CN1974587A - Basic hydrolysis process for preparing 2-fluoro [18F]-2-deoxy-beta-D-glucose in single tube FDG acidic hydrolysis apparatus - Google Patents
Basic hydrolysis process for preparing 2-fluoro [18F]-2-deoxy-beta-D-glucose in single tube FDG acidic hydrolysis apparatus Download PDFInfo
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- CN1974587A CN1974587A CN 200610095245 CN200610095245A CN1974587A CN 1974587 A CN1974587 A CN 1974587A CN 200610095245 CN200610095245 CN 200610095245 CN 200610095245 A CN200610095245 A CN 200610095245A CN 1974587 A CN1974587 A CN 1974587A
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Abstract
The present invention relates to positive electronic medicine preparation, and is especially basic hydrolysis process for preparing 2-fluoro[18F]-2-deoxy-beta-D-glucose (18F-FDG) in technologically reformed single tube FDG acidic hydrolysis apparatus. The basic hydrolysis process can reach all the quality indexes of 18F-FDG product, including radiochemical pure over 99.0 %, and has shortened preparation time from 50 min to 33 min, raised absolute yield from 40-45 % to 60-65 %, and stable technological process. Changing from acidic hydrolysis process to basic hydrolysis process makes the main side product changed from 2-chloro-2-deoxy-beta-D-glucose hard to metabolize in human body into glucose, and this raises the safety and effectiveness of the medicine greatly. Clinical application shows that the basic hydrolysis process 18F-FDG has the same clinical effect as the acidic hydrolysis process 18F-FDG.
Description
Technical field
This patent relates to the positron emitting tracer preparation field, be specifically related to a kind of with single tube FDG acid hydrolysis equipment carry out basic hydrolysis prepare the 2-fluorine [
18F]-2-deoxidation-β-D-glucose (
18F-FDG) technology.
Background technology
18F-FDG is a most widely used radiopharmaceuticals in the PET research, is widely used in the glucose metabolism mensuration etc. of diagnosis, cardiac muscle and the brain of malignant tumour.Because its importance and widespread use, since reported first in 1977, many documents have been reported in a large number
18The preparation of F-FDG, and develop multiple automatization synthesis device.The preparation method who generally adopts synthesizes 1,3,4 with stereoselectivity nucleophilic reaction method earlier at present, 6-four-O-ethanoyl-2-fluorine [
18F]-β-D-mannopyranose (
18F-FDG-OAc
4) promptly
18F-FDG precursor (Hamacher K, J Nucl Med, 1986,27 (2): 235-238.), use acid-hydrolysis method (PadgettHC then, Appl Radiat Isot, 1989,40 (5): 433-445.) or alkali hydrolysis method (Fuchtner F .ApplRadiat Isot, 1996,47:61-66.) hydrolysis
18F-FDG-OAc
4Go the acetyl protection group to get
18F-FDG.The preparation of basic hydrolysis deacetylate group
18F-FDG though can finish at short notice, causes easily
18F-FDG-OAc
4With
18Elimination reaction on 2 of the F-FDG etc. reduces the chemical purity and the radiochemicsl purity of product, the basic hydrolysis preparation
18The F-FDG radiochemicsl purity can only guarantee more than 95%.
Single tube FDG acid hydrolysis equipment is made by U.S. CFI company, and at present domestic have how tame unit to use this equipment, and it is to adopt hydrochloric acid hydrolysis
18F-FDG-OAc
4Preparation
18The automatization synthesizer of F-FDG has two cover independent parallel operation architectures, and every cover system can both be produced separately, can produce a collection of as required or two batches
18F-FDG.Though this complete equipment has level of automation height, stable preparation process, product radiochemicsl purity advantages of higher, acid hydrolysis deacetylate when group temperature of reaction height, the time is long, productive rate is low.With hydrochloric acid hydrolysis four-O-ethanoyl-2-fluorine [
18F]-β-D-mannopyranose is promptly
18Need be between 100～130 ℃ during the F-FDG precursor hydrolysis 10～15min, during this period of time because of
18The F natural decay will make output reduce 7～10%.The acid-hydrolysis method preparation
18F-FDG takes 45～50min, actual synthetic yield (not correcting yield) 40～45%.
Summary of the invention
The purpose of this invention is to provide and a kind ofly carry out basic hydrolysis preparation with single tube FDG acid hydrolysis equipment
18The technology of F-FDG.It replaces acid hydrolysis by the single tube FDG of U.S. CTI company acid hydrolysis equipment is undergone technological transformation and running state of programs and parameter adjustment with basic hydrolysis, the time weak point that responds,
18Advantages such as F-FDG synthetic yield height, good product quality.
