CN109134381B - Microfluidic synthesis18Method of F-FMISO - Google Patents
Microfluidic synthesis18Method of F-FMISO Download PDFInfo
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- CN109134381B CN109134381B CN201810712241.7A CN201810712241A CN109134381B CN 109134381 B CN109134381 B CN 109134381B CN 201810712241 A CN201810712241 A CN 201810712241A CN 109134381 B CN109134381 B CN 109134381B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C23/00—Other surface treatment of glass not in the form of fibres or filaments
- C03C23/0095—Solution impregnating; Solution doping; Molecular stuffing, e.g. of porous glass
Abstract
The invention discloses a microfluidic synthesis18The method of F-FMISO relates to the fast and efficient preparation of Positron Emission Tomography (PET) imaging agent. The invention is characterized in that the inner wall of the microtube is modified and the microtube is quickly dried18F ion reagent, and is completed in microtube18F substitution labeling and hydrolysis reaction. By modifying the inner wall of the microtube to increase the adsorption area, the solution is injected into the microtube18F reagent solution is spread on the pipe wall to form a liquid film under the push of air flow, so that the evaporation area is increased, and meanwhile, hot air flow can conveniently pass through the hollow pipeline, thereby realizing quick drying, and the adsorption effect of the pipe wall can prevent the dried liquid film18F reagent is agglomerated and blown off, which is beneficial to fully mixing with the reaction reagent and is sequentially finished in the same microtube18F replaces the marking and hydrolyzes the two-step synthesis reaction, shortens the total synthesis operation time, and improves18F-FMISO synthesis yield.
Description
Technical Field
The invention relates to a method for synthesizing a positron radiopharmaceutical, in particular to an imaging agent for hypoxia tissue Positron Emission Tomography (PET) diagnosis18F-Fluomidazole (F-Fluomidazole)18F-FMISO).
Background
PET (positron emission tomography) is a new noninvasive nuclear medicine molecular imaging technology, which utilizes the principle of radioactive tracing and uses different radioactive isotope labeled imaging agents (PET imaging agents) to highly sensitively display the changes of physiology and biochemistry of tissues and organs. The imaging agent is the key of PET and nuclear medicine, and the imaging agent adopted by PET is radionuclide11C、13N、15O、18Since the half-life of the radionuclide used in the labeled drugs such as F is short and it is impossible to store the labeled drugs as commercial products, it is necessary to perform PET imagingThe PET imaging agent is prepared by labeling synthesis on site for producing radionuclide as soon as possible and is used nearby in situ within a limited time. The rapid ultramicro synthesis preparation has extremely high requirements on the process, equipment and automation control thereof because the amount of the developer used each time is extremely small (generally equivalent to the order of nanomole) and the synthesis and purification time is required to be as short as possible.
The synthesis of the PET imaging agent in the microreactor by utilizing the principle of the microfluidic technology has obvious advantages. Firstly, the micro-reactor synthesis system can control a very small reaction volume, so that the relative concentration of reactants is high, the reaction rate is high, the usage amount of a substrate can be greatly reduced, and the purification difficulty is reduced. Secondly, the synthesis time can be greatly shortened, and the production as required can be really realized. Thirdly, the radiochemical yield of the reaction can be obviously improved. Fourthly, the reaction system is small, the protection cost is reduced, and the safety is improved. Fifth, the reaction chip has strong function expansibility, and can fully meet the scientific research requirements.
