CN107970458A - A kind of positron emitting tracer Fully automated synthesis module based on 18F-BF3 marks - Google Patents
A kind of positron emitting tracer Fully automated synthesis module based on 18F-BF3 marks Download PDFInfo
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- CN107970458A CN107970458A CN201810004991.9A CN201810004991A CN107970458A CN 107970458 A CN107970458 A CN 107970458A CN 201810004991 A CN201810004991 A CN 201810004991A CN 107970458 A CN107970458 A CN 107970458A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/025—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus inorganic Tc complexes or compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
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Abstract
The invention discloses a kind of positron emitting tracer Fully automated synthesis module based on 18F BF3 marks, belong to nuclear medicine and molecular imaging field.The synthesis module includes 18F‑Ionic adsorption, purifying, elution circuit, heated reaction system, synthesizing and purifying system and the processing of product sterilization and transfer system, 18F‑Ionic adsorption, purifying, elution circuit and synthesizing and purifying system are connected by pipeline with heated reaction system respectively, and the processing of product sterilization and transfer system are connected by pipeline with synthesizing and purifying system, the 18F‑Ionic adsorption, purifying, elution circuit realize the 18F of micro-scale volume using syringe pump Z2, two six logical proportional valve F2, quantitative loop‑Ion leacheate precisely measures and lossless transfer.Compared with prior art, Fully automated synthesis module of the present invention have modern design, performance stablize, using flexible, easy to safeguard, it is easy to spread the features such as, be particularly suitable for the synthesis of the polypeptide positron medicine based on 18F BF3 labelling strategies under aqueous environment.
Description
Technical field
The present invention relates to nuclear medicine and molecular imaging field, specifically a kind of positive electricity based on 18F-BF3 marks
Sub- radiopharmaceutical Fully automated synthesis module.
Background technology
At present, clinically the most widely used PET positron medicines are 18F-FDG, but the developer can only observe it is swollen
The exception of knurl glycometabolism, and specificity there is also it is certain the problem of (cannot effectively distinguish inflammation and tumor tissues), it is also uncomfortable
Syncerebrum portion images, and comes out one after another to make up many developers with different action target spots of these deficiencies, such as based on propagation
The 18F-FLT of imaging, for the 18F-FMISO of hypoxia imaging, the 18F- ethyl tyrosine of amino acid metabolism class etc., and these
Developer may be by full-automatic synthesizer (such as Tracer Lab of General Electric Company (medical system) of commercialization
FX F-N series；The Syn Chrom R＆D of German Raytest companies；The fluorine multifunctional synthesis module PET- of Beijing Paite Co., Ltd.
MF-2V-IV-I) complete the preparation and its purifying of whole molecular probe, but these commercializations at present to be automatically synthesized instrument main
For be based under water-less environment 18F mark.Therefore, the 18F positive electrons that the automatic synthesizer of these commercializations can be prepared
Medicament categories are limited.
With the rapid development of molecular biology, tumour is among its occurrence and development process, relevant albumen, and polypeptide etc. is raw
Specific change can all occur for thing macromolecular, these large biological molecules are compared with special with conventional small-molecule drug target spot
The advantages of property is strong, and biological safety is high, for tumour early detection provide favourable target molecule storehouse (Jackson I M,
Scott P J H,Thompson S.Clinical Applications of Radiolabeled Peptides for PET
[C]//Seminars in Nuclear Medicine.WB Saunders,2017.).Obviously, to the 18F of these biomolecule
Mark cannot directly be marked by above-mentioned labeling method, and common method is prepared first with automation equipment
The small molecule linking arm of 18F marks, the active function groups that can be coupled with large biological molecule are contained on these linking arms；Secondly will
Biomolecule carries out secondary coupling with these small molecule linking arms, finally prepares target-probe point by HPLC purifying is final again
Son (Richter S, Wuest F.18F-labeled peptides:the future is bright[J].Molecules,
2014,19(12):20536-20556.).But there are following problem for this 18F labelling strategies：1. labeling process is cumbersome, when
Journey is longer；2. marking in two steps, overall labeling yield is relatively low；3. having to pass through HPLC purifying could be effectively by target-probe point
Son separation, takes time and effort.
