CN101597228B - <11>C-acetate preparation method - Google Patents
<11>C-acetate preparation method Download PDFInfo
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- CN101597228B CN101597228B CN2009100407712A CN200910040771A CN101597228B CN 101597228 B CN101597228 B CN 101597228B CN 2009100407712 A CN2009100407712 A CN 2009100407712A CN 200910040771 A CN200910040771 A CN 200910040771A CN 101597228 B CN101597228 B CN 101597228B
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- pak
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Abstract
An <11>C-acetate preparation method comprises the following steps: adopting methyl magnesium bromide or methyl magnesium chloride as precursor, reacting the precursor with <11>CO2 in a Loop to prepare an intermediate <11>C-acetyl bromine or magnesium chloride adduct; without adopting purification process, injecting N2 and removing tetrahydrofuran (THF), adding water in the mixture, injecting the mixture through integral small columns (C18 small column, SEP-PAK TSCX small column and SEP-PAK TIX small column) in turn for isolation and purification where the intermediate <11>C-acetyl bromine or magnesium chloride hydrolyzes, filtrating by aseptic filter membrane, neutralizing by alkaline solution and obtaining <11>C-AC parenteral solution. The preparation method of the invention has the advantages of the realization of column hydrolysis and purification, fully automatic synthesis, short synthesis time, high radiochemical yield, high radiochemical purity and low production cost.
Description
[technical field]
The present invention relates to the Application Areas of PET (Positron Emission Tomography positron emission tomography), be specifically related to
11the preparation method of C-acetate.
[background technology]
PET utilizes photon collimation principle and meets Detection Techniques, surveys in vitro the photon of annihilation radiation that tracer agent produces, and the information exchange of collection is crossed after computer is processed faultage image the quantitative physiological parameter that demonstrates target organ.PET has become a very important diagnostic tool in clinical position at present, especially aspect the early diagnosis and brain function imaging of cancer, for the early diagnosiss such as malignant tumour, cardiovascular disorder, nervous system disorders, guiding treatment, clinical observation on the therapeutic effect and following up a case by regular visits to etc., there is irreplaceable effect.
11the C-acetate (
11c-AC,
11c-Aceate) be for measuring positron emission fault (PET) developer of heart and brain oxidative metabolism, kinds of tumors (as urinary tract tumour, incidence cancer, hepatocellular carcinoma) etc., listed the radiopharmaceuticals kind in China's " medical institutions prepare positive electricity subclass control of radioactive medicine regulation " annex 1 in, context of detection in some tumour has higher sensitivity, is better than 2-
18the F-2-DDG (
18f-FDG) (inventor once proposed
18the patent application of F-FDG automatization synthesis technique, the patent No. is 200510101327.9 patents).Reported multiple abroad
11the automatic synthesis method of C-acetate (reference 1-6), domestic also have document (reference a 7) report.
11the C-AC automatization is synthetic several different methods, and purification process has: (1) liquid-liquid extraction (reference 8).This method trouble is consuming time, obtains
11putting of C-AC productive rate is lower, and generated time is longer.(2) HPLC method of purification (reference 9).This method obtains
11putting of C-AC productive rate higher (correcting yield approximately 72%), radiochemicsl purity is high (>99%) also, but carbon-11 transformation period is short, and HPLC purifying trouble is consuming time, and generated time is longer.(3) distillation method (reference 2).Remove intermediate
11in C-acetyl bromide (or chlorine) change magnesium adducts, after solvents tetrahydrofurane, adding acid and heat will
11c-AC steams from solution.This putting of method productive rate is lower, and generated time is longer, contains organic impurity in the finished product
11c-acetone and
11the C-trimethyl carbinol etc.(4) solid phase pillar partition method (reference 1,3-7).Commonly used is to use solid phase extraction column first the metal ion in thick product and bromine (or chlorine) ion to be removed, product is adsorbed on the solid phase anion column again, rinse pillar with a large amount of water, finally with physiological saline by product wash-out from anion column.This method radiochemical purity, chemical purity and radiological chemistry productive rate are all higher, and generated time is shorter, are the most frequently used methods of current synthesis of acetic acid salt.But the shortcoming of this method maximum is exactly pipeline easily to be stopped up and causes and synthesize unsuccessfully.
