CN109134381A - A kind of micro-fluidic synthesis18The method of F-FMISO - Google Patents
A kind of micro-fluidic synthesis18The method of F-FMISO Download PDFInfo
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- CN109134381A CN109134381A CN201810712241.7A CN201810712241A CN109134381A CN 109134381 A CN109134381 A CN 109134381A CN 201810712241 A CN201810712241 A CN 201810712241A CN 109134381 A CN109134381 A CN 109134381A
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- C—CHEMISTRY; METALLURGY
- 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
- C07D233/91—Nitro radicals
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- C—CHEMISTRY; METALLURGY
- 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 kind of micro-fluidic synthesis18The method of F-FMISO is related to imaging agent that is quick, efficiently preparing positron emission tomography (PET).The method have the characteristics that in the micro-pipe of inner wall modification, rapid draing18F ion reagent, and completed in micro-pipe18F replaces label and hydrolysis.Since modification micro-pipe inner wall increases adsorption area, inject in micro-pipe18F reagent solution is sprawled to form liquid film under air-flow promotion in tube wall, increases disengagement area, while passing through from hollow tube road convenient for thermal current, so that rapid draing is realized, after the suction-operated of tube wall can prevent drying18It the conglomeration of F reagent and dispels, is conducive to be sufficiently mixed with reaction reagent, be sequentially completed in same micro-pipe18F replaces two step synthetic reactions of label and hydrolysis, shortens sum total into the operating time, improves18The synthesis yield of F-FMISO.
Description
Technical field
The present invention relates to a kind of synthetic methods of positron emitting tracer, and in particular to a kind of hypoxic tissue positive electron is disconnected
Layer imaging (PET) diagnoses imaging agent used18F- fluorine miaow rope nitre azoles (18F-FMISO fast synthesis method).
Background technique
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, uses different labelled with radioisotope imaging agents
(PET imaging agent), the change of highly sensitive display histoorgan physiology, biochemical aspect.Imaging agent is the pass of PET and nuclear medicine
Key, imaging agent used by PET is to use radionuclide11C、13N、15O、18The drug of the labels such as F, because of radionuclide used
Half-life short, it is impossible to storage is purchased as commodity, so when carrying out PET imaging, it is necessary at production radionuclide scene
Labelled synthesis prepares PET imaging agent as early as possible, and locally uses within the time of restriction.Due to the imaging agent that uses every time
Dosage is atomic (generally corresponding to nearly nanomole magnitude), and requires synthesis, purifying time-consuming short as far as possible, therefore this quick ultramicron
The requirement being synthetically prepared to technique, equipment and its automation control is high.
The synthesis for carrying out PET imaging agent in microreactor using microflow control technique principle has significant advantage.Firstly, micro-
Reactor synthesis system can manipulate very small reaction volume, therefore the relative concentration of reactant is high, and reaction rate is fast, thus
The usage amount that substrate can be substantially reduced reduces the difficulty of purifying.Secondly, can greatly shorten generated time, really realize
Production on demand.Third can significantly improve the putting yield of reaction.4th, reaction system is small, reduces protection cost, improves safety
Property.5th, reaction chip function expansibility is strong, can sufficiently meet scientific research needs.
Nitro imidazole derivatives are the Hypoxic imaging agents of current most study.It is therein18F- fluorine miaow rope nitre azoles
(18F-FMISO) it is first Hypoxic imaging agent for clinical diagnosis research.Have been used at present tumour, it is cardiovascular with
And cerebrovascular hypoxia imaging research.Due to18F-FMISO is applied extensively in clinical and research, therefore, quickly, efficiently
Synthesis18F-FMISO has become the hot spot of research.Commonly18F-FMISO synthetic route is with 1- (2 '--1 '-imidazoles of nitro
Base) -2-O- THP trtrahydropyranyl -3-O- tosyl propylene glycol (NITTP) is as precursor, by nucleophilic fluoro and acidic hydrolysis
Two-step reaction synthesis18F-FMISO can be used after crude product is purified and non-velum filteration.Before synthetic reaction, first pass through back
Accelerator is revolved to generate18The oxygen-enriched aqueous solution of F- is collected after being enriched with by QMA column18F ion reagent aqueous solution dehydration is dry
Rear can be used for18F label reaction.Existing thermal evaporation dehydrates technology, and since disengagement area is small, slow drying speed is time-consuming
Long and dry18It the conglomeration of F reagent and dispels, is unfavorable for quickly mixing with labeled substrate and sufficiently reacting.In drying intermediate
When, it also will appear similar conglomeration and dispel phenomenon, be unfavorable for reactant and quickly mix and sufficiently react, and product is caused to damage
It loses.In addition, existing18Fluoro and hydrolysis in F-FMISO synthesis process carry out in two reactors respectively, and transfer intermediate needs
Want elapsed time.The present invention successively carries out in same micro-pipe reactor18The drying of F ion reagent,18F replaces label and hydrolysis anti-
It answers, shortens18Total generated time of F-FMISO.