But with the appearance of new 18F labeling methods so as to the probe molecule of large biological molecule, particularly polypeptide
18F " Last-Stage " mark be possibly realized, such as 18F-BF3 labelling strategies, the 18F labeling methods based on B-F keys, by from
The mode that son exchanges realizes 18F-The exchange of 19F in ion and boron trifluoride functional group (BF3), so as to complete the labeled of 18F
Journey (Liu Z, Pourghiasian M, Radtke M A, et al.An Organotrifluoroborate for Broadly
Applicable One‐Step 18F‐Labeling[J].Angewandte Chemie International Edition,
2014,53(44):11876-11880.).Such a 18F labeling methods have the following advantages：1. labeling process can be in aqueous
Carry out, handled without stringent dried over anhydrous；2. marked product is not in the accessory substance of other chemical molecular forms in theory,
Can realize " Last Stage " labelling strategies, because mark system comprises only two kinds of isotope probe molecular forms of F, they it
Between chemical property, targeting potency is equivalent；3. with the signal amplification in Chemical Measurement, each BF3 has three
A F atom, can obtain the 18F marked products of more high specific activity in theory；4, flag condition it is gentle (80 DEG C, pH 2-3,10-
15min), it is simple without any catalyst, purge process.It is common mark flow be：First by labelled precursor solution (10-
20uL) as in reaction tube, pH value is adjusted to 2-3 with corresponding buffer salt solution, secondly by micro-scale volume (50-70uL)
18F-Ion species aqueous solution is moved in reaction tube, heats 15-20min, reaction is finally quenched and is diluted with water, product is adsorbed in
On solid-phase extraction column, most product ethanol elution at last, adds normal saline dilution, crosses the positive electron that sterilised membrane filter obtains 18F marks
Medicaments injection.The key point of such mark reaction is how to realize the 18F of micro-scale volume as can be seen here-Ion leacheate essence
Standard measures and lossless transfer.
At present, micropipettor hand is utilized mainly by staff based on this kind of " Last-Stage " 18F marks of 18F-BF3
The dynamic 18F for completing micro-scale volume-Precisely amount pipettes ion leacheate.In the case of current medication increase in demand, manual operation
The occupational exposure of staff is not only increased, and adds the risk of human error in pharmacy procedure.And existing commodity
Change the preparation that multifunction automatic synthesizer can be only used for limited kinds 18F positron medicines, and the module liquid of commercialization at present
Body transfer scheme is mainly shifted liquid in reagent bottle by positive pressure of nitrogen, it is impossible to realizes accurate measurement and the nothing of micro-scale volume
Damage transfer, therefore be not suitable for the preparation of the new 18F-BF3 positron medicines.
The content of the invention
The technical assignment of the present invention is in view of the above shortcomings of the prior art, there is provided a kind of to be marked just based on 18F-BF3
Electronic radioactive medicine Fully automated synthesis module.The characteristics of module is for such mark reaction, it is possible to achieve more to 18F-BF3
Quick, the efficient Fully automated synthesis of peptides positron medicine, is particularly suitable under aqueous environment based on 18F-BF3 labelling strategies
Polypeptide positron medicine, includes a kind of the soluble small molecular amino acids and polypeptide positron medicine of the functional group containing BF3
Synthesis.
The technical assignment of the present invention is realized in the following manner：A kind of positron radioactivity based on 18F-BF3 marks
Medicine Fully automated synthesis module, its main feature is that including 18F-Ionic adsorption, purifying, elution circuit, heated reaction system, synthesis are pure
Change system and the processing of product sterilization and transfer system, 18F-Ionic adsorption, purifying, elution circuit and synthesizing and purifying system difference
It is connected by pipeline with heated reaction system, the processing of product sterilization and transfer system are connected by pipeline and synthesizing and purifying system
Connect,
The 18F-Ionic adsorption, purifying, elution circuit are real using syringe pump Z2, two six logical proportional valve F2, quantitative loops
The 18F of existing micro-scale volume-Ion leacheate precisely measures and lossless transfer.
Preferably, the 18F-Ionic adsorption, purifying, elution circuit is mainly by syringe pump Z2, two six logical proportional valves
F2, quantitative loop, two-bit triplet solenoid valve V21, two-bit triplet solenoid valve V22, two-bit triplet solenoid valve V23, two-bit triplet electromagnetism
Valve V24, miniature QMA columns, H2 18O returnable bottles, 18F-Ion leacheate bottle is formed, and syringe pump Z2, two six logical proportional valve F2, determine
Amount ring, two-bit triplet solenoid valve V21, two-bit triplet solenoid valve V22 are connected, for drawing the 18F of fixed body accumulated amount-Ion drenches
Washing lotion；Syringe pump Z2, two-bit triplet solenoid valve V21, two-bit triplet solenoid valve V22, two six logical proportional valve F2, quantitative loop, two
Position-3-way solenoid valve V23, miniature QMA columns, two-bit triplet solenoid valve V24 are connected, for by 18F-Ion elution is anti-to heating
Answer in system；H2 18O returnable bottles are connected with two-bit triplet solenoid valve V23, for recycling H2 18O；18F-Ion leacheate bottle and two
The logical proportional valve F2 connections in position six, for providing leacheate；Two-bit triplet solenoid valve V24 meets target water inlet pipe pipeline connector G1.