Nitroimidazole derivatives are currently the most studied hypoxic tissue imaging agents. Therein18F-Fluomidazole (F-Fluomidazole)18F-FMISO) was the first hypoxic tissue imaging agent used in clinical diagnostic studies. It has been used for hypoxic imaging studies of tumors, cardiovascular and cerebrovascular vessels. Due to the fact that18F-FMISO has wide application in clinic and research, so that the F-FMISO can be synthesized quickly and efficiently18F-FMISO has become a hotspot for research. In general use18The F-FMISO synthetic route is synthesized by taking 1- (2 '-nitro-1' -imidazolyl) -2-O-tetrahydropyranyl-3-O-tosyl propylene glycol (NITTP) as a precursor through two steps of nucleophilic fluorination and acidic hydrolysis18F-FMISO, and the crude product can be used after being purified and filtered by a sterile membrane. Before the synthesis reaction, the synthesis reaction is firstly generated by a cyclotron18Enriching the F-oxygen-enriched water solution by a QMA column, and collecting the obtained product18The F ion reagent aqueous solution can be used after dehydration and drying18And F, labeling and reacting. The existing thermal evaporation dehydration drying technology has small evaporation area, slow drying speed, long time consumption and drying18The F reagent is agglomerated and blown off, which is not favorable for fast mixing and filling with the labeled substrateAnd (4) carrying out reaction. Similar agglomeration and blow-off phenomena can also occur when the intermediate is blown dry, which is detrimental to rapid mixing and complete reaction of reactants and results in product loss. In addition, there are existing18The fluorination and hydrolysis during the F-FMISO synthesis are carried out in two reactors, respectively, and the transfer of intermediates takes time. The invention is carried out in the same micro-tube reactor in sequence18F ion reagent is dried,18F substitution labeling and hydrolysis reaction, shortening18Total synthesis time of F-FMISO.
The reaction equation is as follows:
disclosure of Invention
In that18F-labeled synthetic PET imaging agent18In the process of F-FMISO, the18F ion reagent is dried quickly, and the existing thermal evaporation dehydration drying technology has small evaporation area, low drying speed, long time consumption and dry18The reagent F is agglomerated and blown away, which is not favorable for rapid mixing and full reaction with the labeled substrate. Similar agglomeration and blow-off phenomena can also occur when the intermediate is blown dry, which is detrimental to rapid mixing and complete reaction of reactants and results in product loss. In addition, there are existing18The fluorination and hydrolysis during the F-FMISO synthesis are carried out in two reactors, respectively, and the transfer of intermediates takes time. The object of the present invention is to overcome the disadvantages of the prior art and to provide a microfluidic synthesis18Method of F-FMISO and carried out in microtubes in sequence18F ion reagent is dried,18F replaces the mark and the hydrolysis reaction, thereby simplifying the operation and shortening the total synthesis time.
The technical scheme adopted by the invention is as follows:
microtubule synthesis18The method of F-FMISO, the synthetic reaction involved in this method is carried on in the inner wall modified glass microtube, this glass microtube is hollow tubular, and the tube body inner wall is modified and formed the rugged non-smooth surface; the synthetic method comprises the following steps:
1) will be provided with18Introducing F ion reagent into the glass micro-tube, and introducing airflow to one end of the glass micro-tube to ensure that18F ion reagent is spread on the inner surface of the tube wall under the pushing of airflow to form a liquid film; then keeping the air flow continuously until18F ion reagent is completely dried and adsorbed on the inner surface of the pipe wall; injecting the ultra-dry acetonitrile into the glass micro-tube again, and continuously introducing airflow into one end of the glass micro-tube until the acetonitrile is evaporated and dried to obtain the dried product18An F ion reagent;
2) injecting an ultra-dry acetonitrile solution of a precursor 1- (2 '-nitro-1' -imidazolyl) -2-O-tetrahydropyranyl-3-O-tosyl propanediol (NITTP) into the inner wall of the reactor to which the dried substance is attached18Sealing and heating both ends of the glass microtube with the F ion reagent to complete18F substitution labeling reaction; then continuously introducing airflow into one end of the glass micro-tube until acetonitrile is evaporated and dried;
3) injecting a hydrochloric acid solution into the glass micro-tube, sealing two ends of the glass micro-tube and heating to complete hydrolysis reaction;
4) separating and purifying the hydrolysate in the glass micro-tube to obtain18F-FMISO solution.
