CN108786677A - A kind of microreactor of Click labelled synthesis PET developers and its preparation and reaction method - Google Patents
A kind of microreactor of Click labelled synthesis PET developers and its preparation and reaction method Download PDFInfo
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- CN108786677A CN108786677A CN201810550699.7A CN201810550699A CN108786677A CN 108786677 A CN108786677 A CN 108786677A CN 201810550699 A CN201810550699 A CN 201810550699A CN 108786677 A CN108786677 A CN 108786677A
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00002—Chemical plants
- B01J2219/00004—Scale aspects
- B01J2219/00011—Laboratory-scale plants
- B01J2219/00013—Miniplants
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00819—Materials of construction
- B01J2219/00831—Glass
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention discloses a kind of microreactor of Click labelled synthesis PET developers and its preparation and reaction methods.By modifying micro-pipe inner wall to increase its specific surface area and adsorption capacity, the catalyst of marker precursor compound and Click label reactions is fixed and dispersed within reactor wall, after installing heating film and standard interface additional, micro- reaction synthesis system is accessed and can be used.Since precursor agents to be marked and catalyst being fixed in the reactor in advance, as long as marked azido compound injection reactor can be carried out Click reactions when synthesis, it eliminates the operation of transfering reagent and pipeline is avoided to pollute, the operating quantity for reducing post-reaction treatment, so as to shorten the synthetic operation time.The reactor processing cost is low, can be disposable, cross contamination when avoiding synthesizing different developers.The synthesis that other Click mark sugar and polypeptide can be carried out using the reactor.
Description
Technical field
The present invention relates to a kind of microreactor of Click labelled synthesis PET developers, which can be used for synthesizing same
The plain labeled PET tracers in position.
Background technology
PET (positron emission tomography, positron emission tomography) is a kind of completely new noninvasive
Nuclear medicine molecular image technology, it utilizes the principle of radioactive tracer, is imaged according to different labelled with radioisotope is used
Agent (PET developers), the change of highly sensitive display histoorgan physiology, biochemical aspect.Developer is PET and nuclear medicine
Key, developer used by PET is to use radionuclide11C、13N、15O、18The drug of the labels such as F (hydrogen-like), puts because used in
The half-life short of penetrating property nucleic, it is impossible to storage is purchased as commodity, so when carrying out PET imagings, it is necessary to be radiated in production
Property labelled synthesis prepares PET developers as early as possible at nucleic scene, and locally used within the time of restriction.Due to using every time
Developer dosage it is atomic (generally corresponding to nearly nanomole magnitude), and require synthesis, purifying take it is short as possible therefore this
The requirement that quick ultramicron is synthetically prepared to technique, equipment and its automation control is high.
1, the 3- Dipolar Cycloadditions of nitrine and alkynes are that the representativeness in click chemistry (Click Chemistry) is anti-
It answers, there is reaction speed fast, mild condition, easy to operate, reaction selectivity and yield high advantage insensitive to oxygen and water.
Since the triazole linking group of generation has good biocompatibility, click chemistry prothetic group is made to mark (Click
Labeling) strategy is widely applied in PET developers and biomarker synthesis, and the nitrine of copper catalysis and Terminal Acetylenes
Cycloaddition reaction (CuAAC) be the most classical most ripe method being applied in molecular imaging.
The synthesis that PET developers are carried out in microreactor has significant advantage.First, microreactor synthesis system can be with
Very small reaction volume is manipulated, therefore the relative concentration of reactant is high, reaction rate is fast, so as to substantially reduce substrate
Usage amount reduces the difficulty of purifying.Secondly, it can greatly shorten generated time, really realize production on demand.Third can be shown
Write the putting yield for improving reaction.4th, reaction system is small, reduces protection cost, improves safety.5th, reaction chip work(
Energy autgmentability is strong, can fully meet scientific research needs.
Microreactor currently used for synthesizing PET developers mainly has micro-fluidic chip reactor, the reaction of continuous flow micro-pipe
Several classes such as device and micro- pond type reactor.In the building-up process controlled by program, the solution of the reagent and catalyst of reaction is participated in
Inject reactor by pipeline, elapsed time increases the volume and operating quantity of reaction system, and extend be synthetically prepared when
Between.
