, the precursor compound shown in Formula 1 is dissolved to obtain a precursor compound solution. In this invention, the dissolving agent is preferably N-methylpyrrolidone (NMP). The method for preparing the precursor compound shown in Formula 1 will preferably be described later.

[0025] This invention involves dissolving CuCl and CsF to obtain a CuCl-CsF solution. In this invention, the reagent used for dissolution is preferably N-methylpyrrolidone (NMP).

[0026] After obtaining the tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution, the precursor compound solution, and the CuCl-CsF solution, the present invention will... 11 C-CH3I was introduced into the tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution, and the process was terminated after the radioactivity reading stabilized. 11 The dopamine D3 receptor radiotracer is obtained by introducing C-CH3I and sequentially adding a precursor compound solution and a CuCl-CsF solution to the resulting system, followed by radioactive element labeling under sealed conditions.

[0027] In this invention, the preferred mass ratio of the precursor compound shown in Formula 1, tris(2-tolyl)phosphine, tris(dibenzyl-baseacetone)palladium, CuCl, and CsF is 2~3.5:10~15:1~2:1.5~2.5:1~2, and more preferably 1.3:8.1:1.1:1:1.3. In this invention, the preferred molar ratio of the precursor compound shown in Formula 1 to the organic solvent is 2.0~3.5 mg:1 mL.

[0028] In this invention, the gaseous state 11 C-CH3I is preferably dried before introduction, and the drying is preferably carried out on a P2O5 column. In this invention, the gaseous state... 11 The preferred preparation method for C-CH3I will be described in detail later.

[0029] In this invention, the temperature for radioactive element labeling is preferably 50~100℃, specifically preferably 50℃, 60℃, 70℃, 80℃, 90℃ or 100℃, and the time is preferably 5~10min, specifically preferably 5min, 6min, 7min, 8min, 9min or 10min.

[0030] In one specific embodiment of the present invention, the gaseous state 11C-CH3I is preferably generated in a first reaction vessel, and the radioactive element labeling is preferably carried out in a second reaction vessel; the first and second reaction vessels are preferably connected by a pipeline; a P2O5 column is preferably installed on the pipeline. In this invention, the first and second reaction vessels together constitute a synthesis module, which is preferably an All-in-One, Trasis.

[0031] In one specific embodiment of the present invention, the radioactive element labeling process preferably includes: opening the pipeline between the first reaction bottle and the second reaction bottle to allow the gaseous state to... 11 C-CH3I was distilled off from the first reaction flask and dried first by a P2O5 column before entering the second reaction flask, which contained a tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution. The reaction was terminated after the radioactivity reading in the first reaction flask dropped to a stable level and the radioactivity reading in the second reaction flask rose to a stable level. 11 Evaporation and transfer of C-CH3I; 11 After C-CH3I is distilled out and transferred, the precursor compound solution is first added to the second reaction flask, and then the CuCl-CsF solution is added to the second reaction flask; the second reaction flask is then sealed for radioactive element labeling.

[0032] After the radioactive element is labeled, the present invention preferably includes post-processing, which preferably includes the following steps: performing a first dilution on the obtained radioactive element labeled solution, purifying it by semi-preparative HPLC, collecting the HPLC purified solution for a second dilution, passing the second dilution solution through a C18 column, washing, drying and rinsing the C18 column in sequence, and then performing a third dilution and filtration on the resulting eluent to obtain the dopamine D3 receptor radiotracer.

[0033] In this invention, the reagent for the first dilution is preferably an acetonitrile-water solution, wherein the volume ratio of acetonitrile to water in the acetonitrile-water solution is preferably 1:1. In a specific embodiment of this invention, the first dilution is preferably carried out in a second reaction flask.

[0034] In this invention, the mobile phase of the semi-preparative HPLC includes mobile phase A and mobile phase B. Mobile phase A is preferably a TFA aqueous solution with a volume concentration of 0.1%, and mobile phase B is preferably a TFA acetonitrile solution with a volume concentration of 0.1%. The elution method is gradient elution, and the gradient elution program is preferably 0~20 min, in which the volume fraction of mobile phase B is increased uniformly from 50% to 90%.

[0035] In this invention, the second dilution is preferably made with sterile water for injection.

[0036] In this invention, the C18 column is preferably pretreated before use. The pretreatment preferably includes: slowly passing 10 mL of ethanol and 10 mL of sterile water for injection through the C18 column, and then drying it with 10 mL of nitrogen gas.

[0037] In this invention, after the second dilution solution passes through the C18 column, the invention preferably further includes drying the liquid on the C18 column.

[0038] In this invention, the rinsing agent is preferably sterile water for injection.