Reaction equation is as follows:
Summary of the invention
?18F labelled synthesis PET imaging agent18During F-FMISO, need pair18F ion reagent carries out rapid draing,
Existing thermal evaporation dehydrates technology, and since disengagement area is small, slow drying speed, time-consuming, and dry18F reagent conglomeration
With dispel, be unfavorable for quickly mixing with labeled substrate and sufficiently reacting.When drying up intermediate, also will appear similar conglomeration and
Phenomenon is dispelled, is unfavorable for reactant and quickly mixes and sufficiently react, and lead to loss of product.In addition, existing18F-FMISO synthesis
Fluoro and hydrolysis in the process carries out in two reactors respectively, and transfer intermediate needs elapsed time.The purpose of the present invention
It is overcome the deficiencies in the prior art, and a kind of micro-fluidic synthesis is provided18The method of F-FMISO, and successively carried out in micro-pipe18F
Ion reagent drying,18F replaces label and hydrolysis, simplifies operation, shortens total generated time.
The present invention it is specific the technical solution adopted is as follows:
A kind of micro-pipe synthesis18The method of F-FMISO, the glass-micropipe that synthetic reaction involved in this method is modified in inner wall
Interior progress, which is in hollow tubular, and inboard wall of tube body forms rough non-smooth surface by modification；Synthesis side
Steps are as follows for method:
1) will18F ion reagent is passed through in glass-micropipe, is then passed through air-flow to one end of glass-micropipe, is made18F ion examination
Agent sprawls to form liquid film under air-flow promotion in inner surface of tube wall；Then 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 glass-micropipe again, is then continued to one end of glass-micropipe
Air-flow is passed through until acetonitrile evaporation drying, obtains drying18F ion reagent；
2) by precursor 1- (2 '--1 '-imidazole radicals of nitro) -2-O- THP trtrahydropyranyl -3-O- tosyl propylene glycol
(NITTP) super dry acetonitrile solution injection inner wall is attached with dry18In the glass-micropipe of F ion reagent, closed glass micro-pipe
Both ends and heating, complete18F replaces label reaction；Then air-flow is continually fed into one end of glass-micropipe until acetonitrile evaporates
It is dry；
3) hydrochloric acid solution is injected into glass-micropipe again, hydrolysis is completed in the both ends of closed glass micro-pipe and heating；
4) hydrolyzate in glass-micropipe is isolated and purified, is obtained18F-FMISO solution.
In the present invention, rough non-smooth inner surface refer to it is different from conventional smooth glass-micropipe inner wall,
Glass-micropipe inner wall of the invention is out-of-flatness, and surface has indent and convex hole or burr.The inner surface can pass through deposition
The methods of silica is modified.Such glass-micropipe increases absorption internal surface area by modifying inner wall, injects in micro-pipe
's18F reagent solution can be sprawled to form liquid film under air-flow promotion in tube wall, increase disengagement area, therefrom convenient for thermal current
Blank pipe road passes through, so that rapid draing is realized, after the suction-operated of tube wall can prevent drying18F reagent conglomeration, be conducive to instead
Reagent is answered to be sufficiently mixed,18After F replaces label reaction, solvent is dried up with thermal current, injection aqueous hydrochloric acid solution can be hydrolyzed instead
It answers, saves generated time, improve synthesis yield.The glass-micropipe can cooperate sealed interface to carry out using by pipe
The both ends of son install the sealed interface with access way additional, can using glass-micropipe as a reactor, can in micro-pipe according to
Secondary progress18The drying of F ion reagent,18F replaces label and hydrolysis, simplifies operation, shortens total generated time.
