CN109265506A - It is a kind of to prepare 16 α-18The method of F-17 beta estradiol - Google Patents
It is a kind of to prepare 16 α-18The method of F-17 beta estradiol Download PDFInfo
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- CN109265506A CN109265506A CN201811407131.6A CN201811407131A CN109265506A CN 109265506 A CN109265506 A CN 109265506A CN 201811407131 A CN201811407131 A CN 201811407131A CN 109265506 A CN109265506 A CN 109265506A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
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Abstract
16 α-are prepared the present invention relates to a kind of18The method of F-17 beta estradiol, which is characterized in that include the following steps, using precursor MMSE with18F‑Nucleophilic substitution is carried out, intermediate product is generated；Hydrochloric acid is added to the intermediate product, reaction is hydrolyzed, obtains hydrolysate；The hydrolysate is isolated and purified by half preparation HPLC, obtains 16 α-18F-17 beta estradiol；Preparation method provided by the present invention, technical process is succinct, easy to operate, can not only large dosageization, high-purity 16 α of preparation-18F-17 beta estradiol, and failure rate can be effectively reduced.
Description
Technical field
The present invention relates to radiochemistry technical field of medicine synthesis, and in particular to a kind of to prepare 16 α-18F-17 beta estradiol
Method.
Background technique
Breast cancer is the most common tumour of women, and shows quantity and rise year by year and the trend of rejuvenation, is seriously affected
Women is physically and mentally healthy.The expression of about 75% breast cancer tumour estrogen receptor (ER) is positive, and the expression status of ER is that breast cancer is important
Prognostic indicator, ER positive endocrinotherapy for breast cancer is effective.Clinically frequently with Immunohistochemical Method detection tissue specimen
ER expression, Immunohistochemical Method specificity is strong, susceptibility is high, but the shortcomings that detection method is invasive, isolated measuring, reflection
The only ER expression of lesion sample, the case where cannot comprehensively reflecting the ER bioactivity of portion's tumour, can not reflect whole body.
16α-18F-17 beta estradiol is (referred to as18F-FES) be estradiol cyclopentanoperhy drophenanthrene structure D 16, ring hydrogen
Quilt18F is substituted and is formed, and is the analog of estradiol, belongs to the ER molecular imaging agent of specificity；And in the prior art,18F-
FES Positron Emission Computed Tomography PET/CT imaging has the characteristics that sensitive, accurate, quantitative, hurtless measure, primary lesion
And metastatic lesion images simultaneously, can intuitively understand the activity condition of ER, to the assessment of disease, the determination of therapeutic scheme and pre-
It plays an important role afterwards etc., while quantitative analysis can also be carried out to acceptor levels.Therefore, clinically this Novel PET is imaged
The demand of agent is increasingly urgent to,18F-FES needs to obtain large dosage, high quality, efficiently synthesizes, and uses existing preparation process
Synthesis18F-FES, the drawbacks such as amount is few, purity is relatively low, failure rate is higher, this is right18The preparation process of F-FES proposes one
A little new requirements.
Summary of the invention
16 α-are prepared the purpose of the present invention is to provide a kind of18The method of F-17 beta estradiol, can not only large dosageization,
16 α of preparation-of high-purity18F-17 beta estradiol, and failure rate can be effectively reduced.
The technical scheme adopted by the invention is that:
It is a kind of to prepare 16 α-18The method of F-17 beta estradiol, includes the following steps:
Utilize precursor MMSEWith18F-Nucleophilic substitution is carried out, intermediate product is generated
Hydrochloric acid is added to the intermediate product, reaction is hydrolyzed, obtains hydrolysate
The hydrolysate is isolated and purified by half preparation HPLC, obtains 16 α-18F-17 beta estradiol；
Wherein, the half preparation HPLC, is 7~8min by mobile phase appearance time of acetonitrile, ethyl alcohol and water.
In a kind of preferred scheme, specific process flow are as follows:
Step 1, QMA capture: make to have18F-Target water by QMA column, and make18F-It is adsorbed on QMA column；
Preferably, in the step 1, positive pressure is applied to nitrogen, is had by nitrogen extruding18F-Target water, keep target water logical
Cross QMA column.
Step 2,18F-Release: make K222 and K2CO3Mixed solution by QMA column, and by QMA during passing through
On column18F-It elutes in reaction flask；
Step 3, for the first time drying: heating the reaction flask, and heating temperature is 100 DEG C, for evaporating K222
With K2CO3Mixed solution in water；
The addition of step 4, acetonitrile: appropriate anhydrous acetonitrile is added into the reaction flask；
Preferably, the amount of the anhydrous acetonitrile is 0.5mL.
Step 5, second of drying: the reaction flask is heated again, to evaporate the water in reaction flask；
The addition of step 6, precursor: precursor MMSE solution is added into the reaction flask；
Preferably, precursor MMSE is dissolved in anhydrous acetonitrile, obtains the precursor MMSE solution.
In a kind of preferred scheme, the preparation method of the precursor MMSE solution are as follows: 2mg precursor MMSE is dissolved in 1mL
Anhydrous acetonitrile in, obtain the precursor MMSE solution.
Step 7, fluorination: the closed reaction flask, and the reaction flask is heated, so that before described in reaction flask
Body MMSE solution with18F-Nucleophilic substitution is carried out, intermediate product is generated；
Preferably, in the step 7, reaction flask is heated to 115 DEG C, heating time is 15 minutes.
The addition of step 8, hydrochloric acid: appropriate certain density hydrochloric acid is added into the reaction flask；
Preferably, in the step 8, the concentration of the hydrochloric acid is 2M, and the amount for the hydrochloric acid being added in the reaction flask is
1.5mL。
Step 9, hydrolysis: heating the reaction flask, so that the intermediate product in reaction flask and the hydrochloric acid
Reaction is hydrolyzed, and obtains hydrolysate；
Preferably, in the step 9, reaction flask is heated to 120 DEG C, heating time is 200 seconds.