[0039] In this invention, the rinsing agent is preferably ethanol.

[0040] In this invention, the reagent used for the third dilution is preferably physiological saline.

[0041] In this invention, the pore size of the filter membrane is preferably 0.22 μm.

[0042] In one specific embodiment of the present invention, the post-processing preferably includes the following steps: the radiolabeled solution is first diluted in a second reaction flask, and the first diluted solution is extracted from the second reaction flask; it is injected into a semi-preparative HPLC for purification; sterile water for injection is added to the collected HPLC purified solution, the diluted solution is passed through a C18 column, and the liquid on the C18 column is dried; the C18 column is then washed with sterile water for injection and dried; the C18 column is then rinsed with ethanol, the rinsing solution is diluted with physiological saline (third dilution), and filtered through a 0.22 μm filter membrane to finally obtain the dopamine D3 receptor radiotracer.

[0043] In one specific embodiment of the present invention, the post-processing preferably includes: a first dilution of the radiolabeled solution in a second reaction flask; extraction of the first dilution from the second reaction flask; injection of the solution into a semi-preparative HPLC for purification; addition of 40 mL of sterile water for injection to the collected HPLC purified solution, and thorough mixing; slow injection of the mixture through a C18 column, followed by drying of the liquid on the C18 column; slow rinsing of the C18 column with 10 mL of sterile water for injection, followed by drying with 10 mL of nitrogen gas; rinsing of the C18 column with 1.5 mL of ethanol, diluting the eluent with 14 mL of physiological saline, and filtering through a 0.22 μm filter membrane to finally obtain the dopamine D3 receptor radiotracer.

[0044] In this invention, the preparation method of the precursor compound shown in Formula 1 preferably includes the following steps: 4-Chloro-2-fluoro-1-iodobenzene, piperazine, potassium carbonate and organic solvent are mixed and subjected to a first reaction to obtain the first intermediate shown in Formula 2; Formula 2; The first intermediate, triethylamine, N-(4-bromobutyl)phthalimide and an organic solvent were mixed and subjected to a second reaction to obtain the second intermediate shown in Formula 3. Formula 3; The second intermediate, hexa-n-butyltin, the first catalyst, tri-n-butylphosphine tetrafluoroborate, lithium chloride and organic solvent are mixed and a third reaction is carried out to obtain the third intermediate shown in Formula 4. Equation 4; The third intermediate, hydrazine hydrate, and alcohol solvent were mixed to carry out a fourth reaction, yielding the fourth intermediate shown in Formula 5. Formula 5; Benzooxazolin-2-one-5-carboxylic acid, thionyl chloride and organic solvent were mixed and subjected to the fifth reaction to obtain a system containing the fifth intermediate shown in Formula 6. Formula 6; The system containing the fifth intermediate, the fourth intermediate, potassium carbonate, and an organic solvent are mixed and subjected to a sixth reaction to obtain the precursor compound shown in Formula 1.

[0045] In this invention, 4-chloro-2-fluoro-1-iodobenzene, piperazine, potassium carbonate and an organic solvent are mixed to carry out a first reaction to obtain the first intermediate shown in Formula 2.

[0046] In this invention, during the first reaction, the organic solvent preferably includes dimethyl sulfoxide (DMSO); the molar ratio of 4-chloro-2-fluoro-1-iodobenzene and piperazine is preferably 1:1 to 3, specifically preferably 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; the molar ratio of 4-chloro-2-fluoro-1-iodobenzene and potassium carbonate is preferably 1:0.5 to 2, specifically preferably 1:0.5, 1:0.75, 1:1, 1:1.25, 1:1.5, 1:1.75 or 1:2; and the molar ratio of 4-chloro-2-fluoro-1-iodobenzene to the organic solvent is preferably 0.1 mol: 80 mL.

[0047] In this invention, the temperature of the first reaction is preferably 100~150℃, specifically preferably 100℃, 120℃, 130℃, 140℃ or 150℃, and the time is preferably 12~36h, specifically preferably 12h, 18h, 24h, 30h or 36h; the first reaction is preferably carried out under the conditions of oil bath and stirring.

[0048] After the first reaction, the present invention preferably cools the first reaction solution to room temperature, filters it, takes the filtrate, adds 50 mL of water, stirs for 30 min, extracts it twice with 200 mL of ethyl acetate, dries the organic phase, purifies it by column chromatography to obtain the crude product, salts it with hydrochloric acid ethanol solution, purifies it, and obtains the first intermediate.

[0049] After obtaining the first intermediate shown in Formula 2, the present invention mixes the first intermediate, triethylamine, N-(4-bromobutyl)phthalimide and an organic solvent to carry out a second reaction to obtain the second intermediate shown in Formula 3.