In the invention, the uneven non-smooth inner surface means that the inner wall of the glass micro-tube is uneven, and the surface of the glass micro-tube is provided with uneven pores or burrs, which is different from the conventional smooth and flat inner wall of the glass micro-tube. The inner surface may be modified by deposition of silica or the like. The glass microtube has increased adsorption surface area by modifying the inner wall, and is injected into the microtube18The F reagent solution can be spread on the tube wall to form a liquid film under the pushing of the air flow, the evaporation area is increased, the hot air flow can conveniently pass through the hollow pipeline, the rapid drying is realized, and the adsorption effect of the tube wall can prevent the dried liquid film18The reagent F is agglomerated, which is beneficial to fully mixing with the reaction reagent,18after the F substitution labeling reaction, the solvent is dried by hot air flow, and the hydrolysis reaction can be carried out by injecting hydrochloric acid aqueous solution, so that the synthesis time is saved, and the synthesis yield is improved. The glass microtube can be used in cooperation with a sealing interface, and seals with access passages are additionally arranged at two ends of the microtubeThe interface can be used as a reactor, and can be sequentially carried out in the microtubes18F ion reagent is dried,18F replaces the mark and the hydrolysis reaction, thereby simplifying the operation and shortening the total synthesis time.
Preferably, the18The F ion reagent is K222/K2CO3Elution of the acetonitrile/water solution previously enriched18F ion to obtain a solution. K222/K2CO3The acetonitrile/water solution of (A) is prepared by dissolving K222 and K in acetonitrile and water2CO3The resulting mixed solution.
Preferably, the inner diameter of the glass micro-tube is 1-3 mm, and preferably 1.5-2.5 mm. The inner diameter of the glass micro-tube can influence the forming effect of the liquid film, and the too large or too small inner diameter can cause the liquid to form an even liquid film on the inner wall, so that the drying effect when the gas is blown in is not good. Within this inner diameter range, the liquid film formation effect is good.
Preferably, the preparation method of the glass microtube is as follows:
a) heating a mixed solution of hexadecyl trimethyl ammonium bromide and NaOH, adding tetraethoxysilane, and stirring for reaction; then filling the reaction solution into the cleaned hollow glass micro-tube;
b) drying the glass microtube filled with the reaction liquid, and sintering after the reaction liquid is dried to finish the modification of the inner tube wall;
c) taking out the sintered glass microtubes, cleaning and drying to obtain the glass microtubes for drying18Glass microtubes of F ion reagents.
The inner wall of the glass micro-tube prepared by the method has an uneven pore structure, the surface area is large, and a larger ion reagent spreading area can be provided. And the inner surface of the glass micro-tube is rough and non-smooth, so that the ion reagent can be trapped to a certain degree and prevented from being blown out of the glass micro-tube under the driving of airflow. Also, the glass microtube can be used as a reactor, and the intermediate of the reaction can be dried in the same way and then subjected to subsequent reaction.
Further, in the step a), the cleaning step of the glass microtube is as follows: sequentially immersing the glass microtube into deionized water, ethanol, acetone and deionized water for ultrasonic cleaning; immersing the glass micro-tube into a mixed solution of concentrated sulfuric acid and hydrogen peroxide for ultrasonic treatment, and standing in the mixed solution; and finally, ultrasonically cleaning the glass micro-tube in deionized water for several times, and drying.
Preferably, the method for separating and purifying the hydrolysate comprises the following steps: transferring the hydrolyzed solution to AG50/AG11A8 resin column, Al2O3The column is serially connected with C18 column, and is eluted with water for injection, and the eluate is filtered to obtain the final product18F-FMISO solution.
Preferably, the gas flow introduced into the glass microtube for drying is a heated hot gas flow. The hot air flow can be accelerated18F, drying the ionic reagent and removing the reaction solvent. Of course, for pushing18The gas stream in which the F ion reagent spreads into a liquid film may not necessarily require a hot gas stream.
Further, the gas flow is an inert gas flow, preferably a nitrogen gas flow, to maintain an inert atmosphere within the tube.
Preferably, the single injection amount of the reagent in the glass microtube is as follows: all injected reagents can spread on the inner surface of the tube wall to form a liquid film under the pushing of the airflow and cannot be blown out of the glass microtube. When the single injection amount is too large, the liquid film cannot be completely spread on the inner surface of the tube wall, and the liquid film is blown out of the glass micro-tube by the airflow, so that the accuracy of a subsequent test is influenced. For a glass microtube of a given size, the optimal single injection amount can be determined experimentally. In the present invention, the reagent to be injected into the glass microtube comprises18The F ion reagent, the ultra dry acetonitrile solution of the precursor NITTP, and the salt solution should be kept as small as possible without excess.