Step 10 adjusts pH value: a certain amount of sodium bicarbonate solution is added, into the reaction flask to adjust in reaction flask
The pH value of liquid；
Preferably, the mass fraction of the sodium bicarbonate solution is 5.6%.
Step 11, sample introduction: the solution in the reaction flask being transferred in the sample injector of half preparation liquid phase, and from it is described into
The solution is drawn into syringe in sample device, realizes sample introduction；
Step 12, HPLC are isolated and purified: the separation condition of the half preparation liquid phase is: using YMC-PACK-ODS-AM half
Preparative scale chromatography column；The volume ratio of acetonitrile, ethyl alcohol and water is 30:30:40, flow velocity 4.0mL/min, ultraviolet wavelength 280nm；
When liquid chromatogram curve just radioactivity peak will occur, start to collect 16 α-18F-17 beta estradiol, and will be collected by pipeline
16 α-arrived18F-17 beta estradiol inputs revolving bottle, when the radioactivity peak of liquid chromatogram curve is reduced to baseline, stops collecting 16
α-18F-17 beta estradiol；
Step 13 is rinsed: the pipeline is rinsed using ethyl alcohol, so that 16 α-of residual in the duct18F-17 beta estradiol
It is washed into the revolving bottle；
Step 14, outstanding steaming: the revolving bottle is heated to 180 DEG C, and is rotated, is rotated for removing ethyl alcohol；
Step 15, product are collected: being injected the physiological saline containing ethyl alcohol into the revolving bottle, and made dissolved with 16 α-18F-17
The physiological saline containing ethyl alcohol of beta estradiol is filtered by filter membrane, and collects filtrate.Filtrate is synthetic 16
α-18F-17 beta estradiol.
Further, the content of ethyl alcohol is 10% in the physiological saline containing ethyl alcohol.
Preferably, the filter membrane is the sterilised membrane filter of 0.22um.
Preferably, preparation 16 α-18The technical process of F-17 beta estradiol is enterprising in CFN-MPS-200 synthesis module
Capable.
Preferably, in the step 218The addition of acetonitrile in the release of F-, step 4, in step 6 precursor addition and step
The mode that the addition of hydrochloric acid is all made of negative pressure sucking in rapid 8 is realized.
Preferably, the step 1 applies positive pressure to nitrogen, is had by nitrogen extruding18F-Target water, pass through target water
QMA column；And/or in the step 11, positive pressure is applied to nitrogen, is squeezed by nitrogen and all shifts the solution in reaction flask
Into the sample injector.
One kind is for synthesizing 16 α-18The system of F-17 beta estradiol, including target water receiving flask, No. 1 reagent bottle, No. 2 reagents
Bottle, No. 3 reagent bottles, No. 4 reagent bottles, No. 5 reagent bottles, cutting ferrule, QMA column, reaction flask, the first temperature controller, vacuum pump, efficiently
Liquid chromatograph and controller, wherein
The target water receiving flask has for containing18F-Target water, No. 1 reagent bottle is for containing K222 and K2CO3's
Mixed solution, for No. 2 reagent bottles for containing anhydrous acetonitrile, No. 3 reagent bottles are described for containing precursor MMSE solution
No. 4 reagent bottles are for containing hydrochloric acid, and No. 5 reagent bottles are for containing sodium bicarbonate solution；
Pipe network and several valves are provided on the cutting ferrule, the valve is respectively arranged at the pipe network, and the target water is received
Collection bottle, No. 1 reagent bottle, No. 2 reagent bottles, No. 3 reagent bottles, No. 4 reagent bottles and No. 5 reagent bottles pass through pipeline and the pipe respectively
Net is connected；
The both ends of the QMA column pass through pipeline respectively and are connected with the pipe network, and QMA column is in acquisition target water18F-；
The reaction flask is connected by pipeline with the pipe network, and reaction flask is for being reacted；
The vacuum pump is connected by pipeline with the pipe network, and is connected with the controller, and vacuum pump is for controlling
Negative pressure is generated under the control of device processed, to carry out negative pressure transportation；
The sample injector of the high performance liquid chromatograph is connected by pipeline with the pipe network, the high performance liquid chromatograph
For being isolated and purified to the product of collection；
First temperature controller is set at the reaction flask, and is connected with the controller, in controller
Control under adjusting reaction flask temperature；
Valve is provided on the pipeline, the controller is used to control the on/off of each valve, and realizes that target water is collected
Bottle, No. 1 reagent bottle, No. 2 reagent bottles, No. 3 reagent bottles, No. 4 reagent bottles and No. 5 reagent bottles are sequentially communicated with the reaction flask.
It further, further include outstanding steaming bottle, No. 6 reagent bottles, filter and product receiving flask, wherein the outstanding steaming bottle
It is connected by pipeline with the output end of the high performance liquid chromatograph, the product receiving flask and No. 6 reagent bottles pass through pipe respectively
Road is connected with the outstanding steaming bottle, and the filter is set on the outstanding pipeline steamed between bottle and product receiving flask, and No. 6 reagent bottles are used
In containing the physiological saline containing ethyl alcohol, and the physiological saline containing ethyl alcohol is conveyed to the outstanding steaming bottle, filter be used for into
Row filtering, and enter filtrate in the product receiving flask.
Preferably, in No. 6 reagent bottles, the content of ethyl alcohol is 10% in the physiological saline containing ethyl alcohol, contains ethyl alcohol
Physiological saline amount be 10mL.