Preferably, described18F ion reagent is by K222/K2CO3The elution of acetonitrile/water solution first pass through enrichment in advance
's18The solution obtained after F ion.K222/K2CO3Acetonitrile/water solution refer to acetonitrile and water mixing after, dissolution K222 and
K2CO3Obtained mixed solution.
Preferably, the glass-micropipe internal diameter is 1~3mm, preferably 1.5~2.5mm.Glass-micropipe internal diameter can shadow
The formation effect of liquid film is rung, internal diameter is excessive or too small, can all cause liquid that can not form uniform liquid film, Jin Erqi on inner wall
Drying effect when body is blown into is bad.In the inside diameter ranges, the formation effect of liquid film is preferable.
Preferably, the glass-micropipe the preparation method is as follows:
A) by after the heating of the mixed solution of cetyl trimethylammonium bromide and NaOH, it is anti-that ethyl orthosilicate stirring is added
It answers；Then reaction solution is filled to the hollow glass micro-pipe cleaned；
B) glass-micropipe for filling reaction solution is dried, is sintered, is completed to inner tubal wall after reaction solution is dry
Modification；
C) sintered glass-micropipe is taken out, after cleaning and drying, is obtained for drying18The glass-micropipe of F ion reagent.
The glass-micropipe inner wall of this method preparation has rough pore structure, and surface area is larger, is capable of providing more
Big Ion reagent spreading area.And its inner surface is coarse Non-smooth surface, therefore can retain ion to a certain extent
Reagent prevents it to be blown out glass-micropipe under air-flow drive.Equally, this glass-micropipe can be used as reactor, reaction
Intermediate can carry out subsequent reactions with after the drying of same method.
Further, in step a), the cleaning step of glass-micropipe are as follows: glass-micropipe is successively immersed to deionized water, second
It is cleaned by ultrasonic in alcohol, acetone and deionized water；Glass-micropipe is immersed again in the mixed liquor of the concentrated sulfuric acid and hydrogen peroxide and is ultrasonically treated,
It is then allowed to stand in mixed liquor；Finally glass-micropipe is cleaned by ultrasonic in deionized water several times, drying.
Preferably, the isolation and purification method of the hydrolyzate are as follows: the solution after transfer hydrolysis is to by AG50/AG11A8 tree
Rouge column, Al2O3The columns in series of column and C18 column composition is filtered eluate with injection water elution to obtain the final product18F-FMISO solution.
Preferably, being passed through the glass-micropipe for dry air-flow be thermal current that process heats.Thermal current can
Accelerate18The drying of F ion reagent and the process for removing reaction dissolvent.Certainly, for pushing18F ion reagent spread is at liquid film
Air-flow can be not necessarily required to use thermal current.
Further, the air-flow is inert gas flow, preferably nitrogen stream, to keep the inert atmosphere in pipe.
Preferably, the bolus injection amount of reagent should meet in glass-micropipe: the reagent of all injections is under air-flow promotion
It can sprawl to form liquid film in inner surface of tube wall, without being blown out glass-micropipe.When bolus injection amount is excessive, liquid film can not
Inner surface of tube wall is spread over completely, glass-micropipe will be blown out by air-flow, be influenced follow-up test accuracy.It is certain for size
For glass-micropipe, optimal bolus injection amount can be determined by test.In the present invention, the reagent of implantation glass micro-pipe is needed
Including18The super dry acetonitrile solution and salting liquid of F ion reagent, precursor NITTP should keep it not excessive as far as possible.
Preferably, the glass-micropipe length be 10cm, internal diameter 2mm,18The injection rate of F ion reagent is 100 μ
L, the air-flow velocity for being passed through the glass-micropipe is 100 μ L/min.In the glass-micropipe size, push air-flow velocity and note
Enter under amount, synthesis18F-FMISO radiation TLC yield can reach 85%, and radiochemical purity is greater than 95%.