[summary of the invention]
The automatization of a kind of energy is synthetic, generated time is short, putting productive rate is high, radiochemicsl purity is high in order to provide for purpose of the present invention
11the preparation method of C-acetate.
The present invention realizes like this.
The employing On-column hydrolysis completes
11the automatization of C-AC is synthetic.Take methylmagnesium-bromide or methylmagnesium-chloride as precursor, with
11cO
2reaction generates intermediate
11c-acetyl bromide or magnesium chloride adducts.This step, without purge process, is led to N
2except after tetrahydrofuran (THF) (THF), add water by integrated pillar (comprising C18 pillar, strong cation pillar SEP-PAK TSCX pillar and middle weak type negatively charged ion pillar SEP-PAK TIX pillar), intermediate
11c-acetyl bromide (or chlorine) is changed magnesium and is hydrolyzed in SEP-PAK TSCX pillar, and through integrated little column separating purification, through in aseptic membrane filtration, basic solution and after must
11the C-AC injection liquid.
Synthetic route is as follows:
Me
11COOH+NaOH→Me
11COONa+H
2O
In preparation method of the present invention:
(1)
11cO
2: by the PETtrace magnetic resonance acceleator, passed through
14n (p, α)
11the C nuclear reaction is produced
11cO
2;
(2)
11cO
2in Loop ring can be dissolved in tetrahydrofuran (THF) in methylmagnesium-bromide or methylmagnesium-chloride (MeMgBr or MeMgCl/THF) react, the generation intermediate
11c-acetyl bromide (or chlorine) is changed the magnesium adducts;
(3) intermediate
11it is soluble in water that C-acetyl bromide (or chlorine) is changed the magnesium adducts, and hydrolysis reaction occurs in integrated pillar (C18 pillar, SEP-PAK TSCX pillar and SEP-PAK TIX pillar), and through integrated little column purification;
(4) C18 pillar, can adopt SEP-PAK Plus C18 pillar or SEP-PAK C18 pillar [being U.S. Waters company product (http://www.waters.com)], also can adopt Oasis HLB Plus pillar or other the homemade pillar replacement of other C18 pillar as U.S. Waters company;
(5) SEP-PAK TSCX pillar is the strong cation pillar, and its preparation method is: smash sky SEP-PAK PlusC18 pillar or SEP-PAK Al
2o
3neutral pillar, discard bulking agent in post, and pillar first is immersed in 75% ethanol and sterilizes, and discards thimerosal, then is immersed in sterilized water, discards sterilized water, dries; Load the H of Bio-Rad company
+type AG50w-X8 resin; The TSCX pillar can with other strong cation pillars, as the SCX pillar of Alltech company, (composition be sulfonic acid ion exchange resin R-SO
3h) or the Dowex50 pillar of U.S. DOWEX company (composition is sulfonic acid ion exchange resin R-SO
3h) replace;
(6) SEP-PAK TIX pillar is the negatively charged ion pillar, and its preparation method is: smash sky SEP-PAK PlusC18 pillar or Sep-Pak At
2o
3neutral pillar, discard in post the agent of filling a vacancy, and pillar first is immersed in 75% ethanol and sterilizes, and discards thimerosal, then is immersed in sterilized water, discards sterilized water, dries; Load the AG11A8 ion retardation resin of Bio-Rad company; The TIX pillar can replace as carboxylic acid type anionite-exchange resin pillar with similar middle weak type negatively charged ion pillar;
(7) basic solution can select NaOH solution or other basic solution (as KOH, Na
2hPO
4, sodium-acetate or sodium hydrogen carbonate solution etc.);
(8) adopt of the present invention
11the C-acetate (in the present invention,
11c-AC with
11the statement of C-acetate is mixed) preparation method, can realize that automatization is synthetic
11c-AC, total process about 6min consuming time, cumulative correction radiological chemistry productive rate is 40.5 ± 4.6% (n=6), radiochemicsl purity is greater than 95%, preparation
11c-AC, can directly be used as the PET radiopharmaceuticals;
(9) the present invention can directly adopt China production domesticization carbon-11 choline/methionine(Met) synthesis module (send special Beijing Science and Technology Ltd. produce) to complete after slightly improving
11the C-AC automatization is synthetic, and low production cost also can adopt other the full-automatic module automatization of commercialization synthetic.