It further, further include No. 7 reagent bottles and second temperature controller, No. 7 reagent bottles pass through triple valve and company
The pipeline of logical outstanding steaming bottle and high performance liquid chromatograph is connected, and No. 7 reagent bottles are for containing ethyl alcohol, the second temperature controller
It is set at the outstanding steaming bottle, and is connected with the controller, for the outstanding steaming bottle of heating under the control of the controller.
Further, first temperature controller and second temperature controller respectively include temperature sensor, the temperature
Degree sensor is used to detect reaction flask and the outstanding temperature for steaming bottle, and is transferred to controller.
It further, further include target water returnable bottle, the target water returnable bottle is connected with the pipe network by pipeline, is used for
It is connected under the control of the controller with the QMA column, and is lost for collecting18F-Target water afterwards.
It further, further include delivery pump, the delivery pump passes through pipeline respectively and the target water receiving flask, target water recycle
Bottle, No. 6 reagent bottles, No. 7 reagent bottles and the outstanding bottle that steams are connected, and delivery pump is connected with the controller, and delivery pump is for controlling
Input has the nitrogen of certain pressure under the control of device processed, to carry out pressure conveying to reagent.
It further, further include radio-metric probe, the radio-metric probe is respectively arranged at the QMA column and the reaction
At bottle, and it is connected respectively with the controller, is set to the radio-metric probe at QMA column for detecting in target water18F-Whether
It is all adsorbed on QMA column, is set to the radio-metric probe at reaction flask for detecting on QMA column18F-Whether all elution
Into reaction flask.
It further, further include display and camera, the camera is respectively arranged at the reaction flask, efficient liquid phase
At chromatographic sample injector and the outstanding steaming bottle, the display and each camera are connected with the controller respectively, camera shooting
Head is respectively used to acquisition reaction flask, sample injector and the outstanding image information for steaming bottle, and is shown using display.
Preferably, the valve on the cutting ferrule is three-way valve.
In a kind of preferred scheme, the pipe network includes 17 ports, wherein port one and port ten pass through the first pipeline
It is connected, port two is connected by the second pipeline and triple valve one with first pipeline, and port nine passes through with port 15
Third pipeline is connected, and port three is connected by the 4th pipeline and triple valve six with the third pipeline, and port four passes through the
Five pipelines and triple valve two are connected with the 4th pipeline, and port five passes through the 6th pipeline and triple valve three and the 4th pipe
Line is connected, and port seven is connected by the 7th pipeline and triple valve four with the 4th pipeline, and port six passes through the 8th pipeline
And triple valve five is connected with the 7th pipeline, port eight is connected by the 9th pipeline and triple valve seven with the third pipeline
Logical, port 11 is connected by the tenth pipeline and triple valve eight with first pipeline, and port 13 passes through the 11st pipeline
It is connected with port 14, port 12 is connected by the 12nd pipeline and triple valve nine with the 11st pipeline, port
16 are connected by the 13rd pipeline with port 17, and are provided with valve on the 13rd pipeline, the 14th pipeline
One end is connected with the 4th pipeline, and the other end is connected by triple valve ten with the 11st pipeline.
Further, the cutting ferrule further includes bottom plate, and several clamps are provided on the bottom plate, and the clamp is respectively used to
Each pipeline in the fixed pipe network.
In a kind of preferred scheme, the bottom plate is rectangular plate structure.
Preferably, the setting direction of the clamp is divided into two classes, and a kind of clamp is set to along the length direction of the bottom plate
Bottom plate, another kind of clamp are set to bottom plate along the width direction of the bottom plate.
Further, be additionally provided with several notches on the bottom plate, the notch for realizing bottom plate fixation.
Compared with prior art, a kind of 16 α-are prepared using provided by the invention18The method of F-17 beta estradiol, technique mistake
Journey is succinct, easy to operate, can not only large dosageization, high-purity 16 α of preparation-18F-17 beta estradiol, and can effectively drop
Low failure rate.
Detailed description of the invention
In order to illustrate the technical solution of the embodiments of the present invention more clearly, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not construed as pair
The restriction of range for those of ordinary skill in the art without creative efforts, can also be according to this
A little attached drawings obtain other relevant attached drawings.
Attached drawing
Fig. 1 be provided in the embodiment of the present invention 1 a kind of prepare 16 α-18The process flow diagram of F-17 beta estradiol.
Fig. 2 is that during the preparation process, crude product prepares the peak figure out isolated and purified on HPLC half.
Fig. 3 is product standard product (i.e. 16 α-18F-17 beta estradiol) analyzing the uv-spectrogram on HPLC.
Fig. 4 is product (i.e. 16 α-prepared using method provided by embodiment 118F-17 beta estradiol) in analysis HPLC
On radiation map.
Fig. 5 is product (i.e. 16 α-prepared using method provided by embodiment 118F-17 beta estradiol) in analysis HPLC
On uv-spectrogram.
Fig. 6 is that the one kind provided in the embodiment of the present invention 3 is used to synthesize 16 α-18The structure of the system of F-17 beta estradiol is shown
It is intended to.
Description of symbols in figure
The reagent bottle 104,4 reagent bottle 105,5 of reagent bottle 103,3 of reagent bottle 102,2 of target water receiving flask 101,1
Reagent bottle 106, cutting ferrule 107, QMA column 108, reaction flask 109, the first temperature controller 110, vacuum pump 111, high performance liquid chromatography
Instrument 112, valve 113,
Outstanding steaming 201, No. 6 reagent bottles 202 of bottle, filter 203, product receiving flask 204,
No. 7 reagent bottles 301, second temperature controller 302, triple valve 303,
Delivery pump 401, target water returnable bottle 402, radio-metric probe 403,
Port 1, port 22, port 33, port 44, port 55, port 66, port 77, port 88, port
99, port 10, port 11, port 12, port 13, port 14, port 15, port 16
16, port 17,
First pipeline 501, the second pipeline 502, third pipeline 503, the 4th pipeline 504, the 5th pipeline 505, the 6th pipeline
506, the 7th pipeline 507, the 8th pipeline 508, the 9th pipeline 509, the tenth pipeline 510, the 11st pipeline 511, the 12nd pipeline
512, the 13rd pipeline 513,
Triple valve 1, triple valve 2 602, triple valve 3 603, triple valve 4 604, triple valve 5 605, triple valve six
606, triple valve 7 607, triple valve 8 608, triple valve 9 609, triple valve 10.