The present invention increases the adsorption area of Non-smooth surface by modification micro-pipe inner wall, enables glass-micropipe as drying18F
The reactor of Ion reagent.Also, it is based further on the micro-pipe, is successively carried out in micro-pipe18F replaces label and hydrolysis,
Generated time is saved, is improved18The synthesis yield of F-FMISO.Glass-micropipe employed in the present invention has in biggish
Tube wall surface product is injected the reagent solution in micro-pipe and is retained under air-flow promotion by the tube wall of out-of-flatness, forms liquid film, then lead to
It crosses air-flow to be constantly passed through, is evaporated to dryness liquid film constantly, and the suction-operated of tube wall can prevent after drying18F examination
Agent and18F replaces the intermediate conglomeration of label and dispels, and is conducive to be sufficiently mixed with reaction reagent, avoids loss of product.Therefore,
For synthesis18For the reaction of F-FMISO, since it needs repeatedly to be evaporated in the synthesis process dry and airtight heating,
Therefore the glass-micropipe can preferably complete every synthesis flow.And this glass-micropipe is at low cost, can disposably make
With cross contamination when avoiding synthesizing different imaging agents.
Detailed description of the invention
Fig. 1 inner wall modifies the SEM figure of micro-pipe surface topography；
Fig. 2 inner wall modifies the longitudinal sectional SEM figure of micro-pipe；
Fig. 3 glass-micropipe synthesis system structural schematic diagram.
Specific embodiment
Related details of the invention will be further described by embodiment below, but embodiment is not limited to this hair
Bright protection scope.
The preparation of 1 inner wall of embodiment modification glass-micropipe
The glass-micropipe of long 10cm internal diameter 1.5mm is successively immersed into deionized water, ethyl alcohol, acetone, ultrasound in deionized water
10min is cleaned, then immerses and is ultrasonically treated 15min in the concentrated sulfuric acid-hydrogen peroxide mixed solution (volume ratio 1:1), after placing 1.5h, then
Immerse in deionized water and be cleaned by ultrasonic 10min, repeat with deionized water ultrasound twice after, 120 DEG C of dry 2h standby in an oven
With.
0.408g cetyl trimethylammonium bromide is added in round-bottomed flask, 200mL deionized water and 1.2mL is added
2mol/L NaOH solution is heated with stirring to 70 DEG C, is added 2mL ethyl orthosilicate (TEOS), is stirred to react 1h.Reaction solution is infused
Expire in glass-micropipe, in an oven 120 DEG C of dry 1h.It is taken out after 500 DEG C of sintering 2h in Muffle furnace.Immerse deionized water ultrasound
10min is cleaned, it is cooling after 120 DEG C of dry 2h in an oven, it takes out.Sealed interface is installed additional at the both ends of the glass-micropipe, outside
Tube wall install additional heating system after, that is, can access be automatically synthesized in system for pair18F ion reagent is dried.
The SEM figure of the micro-pipe surface topography of the inner wall modification prepared in the present embodiment is as shown in Figure 1, inner wall modification micro-pipe is vertical
The SEM figure cut is 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.When18F ion reagent is pushed by air-flow at this
In glass-micropipe when flowing, reagent can constantly penetrate into the hole on surface, and in tube wall surface under the action of surface tension
Liquid film is formed, finally sprawls reagent uniformly, micro-pipe center still remains a channel for air blowing airflow.Therefore,
Air-flow constantly can carry out rapid evaporation drying by the liquid film to passageway perimeter.Moreover, because liquid film is uniformly sprawled, when it
After drying18Also uniform adsorption is not in clustering phenomena in tube wall surface to F reagent.It is subsequent that other are reacted into required reagent injection
Micro-pipe, can will be after drying18The dissolution of F reagent；It is of course also possible to which directly other are tried using the glass-micropipe as reactor
It is reacted in micro-pipe inner cavity after agent injection.
The preparation of 2 inner wall of embodiment modification glass-micropipe
Compared with Example 1, difference is only that the size of glass-micropipe is long 10cm, internal diameter 2mm to the present embodiment；Other
Pre-treatment and inner wall method of modifying are all the same.Tube wall pattern after modifying in the present embodiment is similar to Example 1.
The preparation of 3 inner wall of embodiment modification glass-micropipe
Compared with Example 1, difference is only that the size of glass-micropipe is long 10cm, internal diameter 2.5mm to the present embodiment；Its
His pre-treatment and inner wall method of modifying are all the same.Tube wall pattern after modifying in the present embodiment is similar to Example 1.
