CN108786677B - A kind of microreactor of Click labelled synthesis PET imaging agent and its preparation and reaction method - Google Patents

Abstract

The invention discloses a microreactor for the synthesis of PET imaging agent with Click mark and its preparation and reaction method. By modifying the inner wall of the microtube to increase its specific surface area and adsorption capacity, the precursor compound of the marker and the catalyst for the Click labeling reaction are fixed and dispersed on the inner wall of the reactor. After installing a heating film and a standard interface, it is connected to the micro reaction synthesis system. be usable. Since the precursor reagent to be labeled and the catalyst are fixed in the reactor in advance, the Click reaction can be carried out only by injecting the labeled azide compound into the reactor during synthesis, which saves the operation of transferring reagents and avoids pipeline pollution, reducing the The operation volume of post-reaction treatment is reduced, thereby shortening the synthesis operation time. The reactor has low processing cost and can be used at one time to avoid cross-contamination when synthesizing different imaging agents. The reactor can be used for the synthesis of other Click-labeled sugars and peptides.

Description

A Microreactor for Synthesizing PET Imaging Agents with Click Marking and Its Preparation and Reaction method

technical field

The invention relates to a microreactor for the synthesis of a PET imaging agent with Click labeling, and the reactor can be used for synthesizing the isotope-labeled PET imaging agent.

Background technique

PET (positron emission tomography, positron emission tomography) is a new non-invasive nuclear medicine molecular imaging technology, which uses the principle of radioactive tracer, according to the use of different radioisotope-labeled imaging agents (PET imaging agents), It is highly sensitive to display the physiological and biochemical changes of tissues and organs. Imaging agents are the key to PET and nuclear medicine. The imaging agents used in PET are drugs labeled with radionuclides ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F (hydrogen-like), etc., due to the half-life of the radionuclides used Short, it is impossible to purchase and store as a commodity, so when performing PET imaging, it is necessary to label and synthesize PET imaging agents as soon as possible at the production site of radionuclides, and use them locally and nearby within a limited time. Since the amount of the imaging agent used each time is very small (usually equivalent to near nanomolar level), and the synthesis and purification time consumption is required to be as short as possible, this kind of fast ultra-micro-synthesis preparation has a great impact on the process, equipment and its automatic control. Very demanding.

The 1,3-dipolar cycloaddition reaction of azide and alkyne is a representative reaction in Click Chemistry, which has fast reaction speed, mild conditions, simple operation, insensitivity to oxygen and water, and excellent reaction selectivity. The advantage of high yield. Due to the good biocompatibility of the generated triazole linker, the Click labeling strategy has been widely used in the synthesis of PET imaging agents and biomarkers, while the copper-catalyzed azide and terminal Alkyne cycloaddition reaction (CuAAC) is the most classic and mature method used in molecular imaging.

Carrying out the synthesis of PET imaging agents in a microreactor has significant advantages. First of all, the microreactor synthesis system can control a very small reaction volume, so the relative concentration of reactants is high and the reaction rate is fast, which can greatly reduce the amount of substrate used and the difficulty of purification. Secondly, the synthesis time can be greatly shortened, and on-demand production can be truly realized. Third, the radiochemical yield of the reaction can be significantly improved. Fourth, the reaction system is small, which reduces protection costs and improves safety. Fifth, the function of the reaction chip is highly scalable, which can fully meet the needs of scientific research.

At present, the microreactors used to synthesize PET imaging agents mainly include microfluidic chip reactors, continuous flow microtube reactors, and micropool reactors. In the synthesis process controlled by the program, the solution of the reagents and catalysts involved in the reaction is injected into the reactor through the pipeline, which consumes time, increases the volume of the reaction system and the amount of operation, and prolongs the time for synthesis and preparation.

Contents of the invention

In the existing program-controlled synthesis process, the reagents and catalyst solutions involved in the reaction are injected into the reactor through the pipeline according to the synthesis process flow, which consumes time, increases the volume of the reaction system and the amount of operation, and prolongs the time for synthesis and preparation. The purpose of the present invention is to overcome the deficiencies of the prior art, and to provide a microreactor for the synthesis of PET imaging agents with Click labeling, which can be used for synthesizing isotope-labeled PET imaging agents.