Invention content
In existing program controls building-up process, the reagent of reaction and the solution of catalyst are participated according to synthesis technology stream
Journey injects reactor by pipeline, elapsed time increases the volume and operating quantity of reaction system, and extends and be synthetically prepared
Time.The purpose of the present invention is overcome the deficiencies of the prior art and provide a kind of micro- reaction of Click labelled synthesis PET developers
Device, the reactor can be used for synthetic isotope labeled PET tracers.
The technical solution that the present invention specifically uses is as follows：
The microreactor of Click labelled synthesis PET developers, the microreactor main body are the hollow tube of metal or glass
Body, the hollow tube inner wall form rough non-smooth surface by modification；Disperse to fix on hollow tube inner wall
There is the catalyst of Click markers precursor compound and label reaction.Due in advance trying precursor to be marked in the microreactor
Agent and catalyst are fixed in the reactor, as long as can carry out marked azido compound injection reactor when synthesis
Click label reactions, eliminate the operation of transfering reagent and pipeline are avoided to pollute, reduce the operating quantity of post-reaction treatment, from
And shorten the synthetic operation time.The reactor processing cost is low, can be disposable, is handed over when avoiding synthesizing different developers
Fork pollution.
In the present invention, the glass-micropipe inner wall that rough non-smooth inner surface refers to from routine is smooth is different,
The glass-micropipe inner wall of the present invention is out-of-flatness, and surface has irregular hole or burr.The inner surface can pass through deposition
The methods of silica is modified.Such pipeline increases absorption internal surface area by modifying inner wall, injects the examination in micro-pipe
Agent solution can be sprawled to form liquid film under air-flow promotion in tube wall, increase disengagement area, be convenient for thermal current from hollow tube road
Pass through, to realize that rapid draing, active principle can be absorbed and fixed on tube wall.And this kind of fixed form can prevent from doing
Reagent conglomeration after dry, the reaction reagent for being conducive to and being subsequently implanted into are sufficiently mixed, and save generated time, are improved synthesis and are received
Rate.
Preferably, the hollow tube both ends are equipped with the sealed interface for connecting external turnover pipeline.
Preferably, the hollow tube outer wall is equipped with the heating system heated to tube body.Heating system can
To be electric heating film etc..
Preferably, the hollow tube internal diameter is 1~3mm, length is 5~10mm.Internal diameter is more preferably
1.5~2.5mm.Glass-micropipe internal diameter can influence the formation effect of liquid film, and internal diameter is excessive or too small, can all cause liquid can not be
Uniform liquid film is formed on inner wall.In the inside diameter ranges, the formation effect of liquid film is preferable.
Preferably, the tube wall specific surface area of the hollow tube of unit length is 150~1000cm2/cm。
Another object of the present invention is to provide a kind of as described in above-mentioned either a program Click labelled synthesis PET developers
Microreactor preparation method, its step are as follows：
To catalysis of the injection in the hollow tube of metal or glass containing Click markers precursor compound and label reaction
The solution of agent, the hollow tube inner wall form rough non-smooth surface by modification；Then to hollow tube
One end is passed through air-flow, and solution is made to sprawl to form liquid film in inner surface of tube wall under air-flow promotion；Air-flow is kept to be continually fed into, until
Solution is dried, and so that the catalyst dispersion of Click markers precursor compound and label reaction is fixed on tube wall, is obtained Click
The microreactor of labelled synthesis PET developers.
Preferably, the inner wall method of modifying of the hollow tube is：
1) after heating the mixed solution of cetyl trimethylammonium bromide and NaOH, it is anti-that ethyl orthosilicate stirring is added
It answers；In then hollow tube that reaction solution is filled to the metal or glass that cleaned；
2) hollow tube for filling reaction solution is dried, is sintered, is completed to inner tubal wall after reaction solution drying
Modification；
3) sintered hollow tube is taken out, after cleaning and drying, obtains the hollow tube modified by inner wall.
Certainly, the operation principle based on the present invention, the modification of glass-micropipe inner wall are not necessarily to use the above method,
Other methods may be used, as long as rough non-smooth inner surface can be formed by modification, increase its internal surface area i.e.
It can.
Preferably, the air-flow being continually fed into dry solution processes is by the thermal current of heating, preferably hot nitrogen
Air-flow.Thermal current can speed up the drying process of reagent.