The synthesizing and purifying system is mainly by syringe pump Z1, a logical N switching valves F1, solid-phase extraction column 52, two-bit triplet electricity
Magnet valve V11, two-bit triplet solenoid valve V12, some reagent bottles 1 and waste liquid bottle are formed, and N is oneself more than or equal to 6, less than or equal to 10
So number, is preferably 6,8 or 10, syringe pump Z1 by a logical N switching valves F1 and each reagent bottle 1, heated reaction system, product without
Bacteriumization processing and transfer system connection, syringe pump Z1 are also connect solid phase and are extracted by a logical N switching valves F1, two-bit triplet solenoid valve V11
Column one end is taken, the solid-phase extraction column other end connects waste liquid bottle by two-bit triplet solenoid valve V12 and product sterilization handles and transfer
System.
In order to preferably adapt to the Fully automated synthesis of the positron emitting tracer based on 18F-BF3 marks, described one logical N
Switching valve F1 is connected by pipeline with 2-5 reagent bottle, and each reagent bottle is respectively used to hold medicinal alcohol, water for injection, production
Product leacheate and/or physiological saline etc..
The filler of solid-phase extraction column is preferably C18, HLB or neutral alumina.
Preferably, the heated reaction system is mainly made of reaction tube, temperature control heating device, reaction tube and 18F-From
Son absorption, purifies, and the logical N switching valves F1 of one in two-bit triplet solenoid valve V24, synthesizing and purifying system in elution circuit is connected
Logical, temperature control heating device is used to heat the reaction medium in reaction tube.
For the ease of controlling heating time, the heated reaction system can also include elevating mechanism, the elevating mechanism
For driving temperature control heating device to lift, to change the distance of reaction tube and temperature control heating device heating region.
The reaction tube is preferably able to bear the plastic material of 150 DEG C of high temperature, and bottom is preferably taper.
The heating unit preferably uses the temperature control system based on pid algorithm, and temperature control precision is less than or equal to ± 1
℃。
The elevating mechanism can use in the prior art any one can realize temperature control heating device lifting machinery, gas
Dynamic, electric structure, for example, whole temperature control heating device is recycled the bands such as stepper motor, screw rod as on stepper motor slide unit
Dynamic stepper motor slide unit moves up and down.
Preferably, the product sterilization processing and transfer system are mainly by rolling bottle, production in negative pressure control, product
Product receiving flask and sterilised membrane filter are formed, and negative pressure control is used to provide negative pressure for product receiving flask, and product receiving flask passes through nothing
Bacterium filter membrane is practiced midwifery rolling bottle in product, and rolling bottle passes through pipeline and a logical N switching valves F1, the two-bit triplet in synthesizing and purifying system in product
Solenoid valve V12 is connected.
Waste liquid bottle of the negative pressure control also for synthesizing and purifying system provides negative pressure, in order to by negative pressure by Solid Phase Extraction
Remaining waste liquid is transferred in waste liquid bottle in column.
Negative pressure control of the present invention can be made of vacuum diaphragm pump and draft regulator, by making product receiving flask
Maintain constant negative pressure.
The control mode of Fully automated synthesis module of the present invention is included by the full-automatic of programmable logic controller (PLC) (PLC) control
Control model, segmented semiautomatic control pattern and MANUAL CONTROL mode.