The technical scheme that the present invention specifically adopts is as follows:

Click marks a microreactor for synthesizing PET imaging agents. The main body of the microreactor is a hollow tube of metal or glass. The inner wall of the hollow tube is modified to form an uneven non-smooth surface; the inner wall of the hollow tube is The catalyst for the labeling reaction and the precursor compound of the Click marker are dispersed and immobilized on the surface. In this microreactor, because the precursor reagent to be labeled and the catalyst are fixed in the reactor in advance, the Click labeling reaction can be carried out as long as the labeled azide compound is injected into the reactor during synthesis, which saves the operation of transferring reagents and avoids Pipeline pollution reduces the operation volume of post-reaction treatment, thereby shortening the synthesis operation time. The reactor has low processing cost and can be used at one time to avoid cross-contamination when synthesizing different imaging agents.

In the present invention, the uneven non-smooth inner surface means that the inner wall of the glass microtube of the present invention is uneven, and has uneven pores or burrs on the surface, which is different from the smooth and flat inner wall of the glass microtube. This inner surface can be modified by methods such as depositing silica. In this kind of pipeline, the inner surface area of adsorption is increased by modifying the inner wall, and the reagent solution injected into the microtube can spread and form a liquid film on the tube wall under the push of the airflow, which increases the evaporation area and facilitates the passage of hot air through the hollow pipeline, thus realizing rapid After drying, the effective components can be adsorbed and fixed on the tube wall. Moreover, this immobilization method can prevent the dried reagents from agglomerating, which is beneficial to fully mixing with the subsequent injection of the reaction reagents, saves the synthesis time, and improves the synthesis yield.

Preferably, the two ends of the hollow pipe body are provided with sealing interfaces for connecting external inlet and outlet pipelines.

Preferably, the outer wall of the hollow tube is equipped with a heating system for heating the tube body. The heating system can be electric heating film and so on.

Preferably, the inner diameter of the hollow tube is 1-3 mm, and the length is 5-10 mm. The inner diameter is more preferably 1.5 to 2.5 mm. The inner diameter of the glass microtube will affect the formation of the liquid film. If the inner diameter is too large or too small, the liquid will not be able to form a uniform liquid film on the inner wall. Within this inner diameter range, the formation effect of the liquid film is better.

Preferably, the specific surface area of the tube wall of the hollow tube body per unit length is 150-1000 cm ² /cm.

Another object of the present invention is to provide a kind of preparation method of the microreactor of the Click mark synthesis PET imaging agent described in any scheme above, its steps are as follows:

Inject the solution containing the Click marker precursor compound and the catalyst of the marking reaction into the hollow tube body of metal or glass, and the inner wall of the hollow tube is modified to form an uneven non-smooth surface; One end of the tube is fed with airflow, so that the solution is pushed by the airflow to spread on the inner surface of the tube wall to form a liquid film; keep the airflow continuously flowing until the solution is dry, so that the Click marker precursor compound and the catalyst for the labeling reaction are dispersed and fixed on the tube wall , to obtain a microreactor for the Click-labeled synthetic PET imaging agent.

As a preference, the method for modifying the inner wall of the hollow pipe body is:

1) After heating the mixed solution of cetyltrimethylammonium bromide and NaOH, add tetraethyl orthosilicate and stir to react; then fill the hollow tube body of cleaned metal or glass with the reaction solution;

2) drying the hollow tube body filled with the reaction solution, and sintering after the reaction solution is dried to complete the modification of the inner tube wall;

3) Taking out the sintered hollow pipe body, cleaning and drying, and obtaining a hollow pipe body with the inner wall modified.

Of course, based on the working principle of the present invention, the modification of the inner wall of the glass microtube does not necessarily have to use the above method, and other methods can also be used, as long as the modification can form an uneven and non-smooth inner surface and increase its inner surface area.

Preferably, the gas flow continuously introduced during the drying of the solution is a heated hot gas flow, preferably a hot nitrogen gas flow. The hot air flow can speed up the drying process of the reagents.