Specific embodiment
Below in conjunction with attached drawing in the embodiment of the present invention, technical solution in the embodiment of the present invention carries out clear, complete
Ground description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Usually exist
The component of the embodiment of the present invention described and illustrated in attached drawing can be arranged and be designed with a variety of different configurations herein.Cause
This, is not intended to limit claimed invention to the detailed description of the embodiment of the present invention provided in the accompanying drawings below
Range, but it is merely representative of selected embodiment of the invention.Based on the embodiment of the present invention, those skilled in the art are not doing
Every other embodiment obtained under the premise of creative work out, shall fall within the protection scope of the present invention.
Embodiment 1
It is provided in the present embodiment and a kind of prepares 16 α-18The method of F-17 beta estradiol, includes the following steps:
Firstly, utilizing precursor MMSEWith18F-Nucleophilic substitution is carried out, in generation
Between product
Then, hydrochloric acid is added to the intermediate product and reaction is hydrolyzed, obtain hydrolysateObtaining hydrolysate at this time is18F-FES(16α-18F-17 beta estradiol is write a Chinese character in simplified form, hereinafter no longer
Repeat) crude product, need further purification process；
Finally, the hydrolysate is isolated and purified by half preparation HPLC, it is hereby achieved that purity is higher18F-FES product；
Wherein, the half preparation HPLC, using acetonitrile, ethyl alcohol and water as mobile phase, appearance time is 7~8min.
Preparation method provided by the present embodiment is simple, efficient, prepares 16 α-using this method18F-17 beta estradiol, no
Only can large dosageization, high-purity 16 α of preparation-18F-17 beta estradiol, and the failure in preparation process can be effectively reduced
Rate.
As shown in Figure 1, specifically, in a kind of preferred scheme provided by the present embodiment, it is specific to prepare 16 α-18The process flow of F-17 beta estradiol are as follows:
Step 1, QMA capture: make to have18F-Target water by QMA column 108, and make18F-It is adsorbed on QMA column 108.
In preferred scheme, in the step 1, positive pressure can be applied to nitrogen, be had by nitrogen extruding18F-Target
Water makes target water by QMA column 108, during target water passes through QMA column 108, in target water18F-QMA column can be adsorbed on
On 108, thus will18F-It is separated from target water.
Step 2,18F-Release: make K222 and K2CO3Mixed solution by QMA column 108, and by during will
On QMA column 10818F-It elutes in reaction flask 109；So as to will be on QMA column 10818F-It is transferred in reaction flask 109；
In this step, K222 and K2CO3Mixed solution be by K222 solution and K2CO3Gained after solution is mixed
Solution, wherein the amount of K222 solution can be 0.7mL, K2CO3The amount of solution can be 0.2mL.
In the preferred scheme, the preparation method of K222 solution, which may is that, is dissolved in the anhydrous second of 7mL for 220mg K222 powder
In nitrile, to obtain K222 solution；The preparation method of K2CO3 solution is: by 58.5mg K2CO3Powder is dissolved in 2mL water, thus
K2CO3 solution can be obtained.
Step 3, for the first time drying: heating the reaction flask 109, and heating temperature is 100 DEG C, will pass through heating
Evaporate K222 and K2CO3Mixed solution in water；
In the present embodiment, nitrogen can be pressed into reaction flask 109 by one end of reaction flask 109 and forms positive pressure,
Meanwhile another termination vacuum pump 111 of reaction flask 109 forms negative pressure, then heats again to reaction flask 109, in this process
In, heat that evaporated moisture can be convenient as the direction of pressure drop is mobile, to be discharged from reaction flask 109.
The addition of step 4, acetonitrile: appropriate anhydrous acetonitrile is added into the reaction flask 109.
Preferably, in this step, the amount of the anhydrous acetonitrile can be 0.5mL.
Step 5, second of drying: the reaction flask 109 is heated again, to evaporate in reaction flask 109
Water.
Preferably, in this step, the temperature of heating can preferentially use 95 DEG C, thoroughly to remove in reaction flask 109
Water, it is ensured that reacts in next step is normally carried out.
The addition of step 6, precursor: precursor MMSE solution is added into the reaction flask 109.
In preferred scheme, precursor MMSE is dissolved in anhydrous acetonitrile, the precursor MMSE solution can be obtained.
In a kind of preferred scheme provided by the present embodiment, the preparation method of the precursor MMSE solution are as follows: before 2mg
Body MMSE is dissolved in the anhydrous acetonitrile of 1mL, it is hereby achieved that the precursor MMSE solution.
It in the present embodiment, can be preferentially using the precursor MMSE of German ABX's production, the chemical structure of precursor MMSE
It is as follows:
Step 7, fluorination: the closed reaction flask 109, and the reaction flask 109 is heated, so that reaction flask 109
In the precursor MMSE solution with18F-Nucleophilic substitution is carried out, intermediate product is generated
Preferably, in this step, reaction flask 109 can be heated to 115 DEG C, heating time is 15 minutes, to ensure
Reaction is normally carried out, and reaction principle is as follows:
The addition of step 8, hydrochloric acid: appropriate certain density hydrochloric acid is added into the reaction flask 109.
Preferably, in this step, the concentration of the hydrochloric acid can be 2M, and the hydrochloric acid in the reaction flask 109 is added
Amount can be 1.5mL.