Preferably, the length of the glass microtube is 10cm, the inner diameter is 2mm,18the injection amount of the F ion reagent is 100 mu L, and the flow rate of the air flow introduced into the glass micro-tube is 100 mu L/min. Synthesized under the size, flow rate and injection quantity of the glass microtube18The yield of F-FMISO radio TLC can reach 85%, and the radiochemical purity is more than 95%.
The invention increases the non-smooth adsorption area by modifying the inner wall of the microtube, so that the glass microtube can be used for drying18F ion reagent reactor. And, further based on the microtube, sequentially performing in the microtube18F substitutes for marking and hydrolysis reaction, saves synthesis time and improves18F-FMISO synthesis yield. The glass microtube adopted in the invention has larger surface area of the inner tube wall, the reagent solution injected into the microtube is intercepted by the uneven tube wall under the pushing of airflow to form a liquid film, the liquid film is continuously evaporated and dried by the continuous introduction of airflow, and the adsorption effect of the tube wall can prevent the dried liquid film18F reagent and18f substitutes the agglomeration and blowing-off of the marked intermediate, so that the intermediate is favorably and fully mixed with a reaction reagent, and the product loss is avoided. Thus, for the synthesis18In the reaction of F-FMISO, evaporation drying and closed heating are carried out for many times in the synthesis process, so that the glass microtube can well complete various synthesis processes. And the glass microtube has low cost and can be used at one time, thereby avoiding cross contamination when different developers are synthesized.
Drawings
FIG. 1 is an SEM image of the surface topography of the inner wall modified microtube;
FIG. 2 is an SEM image of a longitudinal cut of an inner wall modified microtube;
FIG. 3 is a schematic diagram of a glass microtubule synthesis system.
Detailed Description
The present invention will be further described in detail by the following examples, which are not intended to limit the scope of the present invention.
Example 1 preparation of inner wall-modified glass microtubes
Sequentially immersing a glass micro-tube with the length of 10cm and the inner diameter of 1.5mm into deionized water, ethanol, acetone and deionized water for ultrasonic cleaning for 10min, immersing into a concentrated sulfuric acid-hydrogen peroxide mixed solution (volume ratio is 1:1) for ultrasonic treatment for 15min, standing for 1.5h, immersing into deionized water for ultrasonic cleaning for 10min, repeating the ultrasonic treatment twice with the deionized water, and drying in an oven at 120 ℃ for 2h for later use.
In a round flask0.408g of hexadecyltrimethylammonium bromide was added, 200mL of deionized water and 1.2mL of a 2mol/L NaOH solution were added, the mixture was heated to 70 ℃ with stirring, 2mL of Tetraethylorthosilicate (TEOS) was added, and the mixture was reacted for 1 hour with stirring. The reaction solution was filled in a glass microtube and dried in an oven at 120 ℃ for 1 h. Sintering the mixture for 2 hours in a muffle furnace at 500 ℃ and taking out the mixture. Immersing in deionized water, ultrasonic cleaning for 10min, drying in an oven at 120 deg.C for 2h, cooling, and taking out. The two ends of the glass micro-tube are provided with sealing interfaces, and the glass micro-tube can be connected into an automatic synthesis system for butt joint after the outer tube wall is provided with a heating system18And F, drying the ionic reagent.
The SEM image of the surface topography of the inner wall modified microtube prepared in this example is shown in fig. 1, and the SEM image of the longitudinal cut of the inner wall modified microtube is shown in fig. 2. As is obvious from the figure, the modified inner wall surface of the microtube has the rugged porous rough shape, and the surface area of the microtube is obviously improved compared with the surface of the conventional smooth tube wall. When in use18When the F ion reagent is pushed by the airflow to flow in the glass micro-tube, the reagent can continuously permeate into pores on the surface, and a liquid film is formed on the surface of the tube wall under the action of surface tension, so that the reagent is uniformly spread finally, and a channel for flowing of the blowing airflow is still reserved in the center of the micro-tube. Therefore, the air flow can continuously carry out rapid evaporation drying on the liquid film at the periphery of the channel. Moreover, since the liquid film is uniformly spread, it dries out18The F reagent is also uniformly adsorbed on the surface of the tube wall, and the agglomeration phenomenon can not occur. Subsequently injecting other reagents required by the reaction into the microtube, namely drying the microtube18Dissolving out the reagent F; of course, the glass microtube can be directly used as a reactor, and other reagents can be injected into the microtube to react in the inner cavity of the microtube.