It is dry in the glass-micropipe of above-mentioned tube wall modification in the present invention18The operating procedure of F ion reagent is as follows:
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 handle18F ion is enriched on QMA column, while heavy-oxygen-enriched water is collected in returnable bottle
It is interior.Shift 1mL K222/K2CO3Acetonitrile/water solution (K222,15mg/mL；K2CO3, 1.2mg/mL；Acetonitrile and water in solvent
Volume ratio be 1:1) by QMA column elute18F ion obtains18F ion reagent.Certainly, herein18The preparation of F ion reagent
Journey, specifically can be according to corresponding adjustment be actually done, not as restriction merely to those skilled in the art more fully understand.
It will be to be dried18In F ion reagent implantation glass micro-pipe, it then is passed through air-flow to one end of glass-micropipe, is made18F
Ion reagent is sprawled to form liquid film under air-flow promotion in inner surface of tube wall；Then air-flow is kept to be continually fed into, until18F ion
Reagent, which is completely dried, is adsorbed in inner surface of tube wall.Dry gas stream preferably uses flow of warm nitrogen gas.The glass-micropipe can be made later
For reactor, injects reacting precursor and carry out18The label reaction of F fluoro, generates intermediate, then with hydrochloric acid hydrolysis18F-FMISO。
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 as shown in figure 3,18F ion reagent and other reagents can in advance can be by synthesis systems
Switching Vavle switching inject connecting pipe, then pushed it by air-flow, it is vertical to be injected by connecting pipe via sealed interface
In the glass-micropipe inner cavity of placement.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 is bad.In actual use, optimal gas should be determined by test according to added amount of reagent and glass-micropipe size
Flow flow velocity.When needing when micro-pipe inner cavity is reacted, it can stop ventilating, keep sealing in pipe, the outer heating system that can be aided with of pipe
Adjust temperature.
Related details of the invention will be further described by embodiment below, but embodiment is not limited to this hair
Bright protection scope.
Embodiment 4 is dry using glass-micropipe prepared by embodiment 118F ion reagent and synthesis18F-FMISO
18The production of F ion reagent: it uses18O (p, n)18F nuclear reaction, the H for being 2.4mL using volume2O[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: will18The oxygen-enriched aqueous solution of F- passes through QMA column, 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 column, while heavy-oxygen-enriched water is collected in returnable bottle.
18The drying of F ion reagent and18F label reaction: transfer 1mL K222/K2CO3Acetonitrile/water solution (K222,
15mg/mL；K2CO3, 1.2mg/mL) and it is eluted by QMA column18100 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 dry；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 precursors
The super dry acetonitrile solution (2mg/mL) of NITTP heats 120 DEG C, after confined reaction 5min, is passed through nitrogen stream (100 μ of flow velocity while hot
L/min acetonitrile) is removed.
Hydrolysis: to process18100 μ L 1M HCl solutions are injected in the glass-micropipe of F label reaction, are heated to 110
DEG C, confined reaction 5min completes hydrolysis.
It isolates and purifies: shifting the solution after hydrolyzing to AG50/AG11A8 resin column, Al2O3The series connection of column and C18 column composition
Column carries out post separation, retransfers 5mL injection water and is eluted by the columns in series, collect eluate and pass through eluate
0.22 μm of membrane filtration to obtain the final product18F-FMISO solution.Gained18The radiochemical purity of F-FMISO is greater than 95%, and radiation TLC is produced
Rate is 75%.
Embodiment 5 is dry using glass-micropipe prepared by embodiment 218F ion reagent and synthesis18F-FMISO
Compared with Example 4, difference is only that replace with glass-micropipe therein is made the present embodiment using embodiment 2
Standby glass-micropipe, other methods and parameter keep identical with embodiment 4.
Obtained by the present embodiment18The radiochemical purity of F-FMISO is greater than 95%, and radiation TLC yield is 85%.
It is dry that embodiment 6 adopts glass-micropipe prepared with embodiment 318F ion reagent and synthesis18F-FMISO
Compared with Example 4, difference is only that replace with glass-micropipe therein is made the present embodiment using embodiment 3
Standby glass-micropipe, other methods and parameter keep identical with embodiment 4.
Obtained by the present embodiment18The radiochemical purity of F-FMISO is greater than 95%, and radiation TLC yield is 57%.