[0050] In this invention, during the second reaction, the organic solvent preferably includes acetonitrile; the molar ratio of the first intermediate to triethylamine is preferably 1:1 to 3, specifically preferably 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; the molar ratio of the first intermediate to N-(4-bromobutyl)phthalimide is preferably 1:1 to 2, specifically preferably 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2; the preferred ratio of the first intermediate to the organic solvent is 30 mmol: 150 mL.

[0051] In this invention, the temperature of the second reaction is preferably 70~100℃, specifically preferably 70℃, 75℃, 80℃, 82℃, 85℃, 90℃, 95℃ or 100℃, and the time is preferably 12~36h, specifically preferably 12h, 18h, 24h, 30h or 36h.

[0052] After the second reaction, the present invention preferably further includes: cooling the obtained second reaction solution to room temperature, adding a small amount of methanol, stirring at room temperature, precipitating a large amount of solid, filtering, recrystallizing the filter cake with methanol to obtain the second intermediate.

[0053] After obtaining the second intermediate shown in Formula 3, the present invention mixes the second intermediate, hexa-n-butyltin, the first catalyst, tri-tert-butylphosphine tetrafluoroborate (PtBu3HBF4), lithium chloride and organic solvent to carry out a third reaction to obtain the third intermediate shown in Formula 4.

[0054] In this invention, during the third reaction, the organic solvent preferably comprises 1,4-dioxane; the first catalyst is preferably bis(dibenzylacetone)palladium (Pd(dba)2); the molar ratio of the second intermediate to hexa-n-butylditin is preferably 1:1 to 2, specifically preferably 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2; the molar ratio of the second intermediate to the first catalyst is preferably 1:0.01 to 0.5, specifically preferably 1:0.01, 1:0.05, 1:0.1, or 1: The molar ratio of the second intermediate to tri-n-butylphosphine tetrafluoroborate is preferably 1:0.1 to 1, specifically 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, or 1:1. The molar ratio of the second intermediate to LiCl is preferably 1:1 to 10, specifically 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. The preferred molar ratio of the second intermediate to the organic solvent is 10 mmol: 60 mL.

[0055] In this invention, the temperature of the third reaction is preferably 25~100℃, specifically preferably 25℃, 30℃, 40℃, 50℃, 55℃, 60℃, 70℃, 80℃, 90℃ or 100℃, and the time is preferably 12~48h, specifically preferably 12h, 18h, 24h, 30h, 36h, 42h or 48h.

[0056] In this invention, the third reaction is preferably carried out under nitrogen protection, an oil bath, and stirring. The process of the third reaction is preferably monitored by TLC; the third reaction is considered complete once the second intermediate has fully reacted.

[0057] Following the third reaction, the present invention preferably further includes: cooling the obtained third reaction solution to room temperature, filtering with diatomaceous earth, concentrating under reduced pressure, adding KF aqueous solution to the residue and stirring for 2 hours, then adding ethyl acetate for extraction, separating the organic phase, washing the organic phase with saturated brine, drying with anhydrous sodium sulfate, and purifying by column chromatography to obtain the third intermediate. In the present invention, the eluent for the column chromatography purification is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixture is preferably 20:1 to 10:1.

[0058] After obtaining the third intermediate shown in Formula 4, the present invention mixes the third intermediate, hydrazine hydrate and alcohol solvent to carry out a fourth reaction to obtain the fourth intermediate shown in Formula 5.

[0059] In this invention, during the fourth reaction, the alcohol solvent preferably includes ethanol; the mass concentration of the hydrazine hydrate is preferably 69-85%, more preferably 85%; the molar ratio of the third intermediate to the hydrazine hydrate is preferably 1:1-5, specifically preferably 1:1, 1:2, 1:3, 1:4 or 1:5; and the volume ratio of the third intermediate to the alcohol solvent is preferably 7 mmol:90 mL.

[0060] In this invention, the fourth reaction is preferably carried out under reflux conditions, and the reaction time is preferably 3 to 12 hours, specifically 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In this invention, the fourth reaction is preferably carried out under stirring conditions.

[0061] Following the fourth reaction, the present invention preferably further includes: cooling the obtained fourth reaction solution overnight, filtering to remove insoluble matter, and obtaining an ethanol solution; concentrating the ethanol solution under reduced pressure, adding water and chloroform to the obtained concentrated residue, taking the chloroform organic phase, drying it with anhydrous sodium sulfate, and performing column chromatography to obtain the fourth intermediate. In the present invention, the eluent for the column chromatography is preferably a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol in the dichloromethane and methanol mixture is preferably 20:1 to 10:1.