Step 9, hydrolysis: the reaction flask 109 is heated, so that the intermediate product and institute in reaction flask 109
It states hydrochloric acid and reaction is hydrolyzed, and obtain hydrolysate
Preferably, in this step, needing for reaction flask 109 to be heated to 120 DEG C, heating time is 200 seconds, so that it is guaranteed that
That reacts is normally carried out, and specific reaction process is as follows:
At this point, obtained 16 α-18F-17 beta estradiol is crude product, it is also necessary to is further processed.
Step 10 adjusts pH value: a certain amount of sodium bicarbonate solution is added into the reaction flask 109, to adjust reaction
The pH value of liquid in bottle 109.
Preferably, in the present embodiment, the mass fraction of the sodium bicarbonate solution can be 5.6%, and sodium bicarbonate is molten
The amount of liquid can be 1.5mL.
Step 11, sample introduction: the solution in the reaction flask 109 being transferred in the sample injector of half preparation liquid phase, and from institute
It states in sample injector and the solution is drawn into syringe, realize sample introduction；
In this step, nitrogen can be pressed into reaction flask 109, and gives positive pressure, so as to easily make to react
Crude product in bottle 109 is transferred completely into the sample injector of half preparation liquid phase；Then crude product injection half is made by syringe
In standby liquid phase, to complete sample introduction work.
Step 12, HPLC are isolated and purified: the separation condition of the half preparation liquid phase is: using YMC-PACK-ODS-AM half
Preparative scale chromatography column；The volume ratio of acetonitrile, ethyl alcohol and water is 30:30:40, flow velocity 4.0mL/min, ultraviolet wavelength 280nm；
When liquid chromatogram curve just radioactivity peak will occur (when i.e. liquid chromatogram curve is begun to ramp up), start to collect18F-FES, and
It will be collected by pipeline18F-FES inputs revolving bottle, when the radioactivity peak of liquid chromatogram curve is reduced to baseline, stops
It collects18F-FES, as shown in Fig. 2, after the step, can obtain the higher product of radiochemical purity (18F-FES), such as
It, not only can be with by comparison diagram 3, Fig. 4 and Fig. 5 it is found that using technique provided by this method shown in Fig. 3, Fig. 4 and Fig. 5
Effective preparation 16 α-18F-17 beta estradiol product, and prepared 16 α-18The radiochemical purity of F-17 beta estradiol
It is very high, it is very beneficial for imaging；
Those skilled in the art is perfectly clear the process and operation that HPLC is isolated and purified, and is not discussed here.
Step 13 is rinsed: the pipeline is rinsed using ethyl alcohol, so that remaining in the duct18F-FES is washed into described
In revolving bottle；
It is usually necessary to use pipelines by the transferred product after HPLC is isolated and purified into revolving bottle, will necessarily in pipeline
Residual fraction product causes to waste, therefore in this step, using ethyl alcohol flushing pipe, product can be reduced to greatest extent
Loss, fully enters the product being attached on duct wall in revolving bottle.
Step 14, outstanding steaming: the revolving bottle is heated to 180 DEG C, and is rotated, revolving is used for flushing pipe for removing
The ethyl alcohol in road realizes the purification to product.
Step 15, product collect: into the revolving bottle inject the physiological saline containing ethyl alcohol, and make dissolved with18The institute of F-FES
It states the physiological saline containing ethyl alcohol to be filtered by filter membrane, and collects filtrate, filtrate is synthetic18F-FES；By this step
Suddenly, it help to obtain higher 16 α-of purity18F-17 beta estradiol.
It is appreciated that18F-FES can be dissolved in the physiological saline containing ethyl alcohol, as an example, the physiological saline containing ethyl alcohol
The content of middle ethyl alcohol is 10%, and as an example, the amount of the physiological saline containing ethyl alcohol can be 10mL, and be provided in the present embodiment
Preferred embodiment in, the filter membrane can preferentially use 0.22um sterilised membrane filter.
Further, in the prioritization scheme provided by the present embodiment, in the step 218F-Release, second in step 4
The addition of hydrochloric acid be realized by the way of being sucked using negative pressure in the addition and step 8 of precursor in the addition of nitrile, step 6,
Required reagent is added in reaction flask 109 by the way of negative pressure sucking, it is very convenient.
Embodiment 2
It is a kind of provided in above-described embodiment 1 to prepare 16 α-18The method of F-17 beta estradiol, technical process can be
It is carried out on CFN-MPS-200 synthesis module.
CFN-MPS-200 synthesis module is to some novel positron radioactivity imaging agents (including 16 α-18F-17 β-female two
Alcohol) it is synthesized, there are some new advantages on synthesis technology, specifically include that
First, which uses novel cutting ferrule technology, synthesis pipeline is concentrated in lesser cutting ferrule 107, gas
Close property is good, has both avoided route of the gas in pipeline is too long from blocking, and in turn avoids a large amount of residuals of the reagent in pipeline.
Second, self-check program is configured in synthesis module, i.e., can carry out gas stream to each synthetic line before synthesis
Amount and airtight test, have only passed through throughput and airtight test, can just enter synthesis step；In this way, in synthesis
The preceding possibility for just eliminating pipeline blocking or gas leakage, provides better synthetic environment.
Using CFN-MPS-200 synthesis module, then cooperate method described in embodiment 1, it not only can be large dosage of, high-purity
16 α of realization-of degree18The preparation of F-17 beta estradiol, and 16 α of preparation-that can be automated18F-17 beta estradiol, very just
Just, efficiently, facts proved that, 16 α-are prepared using CFN-MPS-200 synthesis module18F-17 beta estradiol, yield can reach several
Hundred mCi, and higher 16 α-of top coal drawing can be obtained18F-17 beta estradiol.