Example 2 preparation of inner wall-modified glass microtubes
This example is different from example 1 only in that the glass microtube has dimensions of 10cm long and 2mm inner diameter; other pretreatment and inner wall modification methods are the same. The modified tube wall morphology in this example is similar to that of example 1.
Example 3 preparation of inner wall modified glass microtubes
This example is different from example 1 only in that the glass microtube has dimensions of 10cm long and 2.5mm inner diameter; other pretreatment and inner wall modification methods are the same. The modified tube wall morphology in this example is similar to that of example 1.
In the present invention, the glass microtube with the modified tube wall is dried18The operation steps of the F ion reagent are as follows:
to be delivered from a medical cyclotron18The F ions and water pass into a receiving bottle. Starting the automatic control system to control18The F ions and water are passed to an anion exchange column (QMA) and18the F ions were enriched on the QMA column while the oxygen-enriched water was collected in a recovery bottle. Transfer 1mL K222/K2CO3Acetonitrile/water solution (K222, 15 mg/mL; K2CO31.2 mg/mL; the volume ratio of acetonitrile to water in the solvent is 1:1) is eluted by a QMA column18F ion to obtain18And F, an ionic reagent. Of course, here18The preparation process of the F ion reagent is only for better understanding by those skilled in the art, and may be adjusted according to the actual situation, and is not limited.
To be dried18Injecting F ion reagent into the glass micro tube, and introducing airflow to one end of the glass micro tube to make the glass micro tube18F ion reagent is spread on the inner surface of the tube wall under the pushing of airflow to form a liquid film; then keeping the air flow continuously until18F ion reagent is completely dried and adsorbed on the inner surface of the tube wall. The drying gas stream is preferably a hot nitrogen stream. Then the glass microtube can be used as a reactor, and reaction precursors are injected for carrying out18F fluoro-labeling reaction to generate intermediate, and hydrolyzing with hydrochloric acid to synthesize18F-FMISO。
When the glass micro-tube is used, the two ends of the glass micro-tube can be additionally provided with sealing interfaces, and then the glass micro-tube is connected into an automatic synthesis system through a connecting pipeline. A schematic diagram of the use state of the glass microtube is shown in figure 3,18the F ion reagent and other reagents can be injected into the connecting pipeline in advance through a switching valve in the synthesis system in a switching mode, and then the F ion reagent and other reagents are pushed by air flow and injected into the inner cavity of the glass microtube which is vertically placed through the connecting pipeline through the sealed interface. The flow velocity of the air flow is not suitable to be too large or too small in the pushing process of the air flow, otherwiseThe film forming effect of the reagent tends to be poor. In practice, the optimum flow rate should be determined by experiment according to the amount of reagent added and the size of the glass microtube. When the reaction is required to be carried out in the inner cavity of the microtube, the ventilation can be stopped, the sealing in the microtube is kept, and the temperature can be adjusted by a heating system outside the microtube.
The present invention will be further described in detail by the following examples, which are not intended to limit the scope of the present invention.
Example 4 drying of glass microtubes prepared in example 118F ion reagent and synthesis18F-FMISO
18Production of F ion reagent: by using18O(p，n)18F Nuclear reaction, using 2.4mL volume of H2O[18O]Continuously bombarding a 95 percent oxygen-enriched water target on a cyclotron by using a proton beam of 11MeV and 35 mu A for 30-60 min to obtain a target required by the reaction18F ion oxygen-enriched water solution.
18Separation and enrichment of F ion reagent: will be provided with18Passing the F-oxygen-rich aqueous solution through QMA column, and purifying18The F ions were enriched on the QMA column while the oxygen-enriched water was collected in a recovery bottle. Starting the automatic control system to control18The F ions and water are passed to an anion exchange column (QMA) and18the F ions were enriched on the QMA column while the oxygen-enriched water was collected in a recovery bottle.