Under the automatic running status of program, utilize the single tube FDG acid hydrolysis equipment first cover system to prepare acetylize
18F-FDG (
18F-FDG-OAc4).Accelerator-produced
18F
-After being caught by anion column QMA (Waters); acetonitrile water mixed solution wash-out with salt of wormwood and cave ether; elutriant between 100～120 ℃ evaporating solvent and with the acetonitrile azeotropic water removing: residue cooling back adds 1; 3; 4; nucleophilic substitution reaction takes place and generates acetylize in 6-four-O-ethanoyl-2-trifyl-β-D-seminose (abbreviation mannose triflate) acetonitrile solution between 85～90 ℃
18F-FDG, acetonitrile is removed in evaporation between 100～120 ℃ then, and this process is identical during with acid hydrolysis.
When hydrolysis reaction is arrived in program run, add an amount of sodium hydroxide solution, reaction tubes self-initialize position changed 8 seconds into by 14 seconds fall time, make temperature of charge remain on 40～45 ℃ of hydrolysis: the automatic running status of program is switched to manual operation state, on the control computer screen, click the V01 valve with mouse, manual unlocking mixes air valve, makes reaction system be in " mixing " state always, and hydrolysis time shortened to 2 minutes by 15 minutes; Hydrolysis finishes, and when whether prompting finished to react, the charging valve V05 with mouse click kingpin correspondence manually added dilute hydrochloric acid neutralization reaction solution, obtains
18The thick product of F-FDG.
Program is switched to automatic running status and finishes reaction, thick product through Zeo-karb AG 50W neutralization, ion energy absorbing resin AG 11 A8 are softening and Alum-N post, C-18 column purification after obtain
18The F-FDG finished product, finished product imports the product receiving flask into after sterilizing filter purifies, obtain clinical with the 2-fluorine [
18F]-2-deoxidation-β-D-glucose. this process is identical during with the acid hydrolysis of single tube FDG acid hydrolysis equipment.
Be used for 2-fluorine of the present invention [
18F]-2-deoxidation-β-D-grape sugar preparation technology's equipment, adopt the CTI single tube FDG of company acid hydrolysis equipment, soft rubber ball 9 with 7 conduits is arranged in the device, 6 reinforced bottles (1 are arranged, 2,3,4,5,6), each reinforced bottle all is connected with pneumavalve (V04, V08, V10, V12, V05, V14), wherein (1,2,3,4,6) 5 reinforced bottle and pneumavalve (V04, V08, V10, V12, V14) the reinforced bottle and the pneumavalve of the synthetic system of first cover in the usefulness single tube FDG acid hydrolysis equipment, kingpin and corresponding charging valve can be " arbitrary group " in the single tube FDG acid hydrolysis equipment second cover reaction system, choosing " headpin; V05 valve " herein.6 reinforced bottles are communicated with reaction tubes 8 by the conduit that passes through soft rubber ball 9, reaction tubes 8 communicates with product receiving flask 7 by the purified post C1 of the conduit that passes through soft rubber ball 9, C2, C3 and sterilizing filter F1, one airway is arranged on the receiving flask 7, and the mouth of pipe has an aseptic air filter F2.Technological transformation is to become 7 conduits by 6 conduits on the soft rubber ball 9, and reinforced bottle also increases to 6 by 5.
Identical when institute's solution of containing is with acid hydrolysis in No. 1, No. 2, No. 3 three bottles in 6 reinforced bottles, the sodium hydroxide solution of Sheng 4.0ml 0.33M in No. 4 bottle, the hydrochloric acid soln of kingpin Sheng 2.0ml 1.0M, Sheng 10.0ml water for injection in No. 6 bottle.The installation of the preparation of purifying products post C1, C2, C3, installation and sterilizing filter F1, F2, receiving bottle 7 and single tube FDG acid hydrolysis equipment be former be provided with identical.
Of the present invention
18F-FDG preparation technology, used alkaline solution is sodium hydroxide or potassium hydroxide solution in its hydrolytic process, consumption is that 4.0mL can make the nearly all acetylize that splashes in the reaction tube wall
18F-FDG is hydrolyzed to product, helps improving output, does not influence purification effect and finished product quality simultaneously again.After basic hydrolysis replacement acid hydrolysis, the main by product of product is difficult to metabolic 2-chloro-2-deoxidation-β-D-glucose (ClDG) by human body and becomes glucose, greatly improved the security of medicine.