Preferably, the bolus injection amount of solutions/reagents should meet in hollow tube：The liquid of all injections is pushed away in air-flow
It can sprawl to form liquid film in inner surface of tube wall under dynamic, without being blown out glass-micropipe.When bolus injection amount is excessive, liquid film
Inner surface of tube wall can not be spread over completely, will glass-micropipe be blown out by air-flow, be influenced follow-up test accuracy.For size one
For fixed pipeline, best bolus injection amount can be determined by testing.
Preferably, the cleaning step of hollow tube is：Glass-micropipe is immersed successively deionized water, ethyl alcohol, acetone and
It is cleaned by ultrasonic in deionized water；Glass-micropipe is immersed again in the mixed liquor of the concentrated sulfuric acid and hydrogen peroxide and be ultrasonically treated, is then allowed to stand
In mixed liquor；Finally glass-micropipe is cleaned by ultrasonic in deionized water several times, drying.
Another object of the present invention is to provide a kind of Click labelled synthesis PET imagings prepared such as above-mentioned either method
The microreactor of agent.Glass-micropipe inner wall prepared by this method has rough pore structure, and surface area is larger, Neng Gouti
For the Ion reagent spreading area of bigger.And its inner surface is coarse Non-smooth surface, therefore can retain to a certain extent
Ion reagent prevents it to be blown out glass-micropipe under air-flow drive.
It is carried out using the microreactor as described in any of the above-described scheme another object of the present invention is to provide a kind of
Click marks the method reacted, and is specially：Marked azido compound is injected in microreactor, closed, heating, into
Row Click label reactions.
Preferably, the label reaction is18F label reactions；The marked azido compound preparation method is：
It will18In the F ion reagent injection hollow tube, it then is passed through air-flow to one end of hollow tube, is made18F from
Sub- reagent is sprawled to form liquid film under air-flow promotion in inner surface of tube wall；Air-flow is kept to be continually fed into, until18F ion reagent is complete
White drying is adsorbed in inner surface of tube wall；Super dry acetonitrile is injected into hollow tube again, is then continued to one end of hollow tube
Air-flow is passed through until dry；The super dry acetonitrile solution of azidoethyl trifluoromethanesulfonic acid fat is injected into hollow tube again, it is closed, add
Heat is obtained by the reaction18The azido compound of F labels.
Further, the hollow tube length be 10cm, internal diameter 2mm,18The injection rate of F ion reagent is 100 μ
L, for pushing18The air-flow velocity of F ion reagent is 100 μ L/min.In the glass-micropipe size, push air-flow velocity and note
Enter under amount, dry fixed effect is best.
Reactor provided by the invention is in the inner wall of glass or metal micro-tubes by depositing the methods of silica, modification
Inner wall is urged by adsorbing by what marker precursor compound and Click labels reacted with increasing its specific surface area and adsorption capacity
Agent is fixed in the reactor, and reactor installs electric heating film and the standard seal interface with access way additional, accesses micro- reaction
Synthesis system can be used.Its hollow cavity can provide reaction compartment, it is ensured that liquid film forming expands disengagement area, and gas is still
Can from liquid film center quickly through, can effectively realize the internal fluid of pipe mesolow manipulation.Due in advance by reaction reagent and
Catalyst is fixed in the reactor, as long as marked azido compound injection reactor can be carried out Click label reactions,
It eliminates transfer operation and pipeline is avoided to pollute, reduce the operating quantity of post-reaction treatment, so as to shorten the synthetic operation time.
The reactor processing cost is low, can be disposable, cross contamination when avoiding synthesizing different developers.It can using the reactor
The synthesis for carrying out other Click labels sugar and polypeptide, can be used for developing, develops various new PET molecular image developers.
Description of the drawings
Fig. 1 inner walls modify the SEM figures of glass-micropipe surface topography；
Fig. 2 inner walls modify the longitudinal sectional SEM figures of glass-micropipe；
(left side), rear (right side) crosscutting optical microphotograph enlarged drawing before the modification of Fig. 3 stainless steel micro pipe inner walls；
Fig. 4 18F mark Octreotide Radio-TLC collection of illustrative plates；
Synthesis system structural schematic diagrams of the Fig. 5 with hollow tube.
Specific implementation mode
The related details of the present invention will be further described by embodiment below, but implements to be not limited to the present invention
Protection domain.