The positron emitting tracer Fully automated synthesis module based on 18F-BF3 marks of the present invention is compared with prior art
With beneficial effect following prominent：
(1) liquid quantifies, and constant speed transfer is realized mainly by syringe pump driven by stepper motors, by with it is corresponding
Valve combine, it is possible to achieve precisely quantitative, constant speed of the liquid in respective line, orientation transfer, more conventional positive pressure of nitrogen transfer
The scheme controllability of liquid is good；
(2) it is innovative to make use of two six logical proportional valves, different volumes can be replaced according to specific embodiment
Quantitative loop, it is possible to achieve to 18F-Ion elution volume is precisely controlled, the mark system particularly suitable for micro-scale volume；
(3) flowing of liquid in the module is mainly by stepper motor driven syringe pump, and by vacuum diaphragm pump and negative pressure
The negative pressure control of adjuster composition, thus eliminates the use of high-pressure nitrogen bottle, eliminates the fiber crops of nitrogen pipeline wiring
It is tired；
(4) it is the temperature control system based on pid algorithm that heating unit is adoptable, has the advantages that temperature control is accurate；It is and whole
Heating unit is fixed on elevating mechanism, can be by up and down adjustment position, whether realizing the heating to reaction tube.Can be anti-
It should first heat up before pipe heating to it, when reaction tube needs heating, directly rise to relevant position and reaction tube is heated, can
To save the time of heat temperature raising, shorten the generated time of positron medicine；
(5) reaction tube is the plastic material that can bear 150 DEG C of high temperature, and bottom is taper.More typical glass material
Reaction tube chemical inertness is high, can reduce in acid condition reaction tube to 18F-The absorption of ion.
Brief description of the drawings
Attached drawing 1 is the structure of the positron emitting tracer Fully automated synthesis module based on 18F-BF3 marks in embodiment
Schematic diagram.
In figure, 11, reagent bottle (spare)；12nd, reagent bottle (0.9% physiological saline)；13rd, reagent bottle (product leacheate)；
14th, reagent bottle (75% medicinal alcohol)；15th, reagent bottle (sterile water for injection)；21、18F-(0.9% life of ion leacheate bottle
Manage brine, pH=2.0)；22、H2 18O returnable bottles；23rd, reaction tube；24th, quantitative loop；31st, waste liquid bottle；32nd, rolling bottle in product；33、
Product receiving flask；34th, 0.22uM sterilised membrane filters；41st, stepper motor；42nd, temperature control heating device；43rd, negative pressure adjustment control device；
44th, vacuum diaphragm pump；45th, slide unit；51st, miniature QMA columns；52nd, C18 solid-phase extraction columns；Z1 is syringe pump, range 20mL；Z2
For syringe pump, range 5mL；F1 is logical ten switching valves；F2 is two six logical proportional valves；V11、V12、V21、V22、V23、
V24 is two-bit triplet solenoid valve；V31, V32, V34 are 2/2-way solenoid valve.
Attached drawing 2 is to be automatically synthesized the radioactivity of positron medicine prepared by module before purification with medicine described in embodiment one
HPLC chromatogram.
Attached drawing 3 is to be automatically synthesized the sterile product after purification of positron medicine prepared by module with medicine described in embodiment one
The radioactivity HPLC chromatogram of liquid.
Attached drawing 4 is the 19F reference substances purple that positron medicine prepared by module is automatically synthesized with medicine described in embodiment one
Outer visible HPLC chromatogram.
Embodiment
The positron emitting tracer based on 18F-BF3 marks with reference to Figure of description with specific embodiment to the present invention
Fully automated synthesis module is described in detail below.
Unless otherwise instructed, the content of following each components used is weight percentage content.
Embodiment：
As shown in Figure 1, the positron emitting tracer Fully automated synthesis module master of the invention based on 18F-BF3 marks
Will be by 18F-Ionic adsorption, purifying, elution circuit, heated reaction system, synthesizing and purifying system and product sterilization are handled and turned
Shifting system forms.
The 18F-Ionic adsorption, purifying, elution circuit is mainly by syringe pump Z2, two six logical proportional valve F2, quantitative loops
24th, two-bit triplet solenoid valve V21, two-bit triplet solenoid valve V22, two-bit triplet solenoid valve V23, two-bit triplet solenoid valve V24, micro-
Type QMA columns 51,18F-Ion leacheate bottle 21, H2 18O returnable bottles 22 are formed.
1, No. 4 passage of the upper and lower ends of quantitative loop 24 respectively with two six logical proportional valve F2 is connected.Two six logical quantitative
No. 2 passages of valve F2 meet syringe pump Z2 by two-bit triplet solenoid valve V22, two-bit triplet solenoid valve V21, and No. 2 passages also pass through
Two-bit triplet solenoid valve V22 connects No. 6 passages.No. 3 passages of two six logical proportional valve F2 meet 18F by pipeline-Ion leacheate
Bottle 21；No. 5 passages connect reaction tube 23 by two-bit triplet solenoid valve V23, miniature QMA columns 51, two-bit triplet solenoid valve V24.Two
Position-3-way solenoid valve V24 also meets target water inlet pipe pipeline connector G1 by pipeline.Two-bit triplet solenoid valve V23 meets H by pipeline2 18O
Returnable bottle 22.The vacant end passage of two-bit triplet solenoid valve V21 connects air.