[0062] After obtaining the fourth intermediate shown in Formula 5, the present invention mixes benzoxazolin-2-one-5-carboxylic acid, sulfoxide and organic solvent to carry out a fifth reaction to obtain a system containing the fifth intermediate shown in Formula 6.

[0063] In this invention, during the fifth reaction, the organic solvent preferably includes 1,2-dichloroethane and N,N-dimethylformamide (DMF); the molar ratio of benzoxazolin-2-one-5-carboxylic acid and sulfoxide is preferably 1:1 to 3, specifically preferably 1:1, 1:1.2, 1:1.5, 1:2, 1:2.5 or 1:3.

[0064] In this invention, the mixing of benzoxazolin-2-one-5-carboxylic acid, sulfoxide and organic solvent preferably includes the following steps: dissolving benzoxazolin-2-one-5-carboxylic acid in 1,2-dichloroethane, adding DMF dropwise, and adding sulfoxide dropwise under ice bath conditions.

[0065] In this invention, the temperature of the fifth reaction is preferably 25~90℃, specifically preferably 25℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃ or 90℃, and the time is preferably 3~24h, specifically preferably 3h, 5h, 6h, 9h, 12h, 15h, 18h, 21h or 24h; the time of the fifth reaction is preferably started from after the thionyl chloride is added.

[0066] After the fifth reaction is completed, the present invention preferably further includes: concentrating the obtained fifth reaction solution under reduced pressure, dissolving the residue in anhydrous acetone, and obtaining the system containing the fifth intermediate shown in Formula 5 for later use. In the present invention, the concentration of the fifth intermediate shown in Formula 5 in the system containing the fifth intermediate shown in Formula 5 is preferably 1.0 mol / L.

[0067] After obtaining the system containing the fifth intermediate shown in Formula 6, the present invention mixes the system containing the fifth intermediate, the fourth intermediate, potassium carbonate and an organic solvent to carry out a sixth reaction to obtain the precursor compound shown in Formula 1.

[0068] In this invention, in the sixth reaction, the organic solvent preferably includes acetone; the molar ratio of the fourth intermediate to potassium carbonate is preferably 1:1 to 3, specifically preferably 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; the molar ratio of the fourth intermediate to benzoxazolin-2-one-5-carboxylic acid is preferably 1:1.0 to 2.0, specifically preferably 1:1, 1:1.2, 1:1.25, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2; and the preferred molar ratio of the fourth intermediate to the organic solvent is 4 mmol:30 mL.

[0069] In this invention, mixing the system containing the fifth intermediate, the fourth intermediate, potassium carbonate, and the organic solvent preferably includes the following steps: dissolving the fourth intermediate in acetone, adding potassium carbonate, and then adding the system containing the fifth intermediate shown in Formula 5 dropwise under ice-water bath conditions.

[0070] In this invention, the temperature of the sixth reaction is preferably room temperature, and the time is preferably 12 to 36 hours, specifically 12 hours, 24 hours or 36 hours; the time of the sixth reaction is preferably started after the system containing the fifth intermediate shown in Formula 5 has been added dropwise.

[0071] Following the sixth reaction, the present invention preferably further includes: filtering the obtained sixth reaction solution to remove insoluble matter, obtaining a filtrate; and sequentially subjecting the filtrate to vacuum concentration and column chromatography purification to obtain the precursor compound shown in Formula I. In the present invention, the eluent for the column chromatography purification is preferably a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate in the mixture is preferably 10:1.

[0072] In this invention, the preparation formula of the precursor compound shown in Formula 1 is as follows: In this invention, gaseous state 11 The preferred method for preparing C-CH3I includes the following steps: Passing through a tetrahydrofuran solution of lithium aluminum hydride 11 C-CO2 undergoes reaction I, reaction II, and reaction III sequentially to obtain the... 11 C-CH3I.

[0073] In this invention, the concentration of lithium aluminum hydride in the tetrahydrofuran solution is preferably 1 mol / L.

[0074] In this invention, the 11 C-CO2 is preferably generated using a medical cyclotron accelerator; C-CO2 is generated using a medical cyclotron accelerator. 11 The preferred parameters for C-CO2 include: the target gas is a mixture of nitrogen and oxygen, wherein the volume ratio of nitrogen to oxygen in the nitrogen-oxygen mixture is preferably 97.5:2.5, and the target material is preferably... 11 For the C-target, the preferred beam size is 50 μA, and the preferred bombardment time is 50 min.

[0075] In this invention, the 11 C-CO2 is preferably filtered and dried sequentially before being introduced. The filter membrane used for filtration is preferably an air filter membrane, and the drying is preferably carried out on a P2O5 column.