1 inner wall of embodiment modifies the preparation of glass-micropipe
The glass-micropipe of long 10cm internal diameters 1.5mm is immersed successively ultrasonic in deionized water, ethyl alcohol, acetone, deionized water
10min is cleaned, then immerses the concentrated sulfuric acid-hydrogen peroxide mixed solution (volume ratio 1：1) 15min is ultrasonically treated in, after placing 1.5h,
Immerse again and be cleaned by ultrasonic 10min in deionized water, repeat with deionized water ultrasound twice after, in an oven after 120 DEG C of dry 2h
It is spare.
0.408g cetyl trimethylammonium bromides are added in round-bottomed flask, 200mL deionized waters and 1.2mL 2 is added
Mol/L NaOH solutions are heated with stirring to 70 DEG C, and 2mL ethyl orthosilicates (TEOS) are added, are stirred to react 1h.Reaction solution is filled
In glass-micropipe, 120 DEG C of dry 1h in an oven.It is taken out after 500 DEG C of sintering 2h in Muffle furnace.It is clear to immerse deionized water ultrasound
10min is washed, in an oven 120 DEG C of dry 2h postcoolings, taken out, obtains inner wall modification glass-micropipe.
The SEM figures of the micro-pipe surface topography of the inner wall modification prepared in the present embodiment are as shown in Figure 1, inner wall modification micro-pipe is vertical
The SEM figures cut are as shown in Figure 2.From the graph, it is apparent that the micro-pipe inner wall surface presentation after modification is rough porous
Rough morphology, surface area are significantly improved relative to traditional smooth tube wall.Reagent can be quickly carried out using the micro-pipe
Drying, when reagent solution by air-flow promotion flowed in the glass-micropipe when, reagent can constantly penetrate into the hole on surface,
And liquid film is formed in tube wall surface under the action of surface tension, finally reagent is made uniformly to sprawl, micro-pipe center still remains
One channel for air blowing airflow.Therefore air-flow constantly can carry out rapid evaporation drying to the liquid film of passageway perimeter.
Moreover, because liquid film is uniformly sprawled, also uniform adsorption, will not in tube wall surface for active ingredient after its drying in reagent
There is clustering phenomena.Reagent needed for other reactions is subsequently injected into micro-pipe, you can dissolve out the active ingredient in reagent；Certainly,
It can also be reacted in micro-pipe inner cavity after injecting other reagents directly using the glass-micropipe as reactor.
2 inner wall of embodiment modifies the preparation of glass-micropipe
Compared with Example 1, the size for differing only in glass-micropipe is long 10cm, internal diameter 2mm to the present embodiment；Other
Pre-treatment and inner wall method of modifying all same.Tube wall pattern after being modified in the present embodiment is similar to Example 1.
3 inner wall of embodiment modifies the preparation of glass-micropipe
Compared with Example 1, the size for differing only in glass-micropipe is long 10cm, internal diameter 2.5mm to the present embodiment；Its
His pre-treatment and inner wall method of modifying all same.Tube wall pattern after being modified in the present embodiment is similar to Example 1.
The inner wall modification glass-micropipe prepared in above three embodiments can form inner wall by further handling
It is attached with the micro-pipe reactor of heterogeneity.It is as follows that target component is fixed to the method being attached in micro-pipe：
It will be fixed containing target in the solution implantation glass micro-pipe of component, be then passed through air-flow to one end of glass-micropipe,
Solution is set to sprawl to form liquid film in inner surface of tube wall under air-flow promotion；Then air-flow is kept to be continually fed into, until solution is complete
Dry, active principle is just by uniform adsorption in inner surface of tube wall.Dry gas stream preferably uses flow of warm nitrogen gas.
When in use, both ends can install sealed interface additional to glass-micropipe, then be automatically synthesized system by connecting pipe access.
The use state diagram of glass-micropipe can pass through synthesis system in advance as shown in figure 5, fixing the reagent of component containing target
In switching Vavle switching inject connecting pipe, then pushed it, injected via sealed interface by connecting pipe perpendicular by air-flow
In the glass-micropipe inner cavity directly placed.In pushing course, air-flow velocity should not be too large or too small air-flow, otherwise be easy to make reagent
Film-formation result it is bad.In actual use, it should be determined most preferably according to added amount of reagent and glass-micropipe size by testing
Air-flow velocity.When needing when micro-pipe inner cavity is reacted, it can stop ventilating, keep pipe interior sealing, pipe is outer can be aided with heating system
System adjusts temperature.