Embodiment 3
The present embodiment 3 is a kind of according to provided in embodiment 1 to prepare 16 α-18The method of F-17 beta estradiol, provides
One kind is for synthesizing 16 α-18The system of F-17 beta estradiol；
The system mainly includes 103, No. 3 reagent bottles 104,4 of reagent bottle of reagent bottle 102,2 of target water receiving flask 101,1
Number 105, No. 5 reagent bottles 106 of reagent bottle, cutting ferrule 107, QMA column 108, reaction flask 109, the first temperature controller 110, vacuum pump
111, high performance liquid chromatograph 112 and controller, as shown in Figure 6, wherein
The target water receiving flask 101 has for containing18F-Target water, No. 1 reagent bottle 102 for contain K222 with
K2CO3Mixed solution, No. 2 reagent bottles 103 are for containing anhydrous acetonitrile, and No. 3 reagent bottles 104 are for containing precursor
MMSE solution, No. 4 reagent bottles 105 are for containing hydrochloric acid, and No. 5 reagent bottles 106 are for containing sodium bicarbonate solution；
Pipe network and several valves are provided on the cutting ferrule 107, the valve is respectively arranged at the pipe network, the target water
The reagent bottle 103,3 of reagent bottle 102,2 reagent bottle 105 of reagent bottle 104,4 of receiving flask 101,1 and No. 5 reagent bottles 106
It is connected respectively by pipeline with the pipe network；
The both ends of the QMA column 108 pass through pipeline respectively and are connected with the pipe network, and QMA column 108 is in acquisition target water
's18F-；
The reaction flask 109 is connected by pipeline with the pipe network, and reaction flask 109 is for being reacted；
The vacuum pump 111 is connected by pipeline with the pipe network, and is connected with the controller, and vacuum pump 111 is used
In generating negative pressure under the control of the controller, to be conveyed using negative pressure, that is, each reagent of negative pressure transportation is utilized；
The sample injector of the high performance liquid chromatograph 112 is connected by pipeline with the pipe network, the high-efficient liquid phase color
Spectrometer 112 is for isolating and purifying the product of collection；Using high performance liquid chromatograph 112, semipreparative height can be used
Effect liquid phase chromatogram method (High Performance Liquid Chromatography, abbreviation HPLC) separate to product pure
Change.
First temperature controller 110 is set at the reaction flask 109, and is connected with the controller, is used for
The temperature of adjusting reaction flask 109 under the control of controller；Such as reaction flask 109 is heated, so that the temperature of reaction flask 109
It is maintained at a certain temperature etc..
Valve 113 is provided on the pipeline, the controller is for controlling each valve (including the valve and pipe on cutting ferrule
The valve of road) on/off, and realize 103, No. 3 reagent bottles of reagent bottle of reagent bottle 102,2 of target water receiving flask 101,1
104, No. 4 reagent bottles 105 and No. 5 reagent bottles 106 are sequentially communicated with the reaction flask 109；So as to according to being mentioned in embodiment 1
Step in the method for confession carries out 16 α-18The synthesis of F-17 beta estradiol is automatically synthesized, it is hereby achieved that purity is relatively high
16 α-18F-17 beta estradiol.
As shown in fig. 6, in further scheme provided by the present embodiment, further include it is outstanding steam 201, No. 6 reagent bottles 202 of bottle,
Filter 203 and product receiving flask 204, wherein the outstanding steaming bottle 201 passes through pipeline and the high performance liquid chromatograph 112
Output end be connected, the product receiving flask 204 and No. 6 reagent bottles 202 are connected by pipeline with the outstanding steaming bottle 201 respectively,
The filter 203 is set on the outstanding pipeline steamed between bottle 201 and product receiving flask 204, and No. 6 reagent bottles 202 are for containing
Physiological saline containing ethyl alcohol, and the physiological saline containing ethyl alcohol is conveyed to the outstanding steaming bottle 201, filter 203 was for carrying out
Filter, and enter filtrate in the product receiving flask 204；The loss of collected product is lower in product receiving flask 204, product
Purity is higher, to be conducive to 16 α-for obtaining large dosageization, high-purity by the system18F-17 beta estradiol.
As an example, in the present embodiment, the amount of the physiological saline containing ethyl alcohol in No. 6 reagent bottles 202 can be 10mL,
And the content of ethyl alcohol can be 10% in the physiological saline containing ethyl alcohol, the physiological saline containing ethyl alcohol is mainly used for dissolving 16 α-18F-
17 beta estradiols.
As shown in fig. 6, further including No. 7 reagent bottles 301 and second temperature in the further scheme provided by the present embodiment
Controller 302, No. 7 reagent bottles 301 pass through triple valve 303 and the pipe for being connected to outstanding steaming bottle 201 and high performance liquid chromatograph 112
Road is connected, and No. 7 reagent bottles 301 are used for flushing pipeline, the second temperature controller 302 for containing ethyl alcohol, the ethyl alcohol
It is set at the outstanding steaming bottle 201, for the outstanding steaming bottle 201 of heating under the control of the controller.
Triple valve can be opening/closing in the realization of the controller of controller, and No. 7 reagent bottles 301 may be implemented and hang to steam bottle 201
Connection steams bottle 201 to hang the ethyl alcohol input in No. 7 reagent bottles 301, and during conveying, pipeline is rushed in realization
It washes.
Further, first temperature controller 110 and second temperature controller 302 respectively include temperature sensor,
The temperature sensor is used to detect reaction flask 109 and the outstanding temperature for steaming bottle 201, and is transferred to controller, so as to controller into
Trip temperature is adjusted；As an example, the first temperature controller 110 and second temperature controller 302 respectively further comprise heater, so as to
It is heated.