Preferably, the single injection volume of the solution/reagent in the hollow tube body should satisfy: all the injected liquid can spread and form a liquid film on the inner surface of the tube wall under the push of the airflow, without being blown out of the glass microtube. When the single injection volume is too large, the liquid film cannot be completely spread on the inner surface of the tube wall, and it will be blown out of the glass microtube by the airflow, which will affect the accuracy of subsequent tests. For a pipeline with a certain size, the best single injection volume can be determined through experiments.

Preferably, the cleaning step of the hollow tube body is: immerse the glass microtube in deionized water, ethanol, acetone and deionized water for ultrasonic cleaning; then immerse the glass microtube in a mixture of concentrated sulfuric acid and hydrogen peroxide for ultrasonic treatment, and then Stand in the mixed solution; finally, ultrasonically clean the glass microtube several times in deionized water and dry it.

Another object of the present invention is to provide a microreactor for the Click-labeled synthetic PET imaging agent prepared by any of the above-mentioned methods. The inner wall of the glass microtube prepared by the method has an uneven pore structure and a large surface area, which can provide a larger spreading area of the ion reagent. Moreover, its inner surface is rough and non-smooth, so it can trap ionic reagents to a certain extent and prevent them from being blown out of the glass microtube driven by the airflow.

Another object of the present invention is to provide a method for carrying out the Click labeling reaction using the microreactor described in any of the above schemes, which specifically includes: injecting the marked azide compound into the microreactor, sealing it, and heating , to make a Click mark reaction.

Preferably, the labeling reaction is ¹⁸ F labeling reaction; the preparation method of the labeled azide compound is:

Inject the ¹⁸ F ionic reagent into the hollow tube body, and then pass airflow to one end of the hollow tube body, so that the ¹⁸ F ionic reagent spreads on the inner surface of the tube wall under the push of the airflow to form a liquid film; keep the airflow continuous Inject until the ¹⁸ F ionic reagent is completely dry and adsorbed on the inner surface of the tube wall; inject ultra-dry acetonitrile into the hollow tube again, and then continue to flow air into one end of the hollow tube until it is dry; then inject it into the hollow tube Inject an ultra-dry acetonitrile solution of azidoethyl trifluoromethanesulfonate, seal it, heat it, and react to obtain ¹⁸ F-labeled azide compound.

Further, the length of the hollow tube is 10 cm, the inner diameter is 2 mm, the injection volume of the ¹⁸ F ion reagent is 100 μL, and the flow rate of the air flow used to push the ¹⁸ F ion reagent is 100 μL/min. Dry fixation works best at this glass microtube size, push air flow rate, and injection volume.

The reactor provided by the present invention is to modify the inner wall to increase its specific surface area and adsorption capacity on the inner wall of glass or metal microtubes by depositing silicon dioxide and other methods, and fix the marker precursor compound and the catalyst for the Click marking reaction by adsorption In the reactor, the reactor is equipped with an electric heating film and a standard sealed interface with access channels, and can be used when connected to the micro-reaction synthesis system. The hollow cavity can provide a reaction space to ensure that the liquid film is formed to expand the evaporation area, while the gas can still pass through the center of the liquid film quickly, which can effectively realize the medium and low pressure control of the fluid inside the tube. Since the reaction reagents and catalysts are fixed in the reactor in advance, the Click labeling reaction can be carried out as long as the labeled azide compound is injected into the reactor, which saves the transfer operation and avoids pipeline pollution, reducing the amount of post-reaction treatment , thereby shortening the synthesis operation time. The reactor has low processing cost and can be used at one time to avoid cross-contamination when synthesizing different imaging agents. The reactor can be used to synthesize other Click-labeled sugars and polypeptides, and can also be used to research and develop various new PET molecular imaging agents.

Description of drawings

The SEM image of the surface morphology of the glass microtubes modified by the inner wall of Fig. 1;

The SEM image of the longitudinal section of the glass microtube modified on the inner wall of Fig. 2;

Fig. 3 Optical microscopic magnification of cross-section before (left) and after (right) modification of stainless steel microtube inner wall;

Figure 4 18F-labeled octreotide Radio-TLC spectrum;

Fig. 5 Schematic diagram of the synthesis system with a hollow tube body.

Detailed ways

The relevant details of the present invention will be further described below through examples, but implementation is not limited to the protection scope of the present invention.