[0076] The 11 The preferred amount of C-CO2 introduced is such that the radioactivity reading of the system no longer increases and remains stable.

[0077] In this invention, the first reaction is preferably carried out under closed conditions, the temperature of the first reaction is preferably 160°C, and the time is preferably 3 minutes.

[0078] In this invention, the second reaction is preferably carried out under the condition of passing high-purity nitrogen gas, the temperature of the second reaction is preferably 160°C, and the time is preferably 0.5 min; after the second reaction, the invention preferably further includes cooling to 40°C.

[0079] In this invention, the reagents for the third reaction preferably further include a hydroiodic acid solution, wherein the mass concentration of the hydroiodic acid solution is preferably 57%, and the volume ratio of the hydroiodic acid solution to the tetrahydrofuran solution of lithium aluminum hydride is preferably 35:28. In this invention, the third reaction is preferably carried out under closed conditions, wherein the temperature of the third reaction is preferably 130°C, and the time is preferably 20 seconds.

[0080] In this invention, the first reaction, the second reaction, and the third reaction are preferably carried out in the first reaction flask.

[0081] In one specific embodiment of the present invention, the medical cyclotron and the first reaction bottle are connected by a transmission pipeline. From the medical cyclotron to the first reaction bottle, an air filter membrane and a P2O5 column are preferably arranged sequentially on the transmission pipeline.

[0082] In one specific embodiment of the present invention, the 11 The preferred method for preparing C-CH3I includes the following steps: using a medical cyclotron accelerator. 11 C-target, loaded with target gas, is bombarded using a beam to produce... 11 C-CO2; 0.28 mL of 1 mol / L lithium aluminum hydride in tetrahydrofuran solution was placed in the first reaction flask, and the solution generated by the medical cyclotron was used. 11 C-CO2 is transferred through a transport pipe, passing sequentially through an air filter membrane and a P2O5 column, to the first reaction flask. The transfer stops when the radioactivity reading in the first reaction flask no longer increases. 11 C-CO2.

[0083] The first reaction flask was sealed and heated at 160°C for 3 minutes. High-purity nitrogen gas was then introduced, and the mixture was heated at 160°C for another 0.5 minutes. After this, the mixture was cooled to 40°C, and 0.35 mL of 57% HI was added. The mixture was then sealed and heated at 130°C for 20 seconds. After heating, the tubing was sealed and ready for use. 11 C-CH3I.

[0084] The present invention also provides the application of the dopamine D3 receptor radiotracer described in the above technical solution in PET imaging.

[0085] The present invention does not specifically limit the application of the dopamine D3 receptor radiotracer; those skilled in the art can set it according to the reagent requirements.

[0086] The dopamine D3 receptor radiotracer of the present invention can selectively recognize dopamine D3 receptors. When the dopamine D3 receptor radiotracer is injected intravenously into the brain as a PET imaging agent, it can bind to the target molecule dopamine D3 receptor for imaging and tracking with only extremely low concentrations or doses, playing a key role in elucidating the role of the dopamine system in neuropsychiatric diseases.

[0087] The following detailed description, in conjunction with embodiments, illustrates the dopamine D3 receptor radiotracer, its preparation method, and its applications provided by the present invention. However, these descriptions should not be construed as limiting the scope of protection of the present invention.

[0088] (a) Equipment and Reagents Consumables 1. Equipment Medical cyclotron: Eclipse HP, Siemens; Synthesis modules: AllinOne, Trasis; 2. Main reagents and consumables: Target gas: 97.5% nitrogen + 2.5% oxygen (99.9999%). Composition module components such as ferrules, tubing, reagent bottles, syringes, and air filters: Trasis develops a series of ferrules; C18 pillar: Sep-Pak, plus type; 57% hydroiodic acid solution (57% HI): Sigma-Aldrich; 1 mol / L lithium aluminum hydride in tetrahydrofuran solution (1 mol / L LiAlH4 in THF): Sigma-Aldrich; Phosphorus pentoxide (P2O5): A traditional Chinese medicine. Sodium hydroxide (NaOH): A traditional Chinese medicine. N-Methylpyrrolidone (NMP): Aladdin; Tris(2-Tolyl)phosphine: Aladdin; Cuprous chloride (CuCl): Aladdin; Cesium fluoride (CsF): Aladdin; Tris(dibenzylene-baseacetone)dipalladium (palladium has a valence of 0): Aladdin; Example 1: Preparation of the precursor compound N-{4-[4-(5-chloro-2-tri-n-butyltinylphenyl)piperazinyl]butyl}-benzoxazolin-2-one-5-carboxamide (1) Preparation of the first intermediate 1-(5-chloro-2-iodophenyl)piperazine shown in Formula 2: 4-chloro-2-fluoro-1-iodobenzene (25.6 g, 0.1 mol), piperazine (17.2 g, 0.2 mol), and potassium carbonate (10.35 g, 0.075 mol) were added to an 80 mL DMSO flask. The mixture was stirred in an oil bath at 130 °C for 24 h. After cooling to room temperature, the mixture was filtered. The filtrate was collected, 50 mL of water was added, and the mixture was stirred for 30 min. The filtrate was then extracted twice with 200 mL of ethyl acetate, and the organic phase was dried. Column chromatography purification yielded 23.9 g of the target compound, with a yield of 66%. 1 H NMR (600 MHz, DMSO) δ 9.68 (s, 1H), 7.87 (dd, J = 8.3, 2.0 Hz, 1H), 7.18(t, J = 2.3 Hz, 1H), 6.99 (dd, J = 8.4, 2.2 Hz, 1H), 3.18-3.23 (m, 8H). + ESI:[M+H]+ =322.98.