As shown in fig. 6, it is further, it further include target water returnable bottle 402, the target water returnable bottle 402 passes through pipeline and institute
It states pipe network to be connected, be lost for being connected under the control of the controller with the QMA column 108, and for collecting18F-Target afterwards
Water.
As shown in fig. 6, it is further, it further include delivery pump 401, the delivery pump 401 passes through pipeline and the target respectively
Water receiving flask 101, the reagent bottle 301 of reagent bottle 202,7 of target water returnable bottle 402,6 and the outstanding bottle 201 that steams are connected, delivery pump
401 are connected with the controller, and delivery pump 401 has the nitrogen of certain pressure for input under the control of the controller, so as to
Pressure conveying is carried out to reagent.
As shown in fig. 6, it is further, it further include radio-metric probe 403, the radio-metric probe 403 is respectively arranged at institute
It states at QMA column 108 and the reaction flask 109, and be connected respectively with the controller, is set to the radioactivity at QMA column 108 and visits
First 403 for detecting in target water18F-Whether all it is adsorbed on QMA column 108, is set to the radioactivity at reaction flask 109 and visits
First 403 for detecting on QMA column 10818F-All whether elution is into reaction flask 109.
It further, further include display and camera, the camera is respectively arranged at the reaction flask 109, efficiently
At the sample injector of liquid chromatograph 112 and the outstanding steaming bottle 201, the display and each camera respectively with the control
Device is connected, and camera is respectively used to acquisition reaction flask 109, sample injector and the outstanding image information for steaming bottle 201, and utilizes display
It is shown.To facilitate operator remotely to be monitored, so as to the process of strict control synthesis, for example, can be by taking the photograph
As head check whether reagent is added in reaction flask 109, whether reaction flask 109 is evaporated, the numerical value of radio-metric probe 403 whether not
It is further added by, and operator can enter back into next step after through camera observation and certain situation, so as to true
It protects each step all to go on smoothly, and then the probability of synthesis failure can be greatly reduced.
In the present embodiment, the valve on cutting ferrule 107 can be three-way valve.
Specifically, the pipe network in cutting ferrule 107 includes 17 ends in a kind of preferred scheme provided by the present embodiment
Mouthful, wherein port 1 is connected with port 10 by the first pipeline 501, and port 22 passes through the second pipeline 502 and triple valve
One 601 are connected with first pipeline 501, and port 99 is connected with port 15 by third pipeline 503, port 33
Be connected by the 4th pipeline 504 and triple valve 6 606 with the third pipeline 503, port 44 by the 5th pipeline 505 and
Triple valve 2 602 is connected with the 4th pipeline 504, port 55 by the 6th pipeline 506 and triple valve 3 603 with it is described
4th pipeline 504 is connected, and port 77 is connected by the 7th pipeline 507 and triple valve 4 604 with the 4th pipeline 504,
Port 66 is connected by the 8th pipeline 508 and triple valve 5 605 with the 7th pipeline 507, and port 88 passes through the 9th pipe
Line 509 and triple valve 7 607 are connected with the third pipeline 503, and port 11 passes through the tenth pipeline 510 and triple valve eight
608 are connected with first pipeline 501, and port 13 is connected by the 11st pipeline 511 with port 14, port
12 are connected by the 12nd pipeline 512 and triple valve 9 609 with the 11st pipeline 511, and port 16 passes through
13rd pipeline 513 is connected with port 17, and is provided with valve on the 13rd pipeline 513 and (is also possible to threeway
Valve), one end of the 14th pipeline is connected with the 4th pipeline 504, and the other end passes through triple valve 10 and the described 11st
Pipeline 511 is connected.
16 α-are prepared using this system, and according to method provided in embodiment 118During F-17 beta estradiol,
Controller can pass through triple valve (i.e. triple valve 1, triple valve two each in valve 113 each in control system and cutting ferrule 107
602 ..., the on/off of triple valve 10 610) runs synthesis process smoothly, conveniently, accurately, can not only be big
16 α of preparation-of dosage, high-purity18F-17 beta estradiol, and the failure rate of synthesis can be effectively reduced；As an example, exist
In step 1 provided by embodiment 1, it is desirable that will have18F-Target water by QMA column 108, and make18F-It is adsorbed on QMA column 108
On；Using this system, controller can pass through control triple valve 1, triple valve 8 608, triple valve 9 609 and triple valve
10, so that target water receiving flask 101, QMA column 108 and reaction flask 109 are sequentially communicated, the then valve in control system
113, so that delivery pump 401 is connected to target water receiving flask 101, reaction flask 109 is connected to vacuum pump 111, finally by delivery pump
401 conveyings have the nitrogen of pressure, negative pressure are generated by vacuum pump 111, so that the target water in target water receiving flask 101
By QMA column 108, so that in target water18F-Be adsorbed on QMA column 108, so conveniently, be efficiently completed step 1, remaining step
Suddenly stringent control can be carried out by controller, to complete 16 α-18The preparation of F-17 beta estradiol, here no longer one by one
It enumerates.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
Those familiar with the art in the technical scope disclosed by the present invention, can easily think of the change or the replacement, and should all contain
Lid is within protection scope of the present invention.
Claims (10)
1. a kind of prepare 16 α-18The method of F-17 beta estradiol, which comprises the steps of:
Utilize precursor MMSEWith18F-Nucleophilic substitution is carried out, intermediate product is generated
Hydrochloric acid is added to the intermediate product, reaction is hydrolyzed, obtains hydrolysateIt will be described
Hydrolysate is isolated and purified by half preparation HPLC, obtains 16 α-18F-17 beta estradiol；
Wherein, the half preparation HPLC, using acetonitrile, ethyl alcohol and water as mobile phase, appearance time is 7~8min.