18Drying of F ion reagent and18f, labeling reaction: transfer 1mL K222/K2CO3Acetonitrile/water solution (K222, 15 mg/mL; K2CO31.2mg/mL) was eluted through a QMA column18F ion, 100. mu.L of the collected solution containing 100. mu. Ci18Injecting the F ion reagent into the glass micro-tube prepared in the example 1 under the push of nitrogen flow with the flow rate of 100 mu L/min, adsorbing the F ion reagent on the tube wall to spread and form a liquid film, and continuously introducing hot nitrogen flow (with the flow rate of 100 mu L/min) at the temperature of 100 ℃ for blowing for 3min to ensure that18F, drying the ionic reagent; then 20. mu.L of ultra-dry acetonitrile was injected into the glass microtube, and a stream of 100 ℃ hot nitrogen (flow rate 100. mu.L/min) was passed through to blow for 2min until dry. Injecting 100 μ L of ultra-dry acetonitrile solution (2mg/mL) of precursor NITTP, heating to 120 deg.C, sealing for reaction for 5min,a stream of nitrogen was passed through the reactor while hot (flow rate 100. mu.L/min) to remove the acetonitrile.
And (3) hydrolysis reaction: to pass through18And (3) injecting 100 mu L of 1M HCl solution into the glass microtube for the F labeling reaction, heating to 110 ℃, and carrying out closed reaction for 5min to finish the hydrolysis reaction.
Separation and purification: transferring the hydrolyzed solution to AG50/AG11A8 resin column, Al2O3Separating with series column composed of column and C18 column, transferring 5mL injection water, eluting with the series column, collecting eluate, and filtering the eluate with 0.22 μm filter membrane18F-FMISO solution. Obtained by18F-FMISO showed greater than 95% radiochemical purity and 75% radiochemical yield.
Example 5 drying of glass microtubes prepared using example 218F ion reagent and synthesis18F-FMISO
This example is compared with example 4, and differs therefrom only in that the glass microtube therein is replaced with the glass microtube prepared in example 2, and other methods and parameters remain the same as in example 4.
Obtained in this example18F-FMISO showed greater than 95% radiochemical purity and 85% radiochemical yield.
Example 6 drying of glass microtubes prepared using example 318F ion reagent and synthesis18F-FMISO
This example is compared with example 4, and differs therefrom only in that the glass microtube therein is replaced with the glass microtube prepared in example 3, and other methods and parameters remain the same as in example 4.
Obtained in this example18F-FMISO showed greater than 95% radiochemical purity and 57% radiochemical yield.
Example 7 drying of glass microtubes prepared using example 218F ion reagent and synthesis18F-FMISO
This example is different from example 5 only in that it will be used for pushing18The flow rate of the F ion reagent was adjusted to 50. mu.L/min, and the other methods and parameters were the same as in example 5.
This exampleObtained by18F-FMISO showed greater than 95% radiochemical purity and 55% radiochemical yield.
Example 8 drying of glass microtubes prepared using example 218F ion reagent and synthesis18F-FMISO
This example is different from example 5 only in that it will be used for pushing18The flow rate of the F ion reagent was adjusted to 150. mu.L/min, and the other methods and parameters were the same as in example 5.
Obtained in this example18F-FMISO showed greater than 95% radiochemical purity and a 50% radiochemical yield.
Comparative example glass microtube drying with the same inner diameter (2mm) as in example 2 and prepared without modification of inner wall18F ion reagent and synthesis18F-FMISO
Compared with the example 5, the difference of this example is that the glass microtube is replaced by the glass microtube which is the same as the original glass microtube in the example 2 and has no inner wall modification (the length is 10cm, the inner diameter is 2mm), and after the sealing interfaces are additionally arranged at the two ends, the glass microtube is directly connected into an automatic synthesis system for use. The other methods and parameters remained the same as in example 4.
Obtained in this example18F-FMISO showed greater than 95% radiochemical purity and 45% radiochemical yield.