The optimal parameter of 4 glass-micropipe of embodiment determines
Below based on the glass-micropipe being prepared in above three embodiments, with synthesis18For the reaction of F-FDG, say
The influence of bright different reagent additive amount, air-flow velocity and micro-pipe size for reaction result.
Experimental group 1：The glass-micropipe prepared using embodiment 1 is dried18F ion reagent and synthesis18F-FDG：
18The production of F ion reagent：Using18O (p, n)18F nuclear reactions, using the H that volume is 2.4mL2O[18O] heavy-oxygen-enriched water
(95%) target continuously bombards 30~60min with the proton beam of 11MeV, 35 μ A on cyclotron, obtains required for reaction
's18The oxygen-enriched aqueous solution of F ion.
18The separation and enrichment of F ion reagent：It will18The oxygen-enriched aqueous solutions of F- are by QMA columns, and handle18F ion is enriched in QMA
On column, while heavy-oxygen-enriched water is collected in returnable bottle.Start automatic control system, it will18F ion and water pass to anion-exchange column
And handle (QMA),18F ion is enriched on QMA columns, while heavy-oxygen-enriched water is collected in returnable bottle.
18The drying of F ion reagent and18F label reactions：Shift 1mL K222/K2CO3Acetonitrile/water solution (K222,
15mg/mL；K2CO3, 1.2mg/mL) and it is eluted by QMA columns18100 μ L of collection are contained 100 μ Ci by F ion18F ion reagent
100 μ L/min of flow velocity nitrogen stream push under injection embodiment 1 prepare glass-micropipe, and be adsorbed on tube wall upper berth spread at
Liquid film continues to be passed through 100 DEG C of flow of warm nitrogen gas (100 μ L/min of flow velocity) and blows 3min, makes18F ion reagent is dried；Again to glass-micropipe
The 20 super dry acetonitriles of μ L of middle injection are passed through 100 DEG C of flow of warm nitrogen gas (100 μ L/min of flow velocity) and blow 2min to drying.Inject 100 μ L tri-
The super dry acetonitrile solution (2mg/mL) of fluorine mannose, is heated to 120 DEG C, after confined reaction 5min, is passed through nitrogen stream (flow velocity while hot
100 μ L/min) remove acetonitrile.
Hydrolysis：To process18100 μ L 1M HCl solutions are injected in the glass-micropipe of F label reactions, 110 DEG C are heated,
Confined reaction 5min completes hydrolysis.
It isolates and purifies：The solution after hydrolysis is shifted to AG50/AG11A8 resin columns, Al2O3The series connection of column and C18 columns composition
Column retransfers 5mL water and passes through the splitter, collects eluate and eluate is passed through 0.22 μm of membrane filtration to obtain the final product18F-FDG solution.
Experimental group 2：This experimental group differs only in glass-micropipe therein replacing with use compared with experimental group 1
Glass-micropipe prepared by embodiment 2, other methods and parameter keep identical with experimental group 1.
Experimental group 3：This experimental group differs only in glass-micropipe therein replacing with use compared with experimental group 1
Glass-micropipe prepared by embodiment 3, other methods and parameter keep identical with experimental group 1.
Experimental group 4：For this experimental group compared with experimental group 2, differing only in will be for pushing18The air-flow of F ion reagent
Flow velocity is adjusted to 50 μ L/min, and other methods and parameter keep identical with experimental group 2.
Experimental group 5：For this experimental group compared with experimental group 2, differing only in will be for pushing18The air-flow of F ion reagent
Flow velocity is adjusted to 150 μ L/min, and other methods and parameter keep identical with experimental group 2.
Experimental group 6：This experimental group differs only in compared with experimental group 2 and replaces with glass-micropipe therein and reality
Apply that glass-micropipe original in example 2 is identical, without the glass-micropipe (long 10cm, internal diameter 2mm) that inner wall is modified, both ends install additional close
After sealing-in mouth, it is directly accessed in the system of being automatically synthesized and uses.Other methods and parameter keep identical with experimental group 2.