[accompanying drawing explanation]
Fig. 1 is that the present invention adopts slightly improved carbon-11 choline/methionine(Met) synthesis module synthetic
11the C-AC schematic diagram has increased 5# and vacuum pump in former module, can realize like this
11the C-AC fully automated is synthetic.
In Fig. 1 Loop1 ring, by magnetic resonance acceleator, passed through
14n (p, α)
11the C nuclear reaction is produced
11cO
2,
11cO
2under cooled with liquid nitrogen, be trapped in the Loop1 ring.
1# is H
2o; 2# and 3# are vacant.
In the Loop2 ring, bromination (or chlorination) methyl magnesium THF solution is housed.
4# is for collecting the aseptic vacuum vessel of thick product.
5# is the product-collecting vacuum vessel containing aseptic sodium hydroxide solution.
[embodiment]
1.1
11c-CA's is synthetic
Adopt slightly improved carbon-11 choline/methionine(Met) synthesis module synthetic
11c-AC, except purification column and reagent change, structurally also only need slightly change, and only increased 5# bottle and vacuum pump in former module, just can realize
11the C-AC fully automated is synthetic, and its synthesis flow is shown in Fig. 1.
Before synthetic, the methylmagnesium-bromide anhydrous tetrahydrofuran solution 0.1mL that to get concentration be 0.87-1.5mol/L is loaded in Loop 2 rings.By the PETtrace magnetic resonance acceleator, passed through
14n (p, α)
11the C nuclear reaction is produced
11cO
2,
11cO
2under cooled with liquid nitrogen, be trapped in Loop 1 ring.At room temperature, with 10mL/min nitrogen, do carrier gas,
11cO
2generate intermediate acetyl magnesium bromide adducts with the Diethylaminoethyl reactive magnesium in LOOP 2 rings, solvents tetrahydrofurane is reached in the waste gas bottle under the nitrogen carrier band.In headpin, 5mL water is at N
2under effect, (30mL/min) is loaded onto integrated pillar (SEP-PAK Plus C18 pillar, SEP-PAK TSCX pillar and SEP-PAK TIX pillar) through LOOP 2 rings by the acetyl magnesium bromide, and hydrolysis reaction occurs on post.Then, thick product-collecting, in aseptic evacuated vial 4, passes into 30mL/min nitrogen except unreacted carbonic acid gas.Finally, under the vacuum pump effect, in No. 4 bottles
11c-AC solution enters kingpin through aseptic filter membrane, through in aseptic sodium hydroxide solution in kingpin and after
11the C-AC injection liquid.
1.2 product purity analysis
With radioactivity HPLC systems measurement
11the chemical purity of C-CA injection liquid and radiochemical purity.The HPLC analysis condition: the C18 post, the acetonitrile solution that moving phase is 5%, flow velocity is 1mL/min, it is 214nm that ultraviolet (UV) detects wavelength; The TLC method: the silica gel aluminium sheet, sample adds point sample after 1mol/L NaOH, and developping agent is methyl alcohol.
2 results
Adopt slightly improved carbon-11 choline/methionine(Met) synthesis module, but automatization is synthetic
11c-AC, total process about 6min consuming time, cumulative correction radiological chemistry productive rate is (40.5 ± 4.6) % (n=6).In waste liquid, radioactivity accounts for 24% left and right, and in integrated pillar (SEP-PAK Plus C18 pillar, SEP-PAK TSCX pillar and SEP-PAK TIX pillar), radioactivity accounts for 8% left and right, and 27% left and right of also having an appointment is unreacted
11cO
2the radioactivity of (logical nitrogen is removed) and reaction process loss.Adopt the PETtrace accelerator, 25 μ A bombardment 5min, produce 7.9GBq's
11cO
2, can produce 2.6GBq's
11the C-AC injection liquid.
Adopt the HPLC method to measure
11the radiochemicsl purity of C-AC, show simple spike, and this peak is consistent with the ultraviolet absorption peak of acetic acid,
11the C-AC radiochemicsl purity is greater than 95%.By radioactivity TLC method, measure,
11cO
2at initial point,
11the Rf=0.8 of C-AC,
11the C-AC radiochemicsl purity is greater than 98%.