[0089] The mass spectrum of the obtained 1-(5-chloro-2-iodophenyl)piperazine is as follows: Figure 1 As shown.

[0090] (2) Preparation of the second intermediate N-{4-[4-(5-chloro-2-iodophenyl)piperazinyl]butyl} phthalimide shown in Formula 3: The first intermediate (10.77 g, 30 mmol) was added to a 150 mL acetonitrile flask, and triethylamine (9 g, 90 mmol) was slowly added. After the solid was completely dissolved, N-(4-bromobutyl) phthalimide (10.2 g, 36 mmol) was added, the temperature was raised to 82 °C, and the reaction was carried out for 18 h. After cooling to room temperature, a small amount of methanol was added, and the mixture was stirred at room temperature. A large amount of solid precipitated. The target compound was obtained by filtration, with a yield of 73%. 1 H NMR (600 MHz, CDCl3) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.79 – 7.64(m, 3H), 6.97 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.4, 2.4 Hz, 1H), 3.73 (t, J = 7.2Hz, 2H), 3.00 (s, 4H), 2.81 – 2.53 (m, 4H), 2.47 (t, J = 7.6 Hz, 2H), 1.80 –1.68 (m, 2H), 1.66 – 1.44 (m, 2H). + ESI:[M+H] + =524.06.

[0091] The mass spectrum of the obtained N-{4-[4-(5-chloro-2-iodophenyl)piperazinyl]butyl}phthalimide is shown below. Figure 2 As shown.

[0092] (3) Preparation of the third intermediate N-{4-[4-(5-chloro-2-tri-n-butyltinylphenyl)piperazinyl]butyl} phthalimide shown in Formula 4: The second intermediate (5.23 g, 10 mmol), hexa-n-butylditin (8.70 g, 15 mmol), Pd(dda)2 (1 g, 1 mmol), P(t-Bu)3HBF4 (580 mg, 2 mmol), and LiCl (2.12 g, 50 mmol) were added to a solution containing 60 mL of... In a three-necked flask containing 1,4-dioxane, the reaction was carried out under nitrogen atmosphere and oil bath at 50°C with stirring for 24 hours. TLC analysis showed complete reaction of the second intermediate. After cooling to room temperature, the mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and water was added to the residue with stirring for 2 hours. Ethyl acetate was then added for extraction, and the organic phase was separated into layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1~10:1) to obtain 4.8 g of an oily substance, with a yield of 69.8%. + ESI:[M+H] + =688.27.

[0093] The mass spectrum of the obtained N-{4-[4-(5-chloro-2-tri-n-butyltinylphenyl)piperazinyl]butyl}phthalimide is shown below. Figure 3 As shown.

[0094] (4) Preparation of the fourth intermediate 4-[4-(5-chloro-2-tri-n-butyltinylphenyl)piperazinyl]butylamine as shown in Formula 5: The third intermediate (4.8 g, 7 mmol) and 85% hydrazine hydrate (1.70 g, 21 mmol) were added to a flask containing 90 mL of ethanol. The mixture was stirred under reflux for 5 hours, and a white solid precipitated out. The mixture was cooled overnight, and the insoluble matter was removed by filtration. The ethanol solution was concentrated under reduced pressure, and water and chloroform were added to the residue. The chloroform organic phase was dried over anhydrous sodium sulfate and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to obtain 2.7 g of an oily substance, with a yield of 69%. +ESI:[M+H]+=558.25.

[0095] The mass spectrum of the obtained 4-[4-(5-chloro-2-tri-n-butyltinylphenyl)piperazinyl]butylamine is shown below. Figure 4 As shown.