Finally, in experimental group 1~6, radiation TLC yields are 76%, 90%, 85%, 80%, 70% and 45%.It is above-mentioned dry
It is dry18F ion reagent and synthesis18In the experimental group 1~3 of F-FDG, the factor of only micro-pipe caliber is different, obtained by each experimental group18The radiation TLC yields of F-FDG and drying18The quality of F ion reagent is directly related.Comparatively, experimental group 2 is optimal, put
It is 90% to penetrate TLC yields.It is prepared using this method18F-FDG took 30 minutes, less than 40 minutes be conventionally synthesized needed for instrument.It is real
Group 2 is tested compared with experimental group 6, does not modify micro-pipe drying using inner wall18F ion reagent and synthesis18F-FDG radiates TLC yields
It is greatly reduced, is 45%.Illustrate that micro-pipe inner wall is modified in the present invention is conducive to drying18F ion reagent.Experimental group 2,4 and 5 compares
Push the nitrogen flow rate factor of solution injection micro-pipe different it can be found that three groups of experiments only have, experimental group 2 is optimal, is illustrated
Under the nitrogen stream of proper flow rates pushes, solution is uniformly sprawled in micro-pipe inner wall, is conducive to drying18F ion reagent and follow-up18F is marked
The progress of note reaction improves synthesis yield so as to shorten the time of entire building-up process.
In conclusion when the inner wall modification glass-micropipe progress solution prepared using the present invention dries fixed, optimized parameter
For：Glass-micropipe length is 10cm, and the injection rate of internal diameter 2mm, solution are 100 μ L, the nitrogen stream flow velocity for pushing solution
For 100 μ L/min.This group of parameter is in addition to being used for drying18Outside F ion reagent, the drying of other Ion reagents is can be used for, is made
Corresponding active principle in advance be fixed in closing by attachment.Certainly, this is only one group of preferably parameter, for various sizes of glass
Glass micro-pipe also can determine its best injection rate and nitrogen flow rate by experiment.
The making of 5 Click labelled synthesis reactors of embodiment
In the present embodiment, it is anti-that Click labelled synthesis is carried out based on the inner wall modification glass-micropipe being prepared in embodiment 2
Answer the making of device.100 μ L are contained to Octreotide (0.01mol/L), copper sulphate (0.001mol/L) and the Vitamin C of Terminal Acetylenes modification
The mixed solution of sour sodium (0.001mol/L) injects in the glass-micropipe, is then passed through 100 μ of flow velocity to the bottom end of glass-micropipe
L/min nitrogen streams make solution sprawl to form liquid film in inner surface of tube wall under air-flow promotion；Then 100 DEG C of hot nitrogens are continually fed into
Air-flow (100 μ L/min of flow velocity), until solution is completely dried, the Octreotide and catalyst dispersion for so that Terminal Acetylenes is modified are fixed on tube wall
On, obtain the microreactor of Click labeled PET tracers.
The micro-pipe outer wall of gained installs electric heating film additional, after both ends install sealed interface additional, you can access is automatically synthesized system
Middle use.
The making of 6 Click labelled synthesis reactors of embodiment
In the present embodiment, compared with Example 5, the inner wall modification micro-pipe for differing only in use is different.The present embodiment
In, long 10cm, the stainless steel micro pipe inner wall of internal diameter 2mm are modified using method same as Example 2, stainless steel micro pipe inner wall is repaiied
(left side), rear (right side) crosscutting optical microphotograph enlarged photograph are as shown in figure 3, it can be found that its inner wall also goes out after modification before decorations
Show the coarse cavernous structure similar with glass-micropipe, increases internal surface area.
Then the Click labelling reactors that the stainless steel micro pipe can be prepared in method same as Example 5.
Stainless steel micro pipe outer wall installs electric heating film additional, after both ends install sealed interface additional, you can access, which is automatically synthesized in system, to be used.
7 Click labelled synthesis of embodiment [18F] fluoro ethyl triazole-Octreotide
18The drying of F ion reagent and18F marks the reaction of azido compound：By what is transmitted from medical cyclotron18F
Ion and water pass in receiving bottle.Start automatic control system, it will18F ion and water pass to anion-exchange column (QMA), and
?18F ion is enriched on QMA columns, while heavy-oxygen-enriched water is collected in returnable bottle.Shift 1mL K222/K2CO3Acetonitrile/water it is molten
Liquid (K222,15mg/mL；K2CO3, 1.2mg/mL) and it is eluted by QMA columns18100 μ L of collection are contained 100 μ Ci by F ion18F
In the glass-micropipe that solion is prepared in the injection embodiment 2 under the promotion of the nitrogen stream of 100 μ L/min of flow velocity, and inhale
Tube wall upper berth spread is attached into liquid film, continues for being passed through 100 DEG C of flow of warm nitrogen gas (100 μ L/min of flow velocity), make18F ion reagent
It is dry；The 20 super dry acetonitriles of μ L are injected into glass-micropipe again, 100 DEG C of flow of warm nitrogen gas (100 μ L/min of flow velocity) is passed through and is blown to drying,
Thus drying is obtained18F ion reagent.The super dry second of 200 μ L azidoethyl trifluoromethanesulfonic acid fat is injected into glass-micropipe again
Nitrile solution, it is closed, 120 DEG C are heated to, 5min is reacted, is obtained18F marks azido compound reaction solution.