Adopt the 0.1mL 1.5mol/L methylmagnesium-bromide in 0.2mL 1.0mol/L methylmagnesium-chloride alternate embodiment 1, in waste liquid, radioactivity descends, in thick product
11cO
2content rises, and mark rate slightly reduces.
The present invention adopts integrated pillar to complete hydrolysis and purifying work at post, and with the pillar method of purification of existing bibliographical information, (reference 1,3-7) compare, and this law is very simple, is easy to realization
11the automatization of C-AC is synthetic, avoid using the Ag+ post to generate the silver halide precipitation blocking pipeline and cause and produce unsuccessfully, and production cost obviously reduces.Intermediate
11c-acetyl bromide (or chlorine) is changed the magnesium adducts can complete hydrolysis in SEP-PAK TSCX pillar; Containing impurity in product is mainly
11cO
2,
11c-acetone and
11c-carbonate,
11the C-trimethyl carbinol, tetrahydrofuran (THF), Mg
2+and Br
-deng, the logical nitrogen of product acidifying can be removed
11cO
2with
11c-carbonate, SEP-PAK Plus C18 pillar can be removed in a large number
11c-acetone, tetrahydrofuran (THF) and part
11the C-trimethyl carbinol, SEP-PAK TSCX pillar can be removed most of Mg
2+, SEP-PAK TIX pillar can be removed most of Br
-thereby, can obtain pure
11the C-AC injection liquid.
Reference
1、Moerlein?SM，Gaehle?GG，Welch?MJ.Robotic?preparation?of?sodiumacetate?
11C?injection?for?use?in?clinical?PET.Nucl?Med?Biol，2002，29：613-621；
2、Mitterhauser?M，Wadsak?W，Kreal?A，et?al.New?aspects?on?thepreparation?of[
11C]acetate-a?simple?and?fast?approach?via?distillation.Appl?Radiat?Isot，2004，61：1147-1150；
3、Roeda?D，Dolle?F，Crouzel.An?improvement?of[
11C]acetate?synthesis-non-radioactive?contaminants?by?irradiation-induced?species?emanatingfrom?the[
11C]carbon?dioxide?production?target.Appl?Radiat?Isot，2002，57：857-860；
4、Kruijer?PS，Linden?TT，Mooij?R，et?al.A?practical?method?for?thepreparation?of[
11C]acetate.Appl?Radiat?Isot，1995，46(5)：317-321；
5、Le?Bars?D，Malleval?M，Bonnefoi?F，et?al.Simple?synthesis?of1-[
11C]-acetate.J?Label?Compd?Radiopharm，2006，49：263-267；
6、Soloviev?D，Tamburella?C.Captive?solvent[
11C]acetate?synthesisin?GMP?conditions.Appl?Radiat?Isot，2006，64：995-1000；
7, Zhang Jinming Tian Jiahe, Chen Yan, etc. carbon-11 choline module is synthesized carbon-11 acetate. Chinese Journal of Nuclear Medicine, 2008,28 (5): 319-322;
8、Berridge?MS，Cassidy?EH，Miraldi?F.[
11C]Acetate?and[
11C][
11C]methionine：Improved?syntheses?and?quality?control.Appl?Radiat?Isot，1995，46(3)：173-175；
9、Pike?VW，Horlock?PL，Brown?C，et?al.The?remotely-controlledpreparation?of?a
11C-labelled?radiopharmaceutical-[1-
11C]acetate.Int?JAppl?Radiart?Isot，1984，35(7)：623-627。
Claims (6)
1. one kind
11the preparation method of C-acetate, the methylmagnesium-bromide or the methylmagnesium-chloride that comprise the steps: to be dissolved in tetrahydrofuran (THF) are precursor, with
11cO
2reaction generates intermediate
11c-acetyl bromide or magnesium chloride adducts; This step, without purge process, is led to N
2except after tetrahydrofuran (THF), adding water is C18 pillar, SEP-PAK TSCX pillar and SEP-PAK TIX pillar by integrated pillar successively, intermediate
11c-acetyl bromide or magnesium chloride are hydrolyzed in SEP-PAK TSCX pillar, and through integrated little column separating purification, in aseptic membrane filtration, basic solution and after
11the C-AC injection liquid;
Wherein, the preparation method of said SEP PAK TSCX pillar smashes sky SEP-PAK Plus C18 pillar or Sep-Pak Al
2o
3neutral pillar, discard in post the agent of filling a vacancy, and pillar first is immersed in 75% ethanol and sterilizes, and discards thimerosal, then is immersed in sterilized water, discards sterilized water, dries, and loads H
+type AG50W-X8 resin;
The preparation method of said SEP PAK TIX pillar smashes sky SEP-PAK Plus C18 pillar or Sep-PakAl
2o
3neutral pillar, discard in post the agent of filling a vacancy, and pillar first is immersed in 75% ethanol and sterilizes, and discards thimerosal, then is immersed in sterilized water, discards sterilized water, dries, and loads AG11A8 ion retardation resin.