Draw 18F-During ion leacheate, by two-bit triplet solenoid valve V21, two-bit triplet solenoid valve V22, two six logical fixed
No. 2 passages of valve F2 (being now in 1) are measured, No. 1 passage, quantitative loop 24, two six lead to proportional valve F2's (being now in 1)
No. 4 passages, No. 3 passages, 18F-Ion leacheate bottle 21 is connected, and quantitative loop 24 is full of leacheate using syringe pump Z2.Draw
After the completion of operation, two-bit triplet solenoid valve V22 is opened, successively by two-bit triplet solenoid valve V21, two-bit triplet solenoid valve V22, two
No. 6 passages of the logical proportional valve F2 (being now in 2) in position six, No. 1 passage, quantitative loop 24, two six logical proportional valve F2 (locate at this time
In 2) No. 4 passages, No. 5 passages, two-bit triplet solenoid valve V23, miniature QMA columns 51, two-bit triplet solenoid valve V24, reaction
Pipe 23 is connected, you can leacheate in quantitative loop 24 is slow transitted through miniature QMA columns 51, finally elutes into reaction tube 23.
The synthesizing and purifying system is mainly by syringe pump Z1, a logical ten switching valve F1, C18 solid-phase extraction column 52, two three
Three-way electromagnetic valve V11, two-bit triplet solenoid valve V12, reagent bottle 11, reagent bottle 12, reagent bottle 13, reagent bottle 14, reagent bottle 15 and
Waste liquid bottle 31 is formed.No. 1 passage of one logical ten switching valve F1 connects air；No. 2 passages connect reaction tube 23；No. 3 passages pass through two
Three-way magnetic valve V11, C18 solid-phase extraction column 52, two-bit triplet solenoid valve V12 connect rolling bottle 32 in waste liquid bottle 31, product；No. 5 logical
Road is practiced midwifery rolling bottle 32 in product；No. 6 passages, No. 7 passages, No. 8 passages, No. 9 passages, No. 10 passages pass through pipeline and reagent bottle respectively
11st, reagent bottle 12, reagent bottle 13, reagent bottle 14, reagent bottle 15 connect.The vacant end passage of two-bit triplet solenoid valve V11 connects greatly
Gas.
Product leacheate in a certain amount of reagent bottle 13 is drawn by syringe pump Z1, then passes through a logical ten switching valve F1's
Product, is eluted in product in rolling bottle 32 from C18 solid-phase extraction columns 52 by No. 3 passages through two-bit triplet solenoid valve V11.Then
Physiological saline in a certain amount of reagent bottle 12 is drawn by syringe pump Z1, No. 5 passages through a logical ten switching valve F1 are by product
Product liquid in rolling bottle 32 is diluted.
The heated reaction system is mainly by reaction tube 23, stepper motor 41, temperature control heating device 42, stepper motor slide unit
45 are formed.The plastic material that 23 use of reaction tube can bear 150 DEG C of high temperature is made, its bottom is taper.Temperature control heating device
The shape of 42 heating regions can be adapted with reaction tube 23, and using the temperature control system based on pid algorithm, temperature-controlled precision is small
In equal to ± 1 DEG C.Temperature control heating device 42 is fixed on stepper motor slide unit 45, and drives stepper motor using stepper motor 41
Slide unit 45 moves up and down.
Preferably, the product liquid sterilization processing and transfer system are mainly by vacuum diaphragm pump 44, draft regulator
43rd, rolling bottle 32, product receiving flask 33 and sterilised membrane filter 34 are formed in product.Negative pressure control be used for for product receiving flask 33,
Waste liquid bottle 31 provides negative pressure.Product receiving flask 33 is practiced midwifery rolling bottle 32 in product by sterilised membrane filter 34.
The control program of above-mentioned Fully automated synthesis module, can be write based on programmable logic controller (PLC) (PLC).Prepare each
Kind of positron medicine have one it is specific perform file, and the execution file program can be carried out by encryption protection and
The opening of editing authority.After the program editted is written to PLC, whole-course automation control, hand can be realized by outer button
Dynamic control, segmented semiautomatic control.