Drying in microtubes as described above18F ion reagent and synthesis18In examples 4, 5 and 6 of F-FMISO, the factors of the diameter of the microtubules are different, and the results of the examples are obtained18RadioTLC yield and drying of F-FMISO18The mass of the F ion reagent is directly related. In comparison, example 5 is optimal, resulting in18F-FMISO showed radiochemical purity of greater than 95% and an radiochemical yield of 85%, corresponding to the parameters: the length of the glass micro-tube is 10cm, the inner diameter is 2mm,18the injection amount of the F ion reagent is 100 mu L for driving18The flow rate of nitrogen flow for the F ion reagent was 100. mu.L/min. Prepared by the method18F-FMISO took 35 minutes. Example 5 comparative example, drying with inner wall having the same inner diameter (2mm) as in example 5 without modifying the microtube18F ionReagents and Synthesis18F-FMISO, the radio TLC yield was greatly reduced to 45%. Shows that the inner wall of the microtube is modified to be beneficial to drying18And F, an ionic reagent. In examples 5, 7 and 8, only the pushing was performed18The nitrogen flow rate factors for injecting the F ion solution into the microtube are different, and example 5 is optimal, which shows that under the nitrogen flow pushing of the proper flow rate,18the F ion solution is uniformly spread on the inner wall of the microtube, which is beneficial to drying18F ion reagent and subsequent18F, carrying out labeling reaction. Because the reaction is carried out in the same micro-tube reactor in sequence18F ion reagent is dried,18F replaces the mark and the hydrolysis reaction, thereby shortening the time of the whole synthesis process and improving the synthesis yield.
The above-described embodiments are merely preferred embodiments of the present invention, which should not be construed as limiting the invention. Various changes and modifications can be made by one of ordinary skill in the pertinent art without departing from the concept and scope of the present invention. For example, although the examples are illustrated by synthesis18F-FMISO is described as an example, but the glass microtube and the drying method using the microtube can be used for other purposes18Drying of F ion reagents, synthesis of labelled intermediates, e.g.18F-FDG. However, the reagents and conditions of the synthesis reaction may be varied and adjusted. Similarly, the preparation method of the glass microtube can be adjusted according to the actual conditions as long as a similar modified surface can be prepared. Therefore, the technical scheme obtained by adopting the mode of equivalent replacement or equivalent transformation is within the protection scope of the invention.
Claims (10)
1. Microfluidic synthesis18Method of F-FMISO, characterized in that: the synthesis reaction is carried out in a glass micro-tube with a modified inner wall, the glass micro-tube is in a hollow tubular shape, and the inner wall of the tube body is modified to form an uneven and non-smooth surface; the method comprises the following steps:
1) will be provided with18Injecting F ion reagent into the glass micro tube, and introducing airflow to one end of the glass micro tube to make the glass micro tube18F ion reagent is pushed by airflow to be on the inner surface of the pipe wallSpreading to form a liquid film; then keeping the air flow continuously until18F ion reagent is completely dried and adsorbed on the inner surface of the pipe wall; injecting the ultra-dry acetonitrile into the glass micro-tube again, and continuously introducing airflow into one end of the glass micro-tube until the acetonitrile is evaporated and dried to obtain the dried product18An F ion reagent;
2) injecting an ultra-dry acetonitrile solution of a precursor 1- (2 '-nitro-1' -imidazolyl) -2-O-tetrahydropyranyl-3-O-tosylpropylene glycol into the inner wall of the reactor, wherein the dried acetonitrile solution adheres to the inner wall18Sealing and heating both ends of the glass microtube with the F ion reagent to complete18F substitution labeling reaction; then continuously introducing airflow into one end of the glass micro-tube until acetonitrile is evaporated and dried;
3) injecting a hydrochloric acid solution into the glass micro-tube, sealing two ends of the glass micro-tube and heating to complete hydrolysis reaction;
4) separating and purifying the hydrolysate in the glass micro-tube to obtain18F-FMISO solution;
the single injection amount of the reagent in the glass microtube is required to satisfy the following conditions: all injected reagents can spread on the inner surface of the tube wall to form a liquid film under the pushing of the airflow and cannot be blown out of the glass microtube.