2. according to claim 1 a kind of
11the preparation method of C-acetate is characterized in that: by the PETtrace magnetic resonance acceleator, passed through
14n (p, α)
11the C nuclear reaction is produced
11cO
2.
3. according to claim 1 a kind of
11the preparation method of C-acetate is characterized in that: the C18 pillar is selected from SEP-PAK Plus C18 pillar, SEP-PAK Light C18 pillar, Oasis HLB Plus pillar or self-control C18 pillar.
4. according to claim 1 a kind of
11the preparation method of C-acetate is characterized in that: SEP PAKTSCX pillar replaces with strong cation pillar SCX pillar or Dowex50 pillar.
5. according to claim 1 a kind of
11the preparation method of C-acetate is characterized in that: SEP PAKTIX pillar replaces with weak type negatively charged ion pillar in other.
6. according to claim 1 a kind of
11the preparation method of C-acetate is characterized in that: basic solution is selected from NaOH, KOH, Na
2hPO
4, sodium-acetate or sodium hydrogen carbonate solution.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101798257B (en) * | 2010-03-04 | 2013-06-05 | 中山大学附属第一医院 | Automatic synthesis method of methylation reagent [11C] CH3Br |
| CN102406952B (en) * | 2011-12-01 | 2013-09-11 | 唐刚华 | Application of <11>C-bicarbonate injection in preparation of acid-base imbalance positron emission tomography (PET) medicament |
| CN106631863B (en) * | 2016-09-06 | 2018-08-17 | 中山大学附属第一医院 | The radiation synthetic method of sub- glutamic acid-type PET developers |
| CN110483278A (en) * | 2019-08-06 | 2019-11-22 | 唐刚华 | The fluoro- 3- of 2,2- bis-18F- fluoropropionic acid and its synthetic method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2223118C1 (en) * | 2003-04-22 | 2004-02-10 | Центральный научно-исследовательский рентгено-радиологический институт | Method for preparing [1-11c]-acetate sodium |
| CN1765911A (en) * | 2005-11-18 | 2006-05-03 | 南方医科大学南方医院 | 2- 18The synthesis technique of F-2-DDG |
| CN101381296A (en) * | 2008-03-28 | 2009-03-11 | 复旦大学附属肿瘤医院 | Method for synthesizing carbon nuclide (<11>C) labeled acetate |
-
2009
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2223118C1 (en) * | 2003-04-22 | 2004-02-10 | Центральный научно-исследовательский рентгено-радиологический институт | Method for preparing [1-11c]-acetate sodium |
| CN1765911A (en) * | 2005-11-18 | 2006-05-03 | 南方医科大学南方医院 | 2- 18The synthesis technique of F-2-DDG |
| CN101381296A (en) * | 2008-03-28 | 2009-03-11 | 复旦大学附属肿瘤医院 | Method for synthesizing carbon nuclide (<11>C) labeled acetate |
Non-Patent Citations (2)
| Title |
|---|
| Robotic preparation of Sodium Acetate C11 Injection for use in clinical PET;Stephen M. Moerlein et al;《Nuclear Medicine and Biology》;2002;第29卷;第616,619页 * |
| Stephen M. Moerlein et al.Robotic preparation of Sodium Acetate C11 Injection for use in clinical PET.《Nuclear Medicine and Biology》.2002,第29卷 |
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