Exemplified by synthesizing 18F-AMBF3-C (RGDfK) medicine, to preparing radioactivity medicine using above-mentioned Fully automated synthesis module
The operating process of thing provides following explanation：
Need that sterile water for injection 30mL will be put into reagent bottle 15 before the synthesis, reagent bottle 14 is put into 75% medical wine
Smart 40mL, is put into 80% ethanol water 10mL in reagent bottle 13, and 0.9% physiological saline is put into reagent bottle 12 and (is used to dilute
Product liquid) 20mL, 0.9% physiological saline (pH=2.0, for eluting 18F is put into reagent bottle 21-Ion is to reaction tube)
10mL, activation C18 solid-phase extraction column 52, activates miniature QMA columns 51.A certain amount of labelled precursor solution is added in reaction tube 23 in advance
(10mM, 10uL), the buffer salt solution (1M, 5uL, pH=2.0) of certain volume amount are spare.
1. detergent line：, it is necessary to all pipelines to equipment before synthesis is formally started, rolling bottle 32 in product, reaction tube
23 are cleaned.
1.1 75% medicinal alcohol：One logical ten switching valve F1 are switched into No. 9 passages, syringe pump Z1 is with 20mL/min's
Speed is drawn the medicinal alcohol of 16mL 75% by bottle 14, and a logical ten switching valve F1 are switched to No. 2 passages, inject 4mL to reaction
Pipe 23；A logical ten switching valve F1 are then switched into No. 3 positions, inject 4mL to waste liquid bottle 31；Then two-bit triplet solenoid valve is opened
V12, injects 4mL rolling bottle 32 into product；One logical ten switching valve F1 are switched into No. 5 passages, inject 4mL rolling bottles into product
32。
1.2 waters for injection clean：Then logical ten switching valves are switched into No. 10 passages, syringe pump Z1 is with 20mL/min's
Speed draws 16mL waters for injection, and with same elution order, pipeline is cleaned.
1.3 all pipelines of drying：Then logical ten switching valves are switched into No. 1 passage (and air communicates), syringe pump Z1
16mL air is drawn with the speed of 20mL/min, with same elution order, dries up all pipelines.
1.4 installation purification columns, reaction tube：Miniature QMA columns 51 are connected to two-bit triplet solenoid valve V23, two-bit triplet electromagnetism
Between valve V24；By C18 solid-phase extraction columns 52 connect with two-bit triplet solenoid valve V11, between two-bit triplet solenoid valve V12；It will be equipped with
Reaction tube on the reaction tube replacement equipment of precursor used in detergent line.
2. 18F-The production of ion：Using 18O (p, n) 18F nuclear reactions, GE Minitrace medical cyclotrons
(30uA, 20-40min) bombardment is equipped with H2 18The target body of O (97%, 2.0mL), then will contain 18F with He gas-The target water of ion
It is transferred to through target water inlet pipe pipeline connector G1, two-bit triplet solenoid valve V24, miniature QMA columns 51, two-bit triplet solenoid valve V23
H2 18In O returnable bottles 22, persistently whole pipeline and miniature QMA columns 51 are done with He air-blowings.
3. 18F-Elution and transfer：Two six logical proportional valve F2 are placed in 1 first, and (passage 1-2 is connected, passage 3-4
Connect, passage 5-6 is connected), with syringe pump Z2 by 18F-18F is drawn in ion leacheate bottle 21-Ion leacheate is by quantitative loop 24
(50uL) is full of；Then two six logical proportional valve F2 being placed in 2, (passage 6-1 is connected, and passage 2-3 is connected, and passage 4-5 connects
It is logical), unnecessary leacheate is returned into 18F-In ion leacheate bottle 21；Two-bit triplet solenoid valve V21 is then turned on to draw necessarily
The air of amount, closes two-bit triplet solenoid valve V21, opens two-bit triplet solenoid valve V22, and two six logical proportional valves are placed in 2,
Two-bit triplet solenoid valve V23, two-bit triplet solenoid valve V24 are opened at the same time, Z2 is pumped with 4mL/min speed bolus infusion, it is quantitative
Passage 5 of the leacheate through two six logical proportional valve F2 in ring 24, two-bit triplet solenoid valve V23, miniature QMA columns 51, two three
Three-way electromagnetic valve V24, eventually enters into reaction tube.