[0096] (5) Preparation of the precursor compound shown in Formula 1: a. Weigh benzoxazolin-2-one-5-carboxylic acid (895.6 mg, 5 mmol) and dissolve it in 20 mL of 1,2-dichloroethane. Add 2-3 drops of DMF and add sulfoxide (714 mg, 6 mmol) dropwise under ice bath conditions. After the addition is complete, heat to 70 °C and react for 5 h. Then concentrate under reduced pressure and dissolve the residue in anhydrous acetone for later use. b. Dissolve the fourth intermediate (2.2 g, 4 mmol) in 30 mL of acetone and add potassium carbonate (1.1 g, 8 mmol). Add the acetone solution of the residue from step a dropwise under ice-water bath conditions. After the addition is complete, react at room temperature for 24 h. Filter to remove insoluble matter, concentrate under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 1.6 g of the target product, with a yield of 57%. +ESI:[M+H]+=719.25.

[0097] The mass spectrum of the obtained precursor compound is as follows: Figure 5 As shown.

[0098] The HPLC chromatogram of the obtained precursor compound is as follows: Figure 6 As shown, from Figure 6 It can be seen that the purity of the obtained precursor compound is 96.8%.

[0099] Example 2 11 Preparation of C-CH3I Using a medical cyclotron 11 C target, loaded with target gas, bombarded with a beam of 50μA for 50min; Medical cyclotron 11 C-CO2 is transferred from the transport pipeline, through an air filter membrane, and after drying on a P2O5 column, to reaction flask No. 1 in the synthesis module. Reaction flask No. 1 is pre-filled with 0.28 mL of a 1 mol / L tetrahydrofuran solution of lithium aluminum hydride. The transfer is stopped when the radioactivity reading of reaction flask No. 1 no longer increases.

[0100] In a sealed reaction flask (No. 1), the mixture was heated at 160°C for 3 minutes, then high-purity nitrogen gas was introduced, and the mixture was heated at 160°C for another 0.5 minutes. After this process, the mixture was cooled to 40°C, and then 0.35 mL of 57% HI was added. The mixture was then heated at 130°C for 20 seconds in a sealed container. After heating, the tubing was sealed and ready for use. 11 C-CH3I.

[0101] Example 3: Preparation of a radioactive tracer for dopamine D3 receptors 2.0 mg of the precursor compound was dissolved in 0.4 mL of NMP until fully dissolved to obtain a precursor compound solution.

[0102] Dissolve 1.9 mg CuCl and 1.5 mg CsF in 0.3 mL NMP until fully dissolved to obtain a mixed solution of CuCl and CsF.

[0103] 12.2 mg of tris(2-tolyl)phosphine, 1.7 mg of tris(dibenzyl-baseacetone)palladium(0) and 0.4 mL of NMP were added to reaction flask No. 2 in advance, and nitrogen gas was introduced to mix them evenly.

[0104] Open the corresponding transfer pipeline and distill off the contents of reaction flask No. 1 at 130°C. 11 C-CH3I, the gaseous form after distillation 11 After being dried on a P2O5 column, C-CH3I was introduced into reaction flask No. 2. The process continued until the radioactivity reading in reaction flask No. 1 dropped to a stable level and the reading in reaction flask No. 2 rose to a stable level, at which point the reaction was terminated. 11 Evaporation and transfer of C-CH3I.

[0105] The precursor compound solution and CuCl-CsF solution were added sequentially.

[0106] Seal reaction flask No. 2, heat at 80°C for 10 minutes, then stop heating.

[0107] Example 4: Purification of Dopamine D3 Receptor Radiotracer 8 mL of 50% acetonitrile-water solution (v / v) was added to reaction flask No. 2 to dilute the reaction solution. After dilution, the diluted solution was extracted and injected into a semi-preparative HPLC system for purification. The mobile phase A consisted of 0.1%-TFA aqueous solution (v / v), and phase B consisted of 0.1%-TFA acetonitrile solution (v / v). The time program was as follows: phase B was gradually increased from 50% to 90% over 20 minutes. The purified product was collected during the HPLC purification process.

[0108] After the HPLC purified solution was collected, it was diluted with sterile water for injection (40 mL). After dilution, the diluted solution was passed through a C18 column (pretreatment as before), then rinsed with 10 mL of sterile water for injection and dried. Finally, the C18 column was rinsed with 1.5 mL of ethanol. The elution solution was diluted with 14 mL of physiological saline and filtered through a 0.22 μm filter membrane to obtain the final product.

[0109] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A dopamine D3 receptor radiotracer, characterized in that, It has the structure shown in Equation I, and its name is 11 C-YQA14: Equation I.