The preparation of embodiment 1 inner wall modification glass microtube

Sonicate a glass microtube with a length of 10 cm and an inner diameter of 1.5 mm in deionized water, ethanol, acetone, and deionized water for 10 min, then immerse in a concentrated sulfuric acid-hydrogen peroxide mixed solution (volume ratio 1:1) for ultrasonic treatment for 15 min, and place it for 1.5 h Afterwards, immerse in deionized water for ultrasonic cleaning for 10 minutes, repeat ultrasonication with deionized water twice, and dry in an oven at 120°C for 2 hours before use.

Add 0.408g cetyltrimethylammonium bromide to the round bottom flask, add 200mL deionized water and 1.2mL 2mol/L NaOH solution, stir and heat to 70°C, add 2mL tetraethyl orthosilicate (TEOS), stir Reaction 1h. The reaction solution was filled into glass microtubes and dried in an oven at 120 °C for 1 h. After sintering at 500°C for 2h in a muffle furnace, take it out. Immerse in deionized water and ultrasonically clean for 10 minutes, dry in an oven at 120° C. for 2 hours, cool, and take out to obtain glass microtubes with inner wall modification.

The SEM image of the surface morphology of the microtubules with the inner wall modification prepared in this example is shown in FIG. 1 , and the SEM image of the longitudinal section of the inner wall modified microtubules is shown in FIG. 2 . It can be clearly seen from the figure that the surface of the modified microtube inner wall presents an uneven porous rough morphology, and its surface area is significantly improved compared with the traditional smooth tube wall. The microtube can be used to quickly dry the reagent. When the reagent solution is pushed by the airflow to flow in the glass microtube, the reagent will continuously penetrate into the pores on the surface and form a liquid film on the surface of the tube wall under the action of surface tension. Finally, the reagent is evenly spread, and the center of the microtube still retains a channel for the blowing air flow. Therefore, the airflow can continuously quickly evaporate and dry the liquid film around the channel. Moreover, since the liquid film is evenly spread, the active ingredients in the reagent will also be evenly adsorbed on the surface of the tube wall after it is dried, and there will be no agglomeration phenomenon. Subsequent injection of reagents required for other reactions into the microtube can dissolve the active ingredients in the reagent; of course, the glass microtube can also be directly used as a reactor, and other reagents can be injected and reacted in the microtube lumen.

The preparation of embodiment 2 inner wall modified glass microtubes

Compared with Example 1, this example differs only in that the size of the glass microtube is 10 cm in length and 2 mm in inner diameter; other pretreatment and inner wall modification methods are the same. The morphology of the modified tube wall in this example is similar to Example 1.

The preparation of the inner wall modified glass microtube of embodiment 3

Compared with Example 1, this example differs only in that the size of the glass microtube is 10 cm in length and 2.5 mm in inner diameter; other pretreatment and inner wall modification methods are the same. The morphology of the modified tube wall in this example is similar to Example 1.

The inner wall-modified glass microtubes prepared in the above three examples can be further processed to form a microtube reactor with different components attached to the inner wall. Methods for immobilized attachment of target components into microtubules are as follows:

Inject the solution containing the target fixed component into the glass microtube, and then pass airflow to one end of the glass microtube, so that the solution is pushed by the airflow to spread on the inner surface of the tube wall to form a liquid film; then keep the airflow continuously until the solution Completely dry, the effective components will be evenly adsorbed on the inner surface of the tube wall. The drying gas flow is preferably a hot nitrogen gas flow.

When the glass microtube is in use, a sealing interface can be installed at both ends, and then connected to the automatic synthesis system through the connecting pipe. The schematic diagram of the use state of the glass microtube is shown in Figure 5. The reagent containing the target fixed component can be switched and injected into the connecting pipe through the switching valve in the synthesis system in advance, and then pushed by the airflow, and injected into the vertical through the connecting pipe through the sealing interface. placed in the lumen of a glass microtube. During the process of pushing the airflow, the flow rate of the airflow should not be too large or too small, otherwise it is easy to make the film-forming effect of the reagent not good. In actual use, the optimum air flow rate should be determined through experiments according to the amount of reagent added and the size of the glass microtube. When the reaction needs to be carried out in the inner cavity of the microtube, the ventilation can be stopped to keep the inside of the tube sealed, and a heating system can be used outside the tube to adjust the temperature.