4. 18F-Ion is marked with precursor 19F-AMBF3-C (RGDfK)：Preset temperature will be had been heated in advance
The temperature control heating device 42 of (85 DEG C) is risen at reaction tube 23 using stepper motor 41, begins to warm up 15min, after heating,
Temperature control heating device 42 declines, and reaction tube 23 cools down 5min.
5. purifying products：
5.1 product hanging columns：One logical ten switching valves are cut into F1 and shift to No. 10 passages, syringe pump Z1 with the speed of 20mL/min from
15mL waters for injection are drawn in bottle 15, No. 2 positions is then switched to, 15mL waters for injection is transferred to reaction tube with identical speed
In 23, reaction system is diluted, dilution will be then drawn in syringe pump Z1 with the speed communicated.By logical ten switching valves
Cut F1 and shift to No. 3 passages, by the reaction solution after dilution through two-bit triplet solenoid valve V11, C18 solid-phase extraction column 52, two-bit triplet
Solenoid valve V12, is injected in waste liquid bottle 31 with the speed of 7mL/min, and most product is adsorbed on C18 solid-phase extraction columns 52 at last.
5.2 rinse C18 solid-phase extraction columns 52：One logical ten switching valve F1 are switched into No. 10 passages, syringe pump Z1 is with 20mL/
The speed of min draws 5mL waters for injection from reagent bottle 15, is then switched to No. 3 positions, through two-bit triplet solenoid valve V11, C18
Solid-phase extraction column 52, two-bit triplet solenoid valve V12, rinses C18 solid-phase extraction columns 52 with the speed water for injection of 7mL/min and arrives
In waste liquid bottle 31, by unlabelled 18F on C18 solid-phase extraction columns 52-Ion washes away.
5.3 drying C18 solid-phase extraction columns 52：Open two-bit triplet solenoid valve V11, make 52 one end of C18 solid-phase extraction columns with
Air communicates, and the other end is connected by two-bit triplet solenoid valve V12 with waste liquid bottle 31, opens two-bit triplet solenoid valve V32, starts
Vacuum pump 44 and draft regulator 43, make the negative pressure a that -70Kpa is formed in waste liquid bottle 31, by negative pressure by C18 Solid Phase Extraction
Remaining water is transferred in waste liquid bottle 31 in column 52.
6. product is eluted to middle rolling bottle 32：One logical ten switching valve F1 are switched into No. 8 passages, syringe pump Z1 is with 4mL/min
Speed by drawing 1mL product leacheates in bottle 13, a logical ten switching valve F1 are then switched into No. 3 positions, open two-bit triplet
Solenoid valve V12, through two-bit triplet solenoid valve V11, C18 solid-phase extraction column 52, two-bit triplet solenoid valve V12, with product leacheate
The product adsorbed on solid-phase extraction column 52 is eluted into (elution speed 4mL/min), most product is transferred to rolling bottle in product at last
In 32.
7. cut-back product liquid：One logical ten switching valve F1 are switched into No. 7 passages, syringe pump Z1 with the speed of 20mL/min by
0.9% physiological saline of 5mL is drawn in bottle 12, a logical ten switching valve F1 are then switched into No. 5 positions, with identical speed by 0.9%
Physiological saline is injected in product in rolling bottle 32.
8. it is transferred to product receiving flask 33：Treat that liquid after mixing, opens two-bit triplet solenoid valve in rolling bottle in product
V31, starts vacuum pump 44 and draft regulator 43, makes the negative pressure a that -40Kpa can be formed in product receiving flask 33, product liquid
It will be transferred to by sterilised membrane filter 34 by rolling bottle in product 32 spare in product receiving flask 33.
Obviously, the above embodiments are merely examples for clarifying the description, and the restriction not to embodiment.It is right
For those of ordinary skill in the art, can also make on the basis of the above description other it is various forms of change or
Person changes.There is no necessity and possibility to exhaust all the enbodiments.And the obvious change thus amplified out or
Among person is changed still in the protection domain of the invention.
Claims (9)
- A kind of 1. positron emitting tracer Fully automated synthesis module based on 18F-BF3 marks, it is characterised in that：Including 18F- Ionic adsorption, purifying, elution circuit, heated reaction system, synthesizing and purifying system and the processing of product sterilization and transfer system, 18F-Ionic adsorption, purifying, elution circuit and synthesizing and purifying system be connected by pipeline with heated reaction system respectively, product without Bacteriumization processing and transfer system are connected by pipeline with synthesizing and purifying system,The 18F-Ionic adsorption, purifying, elution circuit are realized micro using syringe pump Z2, two six logical proportional valve F2, quantitative loop The 18F of volume-Ion leacheate precisely measures and lossless transfer.