Embodiment 7 is dry using glass-micropipe prepared by embodiment 218F ion reagent and synthesis18F-FMISO
Compared with Example 5, difference is only that and will be used to push the present embodiment18The air-flow velocity of F ion reagent adjusts
For 50 μ L/min, other methods and parameter keep identical with embodiment 5.
Obtained by the present embodiment18The radiochemical purity of F-FMISO is greater than 95%, and radiation TLC yield is 55%.
Embodiment 8 is dry using glass-micropipe prepared by embodiment 218F ion reagent and synthesis18F-FMISO
Compared with Example 5, difference is only that and will be used to push the present embodiment18The air-flow velocity of F ion reagent adjusts
For 150 μ L/min, other methods and parameter keep identical with embodiment 5.
Obtained by the present embodiment18The radiochemical purity of F-FMISO is greater than 95%, and radiation TLC yield is 50%.
Comparative example uses the glass-micropipe micro-pipe for not modifying preparation with the identical inner wall of internal diameter (2mm) in embodiment 2 dry18F ion reagent and synthesis18F-FMISO
Compared with Example 5, difference is only that replaces with glass-micropipe therein and 2 Central Plains of embodiment to the present embodiment
The glass-micropipe of beginning is identical, without the glass-micropipe (long 10cm, internal diameter 2mm) that inner wall is modified, after both ends install sealed interface additional,
It is directly accessed in the system of being automatically synthesized and uses.Other methods and parameter keep identical with embodiment 4.
Obtained by the present embodiment18The radiochemical purity of F-FMISO is greater than 95%, and radiation TLC yield is 45%.
It is above-mentioned dry in micro-pipe18F ion reagent and synthesis18In the embodiment 4,5,6 of F-FMISO, only micro-pipe caliber
Factor it is different, obtained by each embodiment18The radiation TLC yield of F-FMISO and drying18The quality of F ion reagent is directly related.
Comparatively, embodiment 5 is optimal, gained18The radiochemical purity of F-FMISO is greater than 95%, and radiation TLC yield is 85%,
Its corresponding parameter are as follows: glass-micropipe length be 10cm, internal diameter 2mm,18The injection rate of F ion reagent is 100 μ L, for pushing away
It is dynamic18The nitrogen stream flow velocity of F ion reagent is 100 μ L/min.It is prepared using this method18F-FMISO is 35 minutes time-consuming.Embodiment 5
Comparative example in, it is dry using micro-pipe is not modified with the identical inner wall of internal diameter (2mm) in embodiment 518F ion reagent and conjunction
At18F-FMISO, radiation TLC yield are greatly reduced, and are 45%.Illustrate that modifying micro-pipe inner wall is conducive to drying18F ion reagent.
In embodiment 5,7,8, only push18The nitrogen flow rate factor that F ion solution injects micro-pipe is different, and embodiment 5 is optimal, explanation
In the case where the nitrogen stream of proper flow rates pushes,18F ion solution is uniformly sprawled in micro-pipe inner wall, is conducive to drying18F ion reagent and
It is subsequent18The progress of F label reaction.Due to successively being carried out in same micro-pipe reactor18The drying of F ion reagent,18F replaces label
And hydrolysis improves synthesis yield so as to shorten the time of entire synthesis process.
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 in the case where not departing from idea of the invention and range
Change and modification.Although for example, with synthesis in embodiment18It is illustrated for F-FMISO, but the glass-micropipe and using this is micro-
The drying means of pipe can be used for other18The drying of F ion reagent, the synthesis for marking intermediate, such as18F-FDG.But no
The actual conditions of same reagent and synthetic reaction are different, can be adjusted.Similarly, the preparation method of glass-micropipe can also be with
According to being actually adjusted, as long as similar modification of surfaces can be prepared.Therefore all to take equivalent replacement or equivalent
The mode of transformation technical solution obtained, falls within the scope of protection of the present invention.