The optimum parameter determination of embodiment 4 glass microtubes

Based on the glass microtubes prepared in the above three examples, the reaction of synthesizing ¹⁸ F-FDG is taken as an example to illustrate the effects of different reagent additions, air flow rates and microtube sizes on the reaction results.

Experimental group 1: use the glass microtube prepared in Example 1 to dry ¹⁸ F ion reagent and synthesize ¹⁸ F-FDG:

Production of ¹⁸ F ion reagents: using ¹⁸ O(p,n) ¹⁸ F nuclear reaction, using a volume of 2.4 mL of H ₂ O[ ¹⁸ O] oxygen-enriched water (95%) target, using 11 MeV, 35 μA on a cyclotron The proton beam was continuously bombarded for 30-60 minutes to obtain the ¹⁸ F ion oxygen-enriched aqueous solution required for the reaction.

Separation and enrichment of ¹⁸ F ion reagents: ¹⁸ F-oxygen-enriched aqueous solution is passed through the QMA column, and ¹⁸ F ions are enriched on the QMA column, while the oxygen-enriched water is collected in the recovery bottle. Start the automatic control system to pass ¹⁸ F ions and water to the anion exchange column (QMA), and enrich the ¹⁸ F ions on the QMA column, while the oxygen-enriched water is collected in the recovery bottle.

Drying of ¹⁸ F ion reagents and ¹⁸ F labeling reaction: transfer 1 mL of K222/K ₂ CO ₃ in acetonitrile/water solution (K222, 15 mg/mL; K ₂ CO ₃ , 1.2 mg/mL) through the QMA column to elute ¹⁸ F ions, The collected 100 μL reagent containing 100 μCi ¹⁸ F ions was injected into the glass microtube prepared in Example 1 under the push of a nitrogen flow at a flow rate of 100 μL/min, and was adsorbed on the tube wall to spread to form a liquid film, and continued to pass through a 100°C hot nitrogen flow ( Flow rate 100 μL/min) and blow for 3 minutes to dry the ¹⁸ F ion reagent; then inject 20 μL ultra-dry acetonitrile into the glass microtube, pass through 100°C hot nitrogen flow (flow rate 100 μL/min) and blow for 2 minutes until dry. Inject 100 μL of mannose trifluoride ultra-dry acetonitrile solution (2 mg/mL), heat to 120 ° C, seal the reaction for 5 minutes, and pass through nitrogen flow (flow rate 100 μL/min) while hot to remove acetonitrile.

Hydrolysis reaction: Inject 100 μL of 1M HCl solution into the glass microtube that has undergone ¹⁸ F labeling reaction, heat at 110°C, and seal the reaction for 5 minutes to complete the hydrolysis reaction.

Separation and purification: transfer the hydrolyzed solution to a series column composed of AG50/AG11A8 resin column, Al ₂ O ₃ column and C18 column, then transfer 5mL water and pass it to the separation column, collect the eluate and pass the eluate through The ¹⁸ F-FDG solution was obtained by filtering with a 0.22 μm filter membrane.

Experimental group 2: Compared with experimental group 1, the only difference between this experimental group is that the glass microtubes were replaced by the glass microtubes prepared in Example 2, and other methods and parameters remained the same as experimental group 1.

Experimental group 3: Compared with experimental group 1, the only difference between this experimental group is that the glass microtubes were replaced with the glass microtubes prepared in Example 3, and other methods and parameters remained the same as in experimental group 1.

Experimental group 4: Compared with experimental group 2, the difference between this experimental group and experimental group 2 is that the air flow rate used to push the ¹⁸ F ion reagent was adjusted to 50 μL/min, and other methods and parameters were kept the same as experimental group 2.

Experimental group 5: Compared with experimental group 2, the difference between this experimental group and experimental group 2 is that the air flow rate used to push ¹⁸ F ion reagents was adjusted to 150 μL/min, and other methods and parameters were kept the same as experimental group 2.