2. preparation 16 α-according to claim 118The method of F-17 beta estradiol, which is characterized in that process flow are as follows:
Step 1, QMA capture: make to have18F-Target water by QMA column, and make18F-It is adsorbed on QMA column；
Step 2,18F-Release: make K222 and K2CO3Mixed solution by QMA column, and will be on QMA column during passing through
's18F-It elutes in reaction flask；
It is step 3, dry for the first time: the reaction flask is heated, heating temperature is 100 DEG C, for evaporate K222 with
K2CO3Mixed solution in water；
The addition of step 4, acetonitrile: appropriate anhydrous acetonitrile is added into the reaction flask；
Step 5, second of drying: the reaction flask is heated again, to evaporate the water in reaction flask；
The addition of step 6, precursor: precursor MMSE solution is added into the reaction flask；
Step 7, fluorination: the closed reaction flask, and the reaction flask is heated, so that the precursor in reaction flask
MMSE solution with18F-Nucleophilic substitution is carried out, intermediate product is generated；
The addition of step 8, hydrochloric acid: appropriate certain density hydrochloric acid is added into the reaction flask；
Step 9, hydrolysis: heating the reaction flask, so that the intermediate product in reaction flask and the hydrochloric acid carry out
Hydrolysis, and obtain hydrolysate；
Step 10 adjusts pH value: the sodium bicarbonate solution that quantitative mass fraction is 5.6% is added, into the reaction flask to adjust
Save the pH value of liquid in reaction flask；
Step 11, sample introduction: the solution in the reaction flask being transferred in the sample injector of half preparation liquid phase, and from the sample injector
It is middle that the solution is drawn into syringe, realize sample introduction；
Step 12, HPLC are isolated and purified: the separation condition of half preparation liquid phase is: using the semi-preparative color of YMC-PACK-ODS-AM
Compose column；The volume ratio of acetonitrile, ethyl alcohol and water is 30:30:40, flow velocity 4.0mL/min, ultraviolet wavelength 280nm；When liquid phase color
When radioactivity peak will just occur in spectral curve, start to collect 16 α-18F-17 beta estradiol, and by pipeline by collected 16 α
-18F-17 beta estradiol inputs revolving bottle, when the radioactivity peak of liquid chromatogram curve is reduced to baseline, stops collecting 16 α-18F-
17 beta estradiols；
Step 13 is rinsed: the pipeline is rinsed using ethyl alcohol, so that 16 α-of residual in the duct18F-17 beta estradiol is rushed
It washes in the revolving bottle；
Step 14, outstanding steaming: the revolving bottle is heated to 180 DEG C, and is rotated, is rotated for removing ethyl alcohol；
Step 15, product are collected: being injected the physiological saline containing ethyl alcohol into the revolving bottle, and made dissolved with 16 α-18F-17 β-female
The salt water containing ethyl alcohol of glycol is filtered by filter membrane, and collects filtrate.
3. preparation 16 α-according to claim 218The method of F-17 beta estradiol, which is characterized in that in the step 4,
The amount of the anhydrous acetonitrile is 0.5mL.
4. preparation 16 α-according to claim 218The method of F-17 beta estradiol, which is characterized in that in the step 7,
Reaction flask is heated to 115 DEG C, heating time is 15 minutes.
5. preparation 16 α-according to claim 218The method of F-17 beta estradiol, which is characterized in that in the step 8,
The concentration of the hydrochloric acid is 2M, and the amount that the hydrochloric acid in the reaction flask is added is 1.5mL.
6. preparation 16 α-according to claim 218The method of F-17 beta estradiol, which is characterized in that in the step 9,
Reaction flask is heated to 120 DEG C, heating time is 200 seconds.
7. preparation 16 α-according to claim 218The method of F-17 beta estradiol, which is characterized in that in the step 15,
The content of ethyl alcohol is 10% in the physiological saline containing ethyl alcohol.
8. preparation 16 α-according to claim 218The method of F-17 beta estradiol, which is characterized in that preparation 16 α-18The technical process of F-17 beta estradiol is carried out on CFN-MPS-200 synthesis module.
9. preparation 16 α-according to claim 218The method of F-17 beta estradiol, which is characterized in that in the step 218F-Release, the addition of acetonitrile in step 4, the addition of hydrochloric acid is all made of negative pressure in the addition and step 8 of precursor in step 6
The mode of sucking is realized.
10. preparation 16 α-according to claim 218The method of F-17 beta estradiol, which is characterized in that in the step 1,
Positive pressure is applied to nitrogen, is had by nitrogen extruding18F-Target water, make target water pass through QMA column；And/or in the step 11,
Positive pressure is applied to nitrogen, is squeezed by nitrogen and the solution in reaction flask is transferred completely into the sample injector.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106431945A (en) * | 2016-07-27 | 2017-02-22 | 四川省肿瘤医院 | Method and device for preparing O-(2-[18F]fluoroethyl)-L-tyrosine |
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2018
- 2018-11-23 CN CN201811407131.6A patent/CN109265506A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106431945A (en) * | 2016-07-27 | 2017-02-22 | 四川省肿瘤医院 | Method and device for preparing O-(2-[18F]fluoroethyl)-L-tyrosine |
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| Title |
|---|
| MANISH DIXIT 等: "Synthesis of Clinical-Grade [18F]-Fluoroestradiol as a Surrogate PET Biomarker for the Evaluation of Estrogen Receptor-Targeting Therapeutic Drug", 《INTERNATIONAL JOURNAL OF MOLECULAR IMAGING》 * |
| TETSUYA MORI等: "Automatic synthesis of 16α-[18F]f luoro-17β-estradiol using a cassette-type [18F]f luorodeoxyglucose synthesizer", 《NUCLEAR MEDICINE AND BIOLOGY》 * |
| 孙传金 等: "国产氟多功能模块合成***受体显像剂１６α－［１８Ｆ］氟－１７β－***", 《同位素》 * |
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