Click marks Octreotide：By above-mentioned 200 μ L18F marks azido compound reaction solution injection embodiment 5 to make
Click labelling reactors, it is closed, 120 DEG C are heated to, 10min is reacted, reaction process is as follows：
By AG50/AG11A8 resin columns, Al after reaction solution cooling2O3The columns in series of column and C18 columns composition, retransfers
10ml water simultaneously passes through above-mentioned splitter, collects eluate, and by 0.22 μm of membrane filtration up to [18F] fluoro ethyl triazole-
Octreotide solution, Radio-TLC collection of illustrative plates are as shown in Figure 4.
Under comparative example routine operation Click labelled synthesis [18F] fluoro ethyl triazole-Octreotide
18The drying of F ion reagent and18F marks the reaction of azido compound：With embodiment 7.
Click label reactions：By above-mentioned 200 μ L18F marks azido compound reaction solution and 100 μ L to contain Terminal Acetylenes modification
The mixed solution of Octreotide (0.01mol/L), copper sulphate (0.001mol/L) and sodium ascorbate (0.001mol/L), by automatic
The flow of program setting is injected separately into micro-pipe reactor, closed, is heated to 120 DEG C, reacts 10min.It is passed through after reaction solution cooling
Cross AG50/AG11A8 resin columns, Al2O3The columns in series of column and C18 columns composition, retransfers 10ml water and passes through above-mentioned splitter,
Collect eluate, and by 0.22 μm of membrane filtration up to [18F] fluoro ethyl triazole-Octreotide solution.
Embodiment 7 is compared with comparative example, due in advance fixing reaction reagent and catalyst in the reactor, as long as will
Marked nitrine precursor injection reactor can carry out Click label reactions, eliminate the operation for shifting other reagents, react
Liquid product is contracted to 200 μ L from 300 μ L, reduces the operating quantity of purifying post-processing, and reactant concentration raising accelerates reaction
Speed, therefore, synthesis [18F] total time-consuming of fluoro ethyl triazole-Octreotide peptide operation foreshortens to 30min from 50min.
Above-mentioned embodiment is only a preferred solution of the present invention, so it is not intended to limiting the invention.Have
The those of ordinary skill for closing technical field can also make various changes without departing from the spirit and scope of the present invention
Change and modification.Although for example, in embodiment with synthesis [18F] it illustrates for fluoro ethyl triazole-Octreotide, but the glass is micro-
Pipe and the synthesis that can be used for other Click labels sugar and polypeptide using the drying means of the micro-pipe.But different reagent
And the actual conditions of synthetic reaction are different, can be adjusted.Similarly, glass-micropipe can also use in embodiment 6 not
The steel reactor that becomes rusty replaces.Moreover, the inner wall of the pipe method of modifying of glass, stainless steel can also according to being actually adjusted, as long as
Similar modification of surfaces can be prepared.Therefore all technologies for taking the mode of equivalent substitution or equivalent transformation to be obtained
Scheme is all fallen in protection scope of the present invention.
Claims (10)
1. a kind of microreactor of Click labelled synthesis PET developers, which is characterized in that microreactor main body is metal or glass
The hollow tube of glass, the hollow tube inner wall form rough non-smooth surface by modification；Hollow tube inner wall
Upper dispersion is fixed with the catalyst of Click markers precursor compound and label reaction.
2. the microreactor of Click labelled synthesis PET developers as described in claim 1, which is characterized in that described is hollow
Tube body both ends are equipped with the sealed interface for connecting external turnover pipeline；The hollow tube outer wall be equipped with to tube body into
The heating system of row heating.
3. the microreactor of Click labelled synthesis PET developers as described in claim 1, which is characterized in that described is hollow
Internal diameter of tube body is 1~3mm, and length is 5~10mm.