Experimental group 6: this experimental group is compared with experimental group 2, and its difference only is that the glass microtube wherein is replaced with original glass microtube in embodiment 2 identical, the glass microtube (long 10cm, Inner diameter 2mm), after installing sealing interface at both ends, it can be directly connected to the automatic synthesis system for use. Other methods and parameters are kept the same as the experimental group 2.

Finally, in experimental groups 1-6, the radiation TLC yields were 76%, 90%, 85%, 80%, 70% and 45%. ^In experimental groups 1 to ³ of the dry ¹⁸ F ionic reagent and synthetic ¹⁸ F-FDG, only the diameter of the microtube was different. Quality is directly related. In comparison, experimental group 2 was the best, with a radiation TLC yield of 90%. It takes 30 minutes to prepare ¹⁸ F-FDG by this method, which is less than 40 minutes required by conventional synthesizers. Compared with experimental group 6, experimental group 2 used unmodified microtubes to dry ¹⁸ F ion reagents and synthesize ¹⁸ F-FDG, and the radiation TLC yield was greatly reduced to 45%. It shows that the modification of the inner wall of microtubules in the present invention is beneficial to the drying of ¹⁸ F ion reagents. Comparing the experimental groups 2, 4 and 5, it can be found that only the nitrogen flow rate factor that pushes the solution into the microtube is different in the three groups of experiments, and the experimental group 2 is the best, indicating that the solution is evenly distributed on the inner wall of the microtube under the propulsion of the nitrogen flow at a suitable flow rate. Spreading facilitates the drying of ¹⁸ F ion reagents and the subsequent ¹⁸ F labeling reaction, thereby shortening the time of the entire synthesis process and increasing the synthesis yield.

In summary, when using the glass microtubes with inner wall modification prepared by the present invention to dry and fix the solution, the optimal parameters are: the length of the glass microtubes is 10 cm, the inner diameter is 2 mm, the injection volume of the solution is 100 μL, and the nitrogen gas used to push the solution The flow rate was 100 μL/min. In addition to drying ¹⁸ F ion reagents, this group of parameters can also be used for drying other ion reagents, so that the corresponding effective components are pre-attached and fixed on the closure. Of course, this is only a set of optimal parameters. For glass microtubes of different sizes, the optimal injection amount and nitrogen flow rate can also be determined through experiments.

Example 5 Fabrication of the Click marker synthesis reactor

In this example, the Click labeling synthesis reactor was fabricated based on the inner wall-modified glass microtubes prepared in Example 2. Inject 100 μL of a mixed solution containing terminal alkyne-modified octreotide (0.01 mol/L), copper sulfate (0.001 mol/L) and sodium ascorbate (0.001 mol/L) into the glass microtube, and then to the bottom of the glass microtube A nitrogen flow at a flow rate of 100 μL/min was introduced to spread the solution on the inner surface of the tube wall under the push of the airflow to form a liquid film; then a hot nitrogen flow at 100°C (flow rate of 100 μL/min) was continuously introduced until the solution was completely dry and the terminal alkyne The modified octreotide and the catalyst are dispersed and fixed on the tube wall to obtain a microreactor of the Click-labeled PET imaging agent.

The outer wall of the obtained microtube is equipped with an electric heating film, and after adding a sealing interface at both ends, it can be connected to an automatic synthesis system for use.

Example 6 Fabrication of the Click marker synthesis reactor

In this example, compared with Example 5, the only difference is that the inner wall modified microtubes are different. In the present embodiment, adopt the method identical with embodiment 2 to modify long 10cm, the stainless steel microtube inner wall of internal diameter 2mm, the optical microscopic magnification photograph of cross-section before (left) and back (right) of stainless steel microtube inner wall modification is as Fig. 3 As shown, it can be found that the rough pore-like structure similar to glass microtubes appears on the inner wall after modification, which increases the inner surface area.

Then the stainless steel microtube can be prepared in the same way as in Example 5 to produce the obtained Click marking reactor. The outer wall of the stainless steel microtube is equipped with an electric heating film, and after installing a sealing interface at both ends, it can be connected to the automatic synthesis system for use.