2. Microfluidic synthesis according to claim 118Method of F-FMISO, characterized in that: said18The F ion reagent is K222/K2CO3Elution of the acetonitrile/water solution previously enriched18F ion to obtain a solution.
3. Microfluidic synthesis according to claim 118Method of F-FMISO, characterized in that: the inner diameter of the glass micro-tube is 1-3 mm.
4. Microfluidic synthesis according to claim 118Method of F-FMISO, characterized in that: the preparation method of the glass microtube comprises the following steps:
a) heating a mixed solution of hexadecyl trimethyl ammonium bromide and NaOH, adding tetraethoxysilane, and stirring for reaction; then filling the reaction solution into the cleaned hollow glass micro-tube;
b) drying the glass microtube filled with the reaction liquid, and sintering after the reaction liquid is dried to finish the modification of the inner tube wall;
c) taking out the sintered glass microtubes, cleaning and drying to obtain the glass microtubes for drying18Glass microtubes of F ion reagents.
5. Microfluidic synthesis according to claim 418Method of F-FMISO, characterized in that: in the step a), the cleaning step of the glass microtube is as follows: sequentially immersing the glass microtube into deionized water, ethanol, acetone and deionized water for ultrasonic cleaning; immersing the glass micro-tube into a mixed solution of concentrated sulfuric acid and hydrogen peroxide for ultrasonic treatment, and standing in the mixed solution; and finally, ultrasonically cleaning the glass micro-tube in deionized water for several times, and drying.
6. Microfluidic synthesis according to claim 118Method of F-FMISO, characterized in that: the method for separating and purifying the hydrolysate comprises the following steps: transferring the hydrolysate to AG50/AG11A8 resin column, Al2O3Column in series with C18 column, washing column with water for injection, and filtering eluate to obtain the final product18F-FMISO solution.
7. Microfluidic synthesis according to claim 118Method of F-FMISO, characterized in that: the air flow introduced into the glass microtube for drying is heated hot air flow.
8. Microfluidic synthesis according to claim 1 or 718Method of F-FMISO, characterized in that: the gas flow is inert gas flow.
9. Microfluidic synthesis according to claim 818Method of F-FMISO, characterized in that: the gas flow is nitrogen flow.
10. As in claimMicrofluidic synthesis as described in claim 118Method of F-FMISO: the length of the glass micro-tube is 10cm, the inner diameter is 2mm,18the injection amount of the F ion reagent is 100 mu L, and the flow rate of the air flow introduced into the glass micro-tube is 100 mu L/min.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891687A (en) * | 2009-05-19 | 2010-11-24 | 中国医学科学院北京协和医院 | Method for synthesizing hypoxia imaging agent 18F-FMISO |
| CN104445215A (en) * | 2014-11-05 | 2015-03-25 | 上海大学 | Preparation method of hollow silicon dioxide nanomaterial |
| CN105170049A (en) * | 2015-09-11 | 2015-12-23 | 中国石油化工股份有限公司 | Method of preparing hydrogen peroxide by utilizing microchannel reactor |
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| WO2008091694A2 (en) * | 2007-01-23 | 2008-07-31 | Siemens Medical Solutions Usa, Inc. | Fully-automated microfluidic system for the synthesis of radiolabeled biomarkers for positron emission tomography |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891687A (en) * | 2009-05-19 | 2010-11-24 | 中国医学科学院北京协和医院 | Method for synthesizing hypoxia imaging agent 18F-FMISO |
| CN104445215A (en) * | 2014-11-05 | 2015-03-25 | 上海大学 | Preparation method of hollow silicon dioxide nanomaterial |
| CN105170049A (en) * | 2015-09-11 | 2015-12-23 | 中国石油化工股份有限公司 | Method of preparing hydrogen peroxide by utilizing microchannel reactor |
Non-Patent Citations (2)
| Title |
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| Microfluidic single vessel production of hypoxia tracer 1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole([18F]-FMISO);Daniel L. Yokell等;《Applied Radiation and Isotopes》;20120607;第70卷(第10期);第2313-2316页 * |
| 快速自动化合成18F-FMISO及其质量控制;李琳等;《核化学与放射化学》;20101231;第32卷(第6期);第354-361页 * |
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