The present invention has adopted in the basic hydrolysis of low temperature short period of time, the acid and mode, has greatly reduced
18F-FDG-OAc
4With
182 of F-FDG etc. go up the possibility that reaction takes place to eliminate, improved the quality of product, its radiochemicsl purity is greater than 99.0%, also shorten to 30～35min with the reaction time by acid-hydrolyzed 45～50min, absolute yield (not correcting yield) increases substantially 60～65% by 40～45%, and process stabilizing.
The applicant uses prepared of the present invention
18F-FDG, through 350 many cases clinical trials, result and acid-hydrolysis method preparation
18F-FDG is identical, also conforms to the pertinent literature report.
Description of drawings
Fig. 1 is through the single tube FDG acid hydrolysis equipment structural representation after the technological transformation.
1,2,3,4,5,6 are reinforced bottle among the figure, and 7 is the product receiving flask, and 8 is reaction tubes, 9 is soft rubber ball, and 10 are the heating oil bath, and V01 is mixed air valve, V02 is a three-way air valve, and V41 is two-way three-way air valve, and V04, V08, V10, V12, V05, V14 are reinforced air valve, F1 is the product cleaner, F2 is an air purifier, and C1 is AG50W and AG11A8 post, and C2 is the Alumin-N post, C3 is the C-18 post, and QMA is the tetramethylammonium anion column
Embodiment
Below in conjunction with accompanying drawing and example the present invention is further detailed.
As shown in Figure 1, adopt U.S. CTI company to produce single tube FDG acid hydrolysis equipment, wherein soft rubber ball 9 has 7 conduits, 6 reinforced bottles 1,2,3,4,5,6 are arranged, each reinforced bottle correspondence is connected with pneumavalve V04, V08, V10, V12, V05, V14, bottle and pneumavalve V04, V08, V10, V12, the V14 corresponding with it reinforced bottle and pneumavalve of the synthetic system of first cover in the single tube FDG acid hydrolysis equipment wherein feed in raw material for 1,2,3,4, No. 6, kingpin and corresponding charging valve can be " arbitrary group " in the second cover reaction system, choosing " headpin, V05 valve " herein.6 reinforced bottles communicate with reaction tubes 8 by the conduit that passes through soft rubber ball 9, reaction tubes 8 communicates with product receiving flask 7 through the pure and mild sterilizing filter F1 of AG50W resin, AG11A8 resin, Alumin-N post and C-18 post by the conduit that passes through soft rubber ball 9, one airway is arranged on the receiving flask 7, and the mouth of pipe has an aseptic air filter F2.
Specifications such as agents useful for same such as salt of wormwood, cave ether, mannose triflate, acetonitrile are analytical pure or the specification that is equivalent to analyze in the preparation process.Kind, concentration and the volume of solution are in each reinforced bottle:
Headpin: 1.0mL salt of wormwood and cave ether acetonitrile solution;
(salt of wormwood: cave ether: water: acetonitrile is 3mg:15mg:0.1mL:0.9mL)
No. 2 bottles: 2.0mL anhydrous acetonitrile;
No. 3 bottle: 1.0mL 1,3,4,6-four-O-ethanoyl-2-O-trifyl-β-D-seminose (mannose triflate) acetonitrile solution (mannose triflate: acetonitrile is 18mg:1.0mL)
No. 4 bottles: 4.0mL 0.33moL sodium hydroxide solution;
Kingpin: 2.0mL 1N hydrochloric acid soln;
No. 6 bottles: 10.0mL water for injection.
It is as follows to use processing step of the present invention:
1. click the initialize button with mouse on computer screen, start the working routine of single tube FDG acid hydrolysis equipment, system's auto-initiation reaction unit is opened oil bath 10 heater switch, is warmed up to 115 ± 1 ℃, and constant temperature.This moment, computer operational program was in automatic control state.
2, by the accelerator warp
18O (P, n)
18F produces
18In the F, target
18F is transmitted by argon gas,
18F is caught by tetramethylammonium QMA post, and oxygen-18 water enters the wastewater collection bottle.
3, open two-way T-valve V41, open magnetic valve V04, the acetonitrile solution that headpin includes salt of wormwood and cave ether is transmitted by nitrogen, adsorbs on the QMA post through two-way T-valve V41
18F drip washing gets off to import into reaction tubes 8, and the time decides on pipeline length and nuclide mass, is generally 200S.End of transmission is closed two-way T-valve V41 and magnetic valve V04.
4, open magnetic valve V01, in reaction tubes, feed nitrogen, elevator decline 14S, evaporating solvent, time 210S closes magnetic valve.Elevator rising 14S gets back to initialized location.