Example 7 Click-labeled synthesis of [ ¹⁸ F]fluoroethyltriazole-octreotide

Drying of ¹⁸ F ion reagents and reaction of ¹⁸ F labeled azide compounds: Transfer ¹⁸ F ions and water from a medical cyclotron to a receiving bottle. Start the automatic control system to pass ¹⁸ F ions and water to the anion exchange column (QMA), and enrich the ¹⁸ F ions on the QMA column, while the oxygen-enriched water is collected in the recovery bottle. Transfer 1 mL of K222/K ₂ CO ₃ in acetonitrile/water solution (K222, 15 mg/mL; K ₂ CO ₃ , 1.2 mg/mL) through the QMA column to elute ¹⁸ F ions, and collect 100 μL of the solution containing 100 μCi ¹⁸ F ions in the A nitrogen flow with a flow rate of 100 μL/min was injected into the glass microtube prepared in Example 2, and was adsorbed and spread on the tube wall to form a liquid film, and continued to feed a 100° C. hot nitrogen flow (flow rate 100 μL/min), so that The ¹⁸ F ion reagent was dried; then, 20 μL of ultra-dry acetonitrile was injected into the glass microtube, and a 100°C hot nitrogen stream (flow rate 100 μL/min) was blown to dryness, thereby obtaining a dry ¹⁸ F ion reagent. Inject 200 μL of an ultra-dry acetonitrile solution of azidoethyl trifluoromethanesulfonate into the glass microtube, seal it, heat to 120° C., and react for 5 minutes to obtain a ¹⁸ F-labeled azide compound reaction solution.

Click-labeled octreotide: inject the above-mentioned 200 μL ¹⁸ F-labeled azide compound reaction solution into the Click-labeled reactor produced in Example 5, seal it, heat to 120°C, and react for 10 minutes. The reaction process is as follows:

After the reaction solution is cooled, it passes through a series column composed of AG50/AG11A8 resin column, Al ₂ O ₃ column and C18 column, then transfers 10ml of water and passes through to the above separation column, collects the eluate, and filters it through a 0.22 μm filter membrane to obtain [ The Radio-TLC spectrum of ¹⁸ F]fluoroethyltriazole-octreotide solution is shown in FIG. 4 .

Synthesis of [ ¹⁸ F]fluoroethyltriazole-octreotide by Click labeling under conventional operation in comparative example

Drying of ¹⁸ F ion reagent and reaction of ¹⁸ F-labeled azide compound: same as Example 7.

Click labeling reaction: mix the above 200 μL ¹⁸ F-labeled azide reaction solution with 100 μL of a mixed solution containing octreotide (0.01mol/L), copper sulfate (0.001mol/L) and sodium ascorbate (0.001mol/L) modified by terminal alkyne , respectively injected into the microtube reactor according to the process set by the automatic program, sealed, heated to 120°C, and reacted for 10 minutes. After the reaction solution is cooled, it passes through a series column composed of AG50/AG11A8 resin column, Al ₂ O ₃ column and C18 column, then transfers 10ml of water and passes through to the above separation column, collects the eluate, and filters it through a 0.22 μm filter membrane to obtain [ ¹⁸ F]fluoroethyltriazole-octreotide solution.

Compared with the comparative example in Example 7, since the reaction reagent and the catalyst are fixed in the reactor in advance, as long as the labeled azide precursor is injected into the reactor, the Click labeling reaction can be carried out, and the operation of transferring other reagents is omitted. The volume of the reaction solution was reduced from 300 μL to 200 μL, which reduced the amount of post-purification treatment, and the increase in the concentration of the reactant accelerated the reaction speed. Therefore, the total time for the synthesis of [ ¹⁸ F]fluoroethyltriazole-octreotide was reduced from 50 min shortened to 30min.

The above-mentioned embodiment is only a preferred solution of the present invention, but it is not intended to limit the present invention. Various changes and modifications can be made by those skilled in the relevant technical fields without departing from the spirit and scope of the present invention. For example, although the synthesis of [ ¹⁸ F]fluoroethyltriazole-octreotide is taken as an example in the example, the glass microtube and the drying method using the microtube can also be used for the synthesis of other Click-labeled sugars and polypeptides. However, the specific conditions of different reagents and synthetic reactions are different and can be adjusted. Similarly, the glass microtube can also be replaced by the stainless steel reactor in Example 6. Moreover, the method for modifying the inner wall of glass and stainless steel pipes can also be adjusted according to the actual situation, as long as a similar modified surface can be prepared. Therefore, all technical solutions obtained by means of equivalent replacement or equivalent transformation fall within the protection scope of the present invention.