2. The method for preparing the dopamine D3 receptor radiotracer according to claim 1, characterized in that, Includes the following steps: Dissolve tris(2-tolyl)phosphine and tris(dibenzylene-baseacetone)dipalladium to obtain a tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution; Dissolve the precursor compound shown in Formula 1 to obtain a precursor compound solution; Dissolve CuCl and CsF to obtain a CuCl-CsF solution; gaseous 11 C-CH3I was introduced into the tris(2-tolyl)phosphine-tris(dibenzylene-baseacetone)dipalladium solution, and the process was terminated after the radioactivity reading stabilized. 11 The C-CH3I was introduced; and the precursor compound solution and CuCl-CsF solution were added sequentially to the resulting system. Radioactive element labeling was performed under sealed conditions to obtain the dopamine D3 receptor radiotracer. Formula 1.

3. The preparation method according to claim 2, characterized in that, The mass ratio of the precursor compound shown in Formula 1, tris(2-tolyl)phosphine, tris(dibenzyl-baseacetone)palladium, CuCl, and CsF is 2~3.5:10~15:1~2:1.5~2.5:1~2; The radioactive element labeling temperature is 50~100℃, and the time is 5~10min.

4. The preparation method according to claim 2, characterized in that, The preparation method of the precursor compound shown in Formula 1 includes the following steps: 4-Chloro-2-fluoro-1-iodobenzene, piperazine, potassium carbonate and organic solvent are mixed and subjected to a first reaction to obtain the first intermediate shown in Formula 2; Formula 2; The first intermediate, triethylamine, N-(4-bromobutyl)phthalimide and an organic solvent were mixed and subjected to a second reaction to obtain the second intermediate shown in Formula 3. Formula 3; The second intermediate, hexa-n-butyltin, the first catalyst, tri-tert-butylphosphine tetrafluoroborate, lithium chloride and organic solvent are mixed and a third reaction is carried out to obtain the third intermediate shown in Formula 4. Equation 4; The third intermediate, hydrazine hydrate, and alcohol solvent were mixed to carry out a fourth reaction, yielding the fourth intermediate shown in Formula 5. Formula 5; Benzooxazolin-2-one-5-carboxylic acid, thionyl chloride and organic solvent were mixed and subjected to the fifth reaction to obtain a system containing the fifth intermediate shown in Formula 6. Formula 6; The system containing the fifth intermediate, the fourth intermediate, potassium carbonate, and an organic solvent are mixed and subjected to a sixth reaction to obtain the precursor compound shown in Formula 1.

5. The preparation method according to claim 4, characterized in that, In the first reaction, the molar ratio of 4-chloro-2-fluoro-1-iodobenzene to piperazine is 1:1~3, and the molar ratio of 4-chloro-2-fluoro-1-iodobenzene to potassium carbonate is 1:0.5~2. The temperature of the first reaction is 100~150℃, and the time is 12~36h.

6. The preparation method according to claim 4, characterized in that, In the second reaction, the molar ratio of the first intermediate to triethylamine is 1:1~3, and the molar ratio of the first intermediate to N-(4-bromobutyl)phthalimide is 1:1~2. The temperature of the second reaction is 70~100℃, and the time is 12~36h.

7. The preparation method according to claim 4, characterized in that, In the third reaction process, the molar ratio of the second intermediate to hexa-n-butyltin is 1:1~2; the molar ratio of the second intermediate to the first catalyst is 1:0.01~0.5; the molar ratio of the second intermediate to tri-n-butylphosphine tetrafluoroborate is 1:0.1~1; and the molar ratio of the second intermediate to LiCl is 1:1~10. The temperature of the third reaction is 25~100℃, and the time is 12~48h.

8. The preparation method according to claim 4, characterized in that, In the fourth reaction, the mass concentration of hydrazine hydrate is 69-85%, and the molar ratio of the third intermediate to hydrazine hydrate is 1:1-5; the fourth reaction is carried out under reflux conditions, and the reaction time is 3-12 hours.

9. The preparation method according to claim 4, characterized in that, In the fifth reaction, the molar ratio of benzoxazolin-2-one-5-carboxylic acid to sulfoxide is 1:1~3; the temperature of the fifth reaction is 25~90℃, and the time is 3~24h. In the sixth reaction, the molar ratio of the fourth intermediate to potassium carbonate is 1:1 to 3, the molar ratio of the fourth intermediate to benzoxazolin-2-one-5-carboxylic acid is 1:1 to 2, and the reaction time is 12 to 36 hours.

10. The application of the dopamine D3 receptor radiotracer according to claim 1 in PET imaging.

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