5, open magnetic valve V08, No. 2 the interior anhydrous acetonitrile of bottle enters reaction tubes 8 by the nitrogen transmission, closes magnetic valve.Open magnetic valve V01 and feed nitrogen, elevator decline 15S, the dehydration of azeotropic evaporate to dryness, time 290S closes breather valve.Elevator rising 15S gets back to initialized location.
6, open magnetic valve V10, No. 3 the interior mannose triflate acetonitrile solution of bottle imports reaction tubes 8 into by nitrogen, closes magnetic valve.Elevator decline 10S opens and closes first set reaction 100S after breather valve V01 feeds nitrogen 3S; Open and close after breather valve V01 feeds nitrogen 3S, react 100S for the second time; Open and close after breather valve V01 feeds nitrogen 3S, react 100S for the third time.The elevator 5S that descends once more opens breather valve V01 and feeds nitrogen, solvent evaporated, time 255S.Elevator rising 15S gets back to initialized location, closes breather valve behind the cooling 10S.
7, residue acetylize
18After the F-FDG cooling, open magnetic valve V12, No. 4 the interior sodium hydroxide solution of bottle enters reaction tubes 8 by the nitrogen transmission, closes magnetic valve.Computer operational program is switched to manual state, elevator decline 8S, manual unlocking magnetic valve V01 makes reaction system be in " mixing " state always, and temperature of charge remains on 40～45 ℃ of reactions that are hydrolyzed, and hydrolysis time is 2 minutes.Close breather valve, elevator is got back to initialized location.
8, hydrolysis finishes, and when whether prompting finished to react, the dilute hydrochloric acid solution in the charging valve V05 of manual unlocking kingpin correspondence, kingpin imported reaction tubes 8 into by nitrogen, closes magnetic valve.Manual unlocking magnetic valve V01 feeds nitrogen, and mixed reaction solution obtains
18The thick product of F-FDG.
9, finish reaction, begin transmission.Computer operational program is switched to automatic running status, and this moment, computer operational program was in automatic control state.Elevator rises to the top and keeps the overload motion, makes reaction tubes 8 mouths of pipe and soft rubber ball 9 keep sealing.Open magnetic valve V08, V10, V12, V14 successively, carry out the product transmission first time, time 130S.Product solution enters product receiving bottle 7 at last through the softening post C1 of neutralization, aluminium nitrogen post C2, carbon-18 post C3 and sterilizing filter F1 successively.After the end of transmission, close magnetic valve V14, V12, V10, V08 and breather valve V01 successively, elevator is got back to initialized location.
10, open magnetic valve V14, No. 6 the interior water for injection of bottle enters reaction tubes 8 by the nitrogen transmission, time 6S, and the about 6.0ml of feeding quantity closes magnetic valve.Open breather valve V01 and magnetic valve V08, V10, V12, V14 successively, repeat previous action, carry out the product transmission second time, the time still is 130S.
11, open magnetic valve V14, import reaction tubes 8 into remaining water for injection in No. 6 bottles, time 4S closes magnetic valve.The same previous action that repeats is carried out product transmission for the third time, and the time is 100S.After the end, elevator is got back to initialized location.Obtain finished product 2-fluorine [
18F]-2-deoxidation-β-D-glucose.
Reaction unit working hour 33min, wherein
18F nucleic elution time 4min,
18F-FDG preparation and product transmission time 29min, every quality index all meets the pharmacopeia regulation, product radiochemicsl purity 99.7%, preparation absolute yield (not proofreading and correct) is 62.5%.
The present invention compares with similar technology, have generated time weak point, process stabilizing, good product quality, The productive rate advantages of higher, concrete condition sees Table 1.