4. a kind of preparation method of the microreactor of the Click labelled synthesis PET developers as described in claims 1 to 3 is any,
It is characterized in that, steps are as follows：
To catalyst of the injection in the hollow tube of metal or glass containing Click markers precursor compound and label reaction
Solution, the hollow tube inner wall form rough non-smooth surface by modification；Then to one end of hollow tube
It is passed through air-flow, solution is made to sprawl to form liquid film in inner surface of tube wall under air-flow promotion；Air-flow is kept to be continually fed into, until solution
It is dry, so that the catalyst dispersion of Click markers precursor compound and label reaction is fixed on tube wall, obtains Click labels
Synthesize the microreactor of PET developers.
5. the preparation method of the microreactor of Click labelled synthesis PET developers as claimed in claim 4, which is characterized in that
The inner wall method of modifying of the hollow tube is：
1) after heating the mixed solution of cetyl trimethylammonium bromide and NaOH, ethyl orthosilicate is added and is stirred to react；So
In the hollow tube that reaction solution is filled to the metal or glass that cleaned afterwards；
2) hollow tube for filling reaction solution is dried, is sintered after reaction solution drying, inner tubal wall is repaiied in completion
Decorations；
3) sintered hollow tube is taken out, after cleaning and drying, obtains the hollow tube modified by inner wall.
6. the preparation method of the microreactor of Click labelled synthesis PET developers as claimed in claim 4, which is characterized in that
The cleaning step of hollow tube is：It is clear that glass-micropipe is immersed to ultrasound in deionized water, ethyl alcohol, acetone and deionized water successively
It washes；Glass-micropipe is immersed again in the mixed liquor of the concentrated sulfuric acid and hydrogen peroxide and be ultrasonically treated, is then allowed to stand in mixed liquor；Finally will
Glass-micropipe is cleaned by ultrasonic several times in deionized water, drying.
7. a kind of microreactor of the Click labelled synthesis PET developers prepared such as any the method for claim 4~6.
8. a kind of method carrying out Click label reactions using microreactor as described in claim 1 or 7, which is characterized in that will
In marked azido compound injection microreactor, closed, heating carries out Click label reactions.
9. the method for carrying out Click label reactions as claimed in claim 8, which is characterized in that the label, which reacts, is18F
Label reaction；The marked azido compound preparation method is：
It will18In the F ion reagent injection hollow tube, it then is passed through air-flow to one end of hollow tube, is made18F ion is tried
Agent sprawls to form liquid film under air-flow promotion in inner surface of tube wall；Air-flow is kept to be continually fed into, until18F ion reagent is completely dry
It is dry to be adsorbed in inner surface of tube wall；Super dry acetonitrile is injected into hollow tube again, is then continually fed into one end of hollow tube
Air-flow is until dry；The super dry acetonitrile solution of azidoethyl trifluoromethanesulfonic acid fat is injected into hollow tube again, it is closed, it heats,
It is obtained by the reaction18The azido compound of F labels.
10. the method for carrying out Click label reactions as claimed in claim 9, which is characterized in that the hollow tube length
For 10cm, internal diameter 2mm,18The injection rate of F ion reagent is 100 μ L, for pushing18The air-flow velocity of F ion reagent is 100
μL/min。
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| WO2008102810A1 (en) * | 2007-02-21 | 2008-08-28 | Sharp Kabushiki Kaisha | Channel reaction method and channel reaction apparatus |
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| CN105985406A (en) * | 2015-02-02 | 2016-10-05 | 中国科学院上海应用物理研究所 | <18>F-labeled polypeptide compound, and preparation method and application thereof |
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| WO2008102810A1 (en) * | 2007-02-21 | 2008-08-28 | Sharp Kabushiki Kaisha | Channel reaction method and channel reaction apparatus |
| CN104445215A (en) * | 2014-11-05 | 2015-03-25 | 上海大学 | Preparation method of hollow silicon dioxide nanomaterial |
| CN105985406A (en) * | 2015-02-02 | 2016-10-05 | 中国科学院上海应用物理研究所 | <18>F-labeled polypeptide compound, and preparation method and application thereof |
| 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 |
| CN107413286A (en) * | 2017-02-04 | 2017-12-01 | 青岛大学 | Disposable thermostabilization microresponse device |
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