Claims (8)

1. A method utilizing a microreactor to carry out the Click marking reaction, characterized in that, the marked azide compound is injected into the microreactor, airtight, heated, and carried out the Click marking reaction; the microreactor main body is made of metal or glass A hollow tube body, the inner wall of the hollow tube is modified to form a rough and non-smooth surface; the inner wall of the hollow tube is dispersed and fixed with a Click marker precursor compound and a catalyst for a marking reaction. 2. the method utilizing microreactor to carry out Click mark reaction as claimed in claim 1, is characterized in that, described hollow pipe body two ends are equipped with the sealing interface that is used to connect external inlet and outlet pipeline; Described hollow A heating system for heating the pipe body is installed on the outer wall of the pipe. 3. the method utilizing microreactor to carry out Click labeling reaction as claimed in claim 1, is characterized in that, described hollow tube internal diameter is 1～3 mm, and length is 5～10 mm. 4. utilize microreactor as claimed in claim 1 to carry out the method for Click mark reaction, it is characterized in that, the preparation method of described microreactor, step is as follows: Inject the solution containing the Click marker precursor compound and the catalyst of the marking reaction into the hollow tube body of metal or glass, and the inner wall of the hollow tube is modified to form an uneven non-smooth surface; One end of the tube is fed with airflow, so that the solution is pushed by the airflow to spread on the inner surface of the tube wall to form a liquid film; keep the airflow continuously flowing until the solution is dry, so that the Click marker precursor compound and the catalyst for the labeling reaction are dispersed and fixed on the tube wall , to obtain a microreactor for the Click-labeled synthetic PET imaging agent. 5. utilize microreactor as claimed in claim 4 to carry out the method for Click labeling reaction, it is characterized in that, the inwall modification method of described hollow pipe body is: 1) After heating the mixed solution of cetyltrimethylammonium bromide and NaOH, add tetraethyl orthosilicate and stir to react; then fill the reaction solution into the cleaned metal or glass hollow tube; 2) Dry the hollow tube body filled with the reaction solution, and sinter the reaction solution after drying to complete the modification of the inner tube wall; 3) Take out the sintered hollow tube body, wash and dry it, and obtain the hollow tube body with the inner wall modified. 6. the method utilizing microreactor to carry out Click labeling reaction as claimed in claim 4, is characterized in that, the cleaning step of hollow tube body is: glass microtube is immersed in deionized water, ethanol, acetone and deionized water successively Ultrasonic cleaning; then immerse the glass microtube in a mixture of concentrated sulfuric acid and hydrogen peroxide for ultrasonic treatment, and then place it in the mixed solution; finally, ultrasonically clean the glass microtube several times in deionized water and dry it. 7. utilize microreactor as claimed in claim 1 to carry out the method for Click labeling reaction, it is characterized in that, described labeling reaction is ¹⁸ F labeling reaction; Described marked azide compound preparation method is: Inject the ¹⁸ F ionic reagent into the hollow tube body, and then pass airflow to one end of the hollow tube body, so that the ¹⁸ F ionic reagent spreads on the inner surface of the tube wall under the push of the airflow to form a liquid film; keep the airflow continuous Inject until the ¹⁸ F ionic reagent is completely dry and adsorbed on the inner surface of the tube wall; inject ultra-dry acetonitrile into the hollow tube again, and then continue to flow air into one end of the hollow tube until it is dry; then inject it into the hollow tube Inject an ultra-dry acetonitrile solution of azidoethyl trifluoromethanesulfonate, airtight, heat, and react to obtain ¹⁸ F-labeled azide compounds; the azidoethyl trifluoromethanesulfonate is . 8. The method for performing a Click labeling reaction as claimed in claim 7, wherein the length of the hollow tube is 10 cm, the inner diameter is 2 mm, and the injection volume of ¹⁸ F ion reagent is 100 μL, which is used for The flow rate of the airflow pushing the ¹⁸ F ion reagent is 100 μL/min.