Claims (10)
1. a kind of micro-fluidic synthesis18The method of F-FMISO, it is characterised in that: synthetic reaction is in the glass-micropipe that inner wall is modified
It carries out, the glass-micropipe is in hollow tubular, and inboard wall of tube body forms rough non-smooth surface by modification；It is described
Method and step is as follows:
1) will18In F ion reagent implantation glass micro-pipe, it then is passed through air-flow to one end of glass-micropipe, is made18F ion reagent exists
Air-flow is sprawled to form liquid film in inner surface of tube wall under pushing；Then 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 glass-micropipe again, is then continually fed into one end of glass-micropipe
Air-flow obtains drying until acetonitrile evaporation drying18F ion reagent；
2) by the super dry second of precursor 1- (2 '--1 '-imidazole radicals of nitro) -2-O- THP trtrahydropyranyl -3-O- tosyl propylene glycol
Nitrile solution injection inner wall is attached with dry18In the glass-micropipe of F ion reagent, the both ends of closed glass micro-pipe and heating are complete
At18F replaces label reaction；Then air-flow is continually fed into one end of glass-micropipe until acetonitrile evaporation drying；
3) hydrochloric acid solution is injected into glass-micropipe again, hydrolysis is completed in the both ends of closed glass micro-pipe and heating；
4) hydrolyzate in glass-micropipe is isolated and purified, is obtained18F-FMISO solution.
2. a kind of micro-pipe synthesis as described in claim 118The method of F-FMISO, it is characterised in that: described18F ion reagent
For by K222/K2CO3The elution of acetonitrile/water solution first pass through enrichment in advance18The solution obtained after F ion.
3. a kind of micro-pipe synthesis as described in claim 118The method of F-FMISO, it is characterised in that: in the glass-micropipe
Diameter is 1~3mm.
4. a kind of micro-pipe synthesis as described in claim 118The method of F-FMISO, it is characterised in that: the system of the glass-micropipe
Preparation Method is as follows:
A) by after the heating of the mixed solution of cetyl trimethylammonium bromide and NaOH, ethyl orthosilicate is added and is stirred to react；So
Reaction solution is filled to the hollow glass micro-pipe cleaned afterwards；
B) glass-micropipe for filling reaction solution is dried, is sintered after reaction solution is dry, inner tubal wall is repaired in completion
Decorations；
C) sintered glass-micropipe is taken out, after cleaning and drying, is obtained for drying18The glass-micropipe of F ion reagent.
5. a kind of micro-pipe synthesis as claimed in claim 418The method of F-FMISO, it is characterised in that: in step a), glass is micro-
The cleaning step of pipe are as follows: glass-micropipe is successively immersed in deionized water, ethyl alcohol, acetone and deionized water and is cleaned by ultrasonic；Again will
It is ultrasonically treated, is then allowed to stand in mixed liquor in the mixed liquor of the glass-micropipe immersion concentrated sulfuric acid and hydrogen peroxide；It is finally that glass is micro-
Pipe is cleaned by ultrasonic several times in deionized water, drying.
6. a kind of micro-pipe synthesis as described in claim 118The method of F-FMISO, it is characterised in that: the separation of the hydrolyzate
Purification process are as follows: hydrolyzate is transferred to by AG50/AG11A8 resin column, Al2O3The columns in series of column and C18 column composition, with injection
Column is washed with water, eluate is filtered to obtain the final product18F-FMISO solution.
7. a kind of micro-pipe synthesis as described in claim 118The method of F-FMISO, it is characterised in that: be passed through the glass-micropipe
For the thermal current that dry air-flow is by heating.
8. a kind of micro-pipe synthesis as claimed in claim 1 or 718The method of F-FMISO, it is characterised in that: the air-flow is
Inert gas flow, preferably nitrogen stream.
9. a kind of micro-pipe synthesis as described in claim 118The method of F-FMISO, it is characterised in that: reagent in glass-micropipe
Bolus injection amount should meet: the reagent of all injections can be sprawled to form liquid film under air-flow promotion in inner surface of tube wall, and
Glass-micropipe will not be blown out.
10. a kind of micro-pipe synthesis as described in claim 118The method of F-FMISO: the glass-micropipe length is 10cm,
Internal diameter is 2mm,18The injection rate of F ion reagent is 100 μ L, and the air-flow velocity for being passed through the glass-micropipe is 100 μ L/min.
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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 |
| 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 |
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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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| CN104445215A (en) * | 2014-11-05 | 2015-03-25 | 上海大学 | Preparation method of hollow silicon dioxide nanomaterial |
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