Table 1: the present invention compares with similar technology
| The author | The technology source | Volume, page or leaf, year | Preparation time (min) | Absolute yield (not proofreading and correct) |
| Padget HC | Appl Radia Isot | 40，433-445，1989 | 50-55 | 39％ |
| Hamacher K | Appl Radia Isot | 41，49-55，1990 | 60 | 40-45％ |
| Culber PA | Appl Radia Isot | 46，887-891，1995 | 60 | 34.6％ |
| Mock BH | Nucl Med Biol | 23，497-501，1996 | 48 | 52％ |
| Zijlstra S | J Lable Comp Radio | 40，229-231，1997 | 40-45 | 40-42％ |
| The present invention | 30-35 | 60-65％ |
Claims (3)
- One kind with single tube FDG acid hydrolysis equipment carry out basic hydrolysis prepare the 2-fluorine [ 18F]-technology of 2-deoxidation-β-D-glucose, it is characterized in that may further comprise the steps:Single tube FDG acid hydrolysis equipment prepares acetylize under the automatic running status of program 18F-FDG.Accelerator-produced 18After F-is caught by anion column QMA, with the acetonitrile water mixed solution wash-out of salt of wormwood and cave ether, elutriant between 100～120 ℃ evaporating solvent and with the acetonitrile azeotropic water removing.Residue cooling back adds 1,3,4, and 6-four-O-ethanoyl-2-trifyl-β-D-seminose acetonitrile solution nucleophilic substitution reaction takes place between 85～90 ℃ generates acetylize 18F-FDG, acetonitrile is removed in evaporation between 100～120 ℃ then.The residue acetylize 18After the F-FDG cooling, add an amount of strong base solution, program is switched to manual operation state from automatic control state, manual unlocking mixes air valve, makes reaction system be in " mixing " state always; Reaction tubes self-initialize position fall time is 8 seconds, makes temperature of charge remain on 40～45 ℃ of reactions that are hydrolyzed, and hydrolysis time is 2 minutes.Hydrolysis finishes, and when whether prompting finished to react, the charging valve of manual unlocking kingpin correspondence added appropriate hydrochloric acid neutralization reaction solution, obtains 18The thick product of F-FDG.Program is switched to automatic running status and finishes reaction, carry out the product transmission, after pressurization is filtered purified column purification of thick product and sterilizing filter finished product 2-fluorine [ 18F]-2-deoxidation-β-D-glucose.
- 2. technology according to claim 1 is characterized in that the highly basic described in the macromolecule alkali for hydrolysis is sodium hydroxide or potassium hydroxide.
- 3. be used for the equipment of technology according to claim 1, it is characterized in that: adopt the CTI single tube FDG of company acid hydrolysis equipment, the soft rubber ball 9 that 7 conduits are arranged, 6 liquid feeding bottles (1 that communicate with reaction flask 8 by conduit, 2,3,4,5,6), each liquid feeding bottle correspondence respectively is connected with pneumavalve (V04, V08, V10, V12, V05, V14), 5 liquid feeding bottles (1 wherein, 2,3,4,6) and pneumavalve V04, V08, V10, V12, V14 synthesizes the liquid feeding bottle and the pneumavalve of system with first cover in the single tube FDG acid hydrolysis equipment, No. 5 liquid feeding bottle and corresponding pneumavalve V05 can be with in 5 bottles in the reaction of the cover of second in the single tube FDG acid hydrolysis equipment and 5 pneumavalves arbitrary groups, reaction flask 8 is by the purified post (C1 of conduit, C2, C3) and sterilizing filter F1 communicate with product receiving flask 7, one airway is arranged on the receiving flask 7, and the mouth of pipe has an air filter F2.
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|---|---|---|---|
| CN 200610095245 CN1974587A (en) | 2006-11-30 | 2006-11-30 | Basic hydrolysis process for preparing 2-fluoro [18F]-2-deoxy-beta-D-glucose in single tube FDG acidic hydrolysis apparatus |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772447A (en) * | 2012-10-18 | 2014-05-07 | 上海原子科兴药业有限公司 | Improved FDG synthesis method |
| CN105612583A (en) * | 2013-10-18 | 2016-05-25 | 通用电气健康护理有限公司 | Closed evaporation system |
| CN106178594A (en) * | 2016-08-10 | 2016-12-07 | 周彤 | Repeatedly, Fast back-projection algorithm18the technique of F FDG and the valve system used |
| CN107474082A (en) * | 2017-08-11 | 2017-12-15 | 深圳市保健委员会办公室 | Double batch PET developers18F FDG pharmaceutical synthesis device and method |
-
2006
- 2006-11-30 CN CN 200610095245 patent/CN1974587A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772447A (en) * | 2012-10-18 | 2014-05-07 | 上海原子科兴药业有限公司 | Improved FDG synthesis method |
| CN105612583A (en) * | 2013-10-18 | 2016-05-25 | 通用电气健康护理有限公司 | Closed evaporation system |
| CN106178594A (en) * | 2016-08-10 | 2016-12-07 | 周彤 | Repeatedly, Fast back-projection algorithm18the technique of F FDG and the valve system used |
| CN107474082A (en) * | 2017-08-11 | 2017-12-15 | 深圳市保健委员会办公室 | Double batch PET developers18F FDG pharmaceutical synthesis device and method |
| CN107474082B (en) * | 2017-08-11 | 2020-07-17 | 深圳市保健委员会办公室 | Double-batch PET developer18F-FDG drug synthesis equipment and method |
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