- 2. the positron emitting tracer Fully automated synthesis module according to claim 1 based on 18F-BF3 marks, it is special Sign is：The 18F-Ionic adsorption, purifying, elution circuit mainly by syringe pump Z2, two six logical proportional valve F2, quantitative loop, It is two-bit triplet solenoid valve V21, two-bit triplet solenoid valve V22, two-bit triplet solenoid valve V23, two-bit triplet solenoid valve V24, miniature QMA columns, H2 18O returnable bottles, 18F-Ion leacheate bottle is formed, syringe pump Z2, two six logical proportional valve F2, quantitative loop, two three Three-way electromagnetic valve V21, two-bit triplet solenoid valve V22 are connected, for drawing the 18F of fixed body accumulated amount-Ion leacheate；Syringe pump Z2, two-bit triplet solenoid valve V21, two-bit triplet solenoid valve V22, two six logical proportional valve F2, quantitative loop, two-bit triplet solenoid valves V23, miniature QMA columns, two-bit triplet solenoid valve V24 are connected, for by 18F-Ion is eluted into heated reaction system；H2 18O Returnable bottle is connected with two-bit triplet solenoid valve V23, for recycling H2 18O；18F-Ion leacheate bottle and two six logical proportional valve F2 Connection, for providing leacheate；Two-bit triplet solenoid valve V24 meets target water inlet pipe pipeline connector G1.
- 3. the positron emitting tracer Fully automated synthesis module according to claim 1 or 2 based on 18F-BF3 marks, It is characterized in that：The synthesizing and purifying system is mainly by syringe pump Z1, a logical N switching valves F1, solid-phase extraction column, two-bit triplet electricity Magnet valve V11, two-bit triplet solenoid valve V12, some reagent bottles and waste liquid bottle are formed, and N is oneself more than or equal to 6, less than or equal to 10 So number,Syringe pump Z1 passes through a logical N switching valves F1 and each reagent bottle, heated reaction system, the processing of product sterilization and transfer system Connection, syringe pump Z1 also connect solid-phase extraction column one end, solid-phase extraction column by a logical N switching valves F1, two-bit triplet solenoid valve V11 The other end connects waste liquid bottle and the processing of product sterilization and transfer system by two-bit triplet solenoid valve V12.
- 4. the positron emitting tracer Fully automated synthesis module according to claim 3 based on 18F-BF3 marks, it is special Sign is：One logical N switching valves F1 is connected by pipeline with 2-5 reagent bottle.
- 5. the positron emitting tracer Fully automated synthesis module according to claim 3 based on 18F-BF3 marks, it is special Sign is：The filler of solid-phase extraction column is C18, HLB or neutral alumina.
- 6. the positron emitting tracer Fully automated synthesis module according to claim 3 based on 18F-BF3 marks, it is special Sign is：The heated reaction system is mainly made of reaction tube, temperature control heating device, reaction tube and 18F-Ionic adsorption, it is pure Change, the logical N switching valves F1 of one in two-bit triplet solenoid valve V24, synthesizing and purifying system in elution circuit is connected, temperature control heating Device is used to heat the reaction medium in reaction tube.
- 7. the positron emitting tracer Fully automated synthesis module according to claim 6 based on 18F-BF3 marks, it is special Sign is：The heated reaction system further includes elevating mechanism, and the elevating mechanism is used to drive temperature control heating device to lift, with Change the distance of reaction tube and temperature control heating device heating region.
- 8. the positron emitting tracer Fully automated synthesis module according to claim 6 based on 18F-BF3 marks, it is special Sign is：Product sterilization processing and transfer system mainly by rolling bottle in negative pressure control, product, product receiving flask and Sterilised membrane filter is formed, and negative pressure control is used to provide negative pressure for product receiving flask, and product receiving flask is practiced midwifery by sterilised membrane filter Rolling bottle in product, rolling bottle passes through pipeline and a logical N switching valves F1, the two-bit triplet solenoid valve V12 in synthesizing and purifying system in product It is connected.
- 9. the positron emitting tracer Fully automated synthesis module according to claim 8 based on 18F-BF3 marks, it is special Sign is：Waste liquid bottle of the negative pressure control also for synthesizing and purifying system provides negative pressure.
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