CN1887828A - Synthesis process of 18F lebeled positive electron radioactive tracer with ionic liquid as phase transfer catalyst - Google Patents

Synthesis process of 18F lebeled positive electron radioactive tracer with ionic liquid as phase transfer catalyst Download PDF

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CN1887828A
CN1887828A CN 200610046764 CN200610046764A CN1887828A CN 1887828 A CN1887828 A CN 1887828A CN 200610046764 CN200610046764 CN 200610046764 CN 200610046764 A CN200610046764 A CN 200610046764A CN 1887828 A CN1887828 A CN 1887828A
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ionic liquid
synthetic
transfer catalyst
phase
tracer agent
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CN100560548C (en
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郭启勇
辛军
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No2 Hospital Attached To China Medical University
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Abstract

The present invention belongs to the field of chemical synthesis, and is especially fluorinating and substituting reaction process for synthesizing 18F labeled positive electron radioactive tracer. The process includes the following steps: 1. transferring 18F ion from medical cyclotron and water to accepting bottle and leading to QMA column; 2. eluting 18F ion in QMA column with K2CO3, acetoitrile and ionic liquid, and heating 18F ion in a reactor bottle under protection of inert gas; 3. dissolving the precursor in acetonitrile and adding to the reactor bottle, and heating under protection of inert gas; 4. cooling, hydrolyzing and purifying the solution inside the reactor bottle; and 5. separating and collecting the target product from the solution. The process may adopt microwave heating. The present invention has the features of multipurpose, great yield, high efficiency, stable process, short synthesis period, low cost, etc.

Description

Adopt ionic liquid synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent
Technical field
The invention belongs to the field of chemical synthesis, particularly a kind of to fluoridize substitution reaction synthetic 18The method of F mark positron radioactivity tracer agent.
Background technology
The positron radionuclide that present clinical use medical cyclotron is produced 15O, 13N, 11C, 18Among the F 18F has 110 minutes transformation period and becomes the clinical positron radioactivity nucleic of paying attention to the most. 18The positron radioactivity tracer agent of F mark is the most frequently used positron radioactivity tracer agent of clinical PET/CT, PET and coincidence system system, 18F-FDG, 18F-FLT, 18The F-acetate, 18F-choline etc. are formulated and observation of curative effect as early diagnosis, treatment plan that positive electricity radial pattern tracer agent has been widely used in tumour, cardiovascular and nervous system disorders at present.But, clinical at present 18The positron radioactivity tracer agent of F mark mainly adopts fluoridizes poly-ammonium (kryptofix/K + 18F -) as phase-transfer catalyst (phase transfer catalysis, PTC), the labeling process relative complex, even adopt the positron radioactivity tracer agent synthesis system of state-of-the-art full-automation, 18The F-FDG building-up process needs 25 minutes at least, and needs to adopt strict dry technology before synthetic and in the building-up process.It is synthetic as phase-transfer catalyst that poly-ammonium is fluoridized in employing 18The problem of the positron radioactivity tracer agent maximum of F mark is in dehydration and two steps of mark water constituent to be arranged, and like this to routine clinical work, particularly big regional routine work has brought serious problem for domestic southern atmospheric moisture.
Summary of the invention
The present invention be intended to overcome the deficiencies in the prior art part and a kind of multi-usage is provided, output is big, efficient is high, method is stable, generated time is short, it is synthetic as phase-transfer catalyst to spend low employing ionic liquid 18The method of F mark positron radioactivity tracer agent.
Can satisfy multi-usage, high yield, stable (not water funk), efficiently and fast and synthetic cheaply in order to reach to design 18F mark positive electricity radioactive tracer technology and method.We adopt following key core technology to reach the technical solution that we require in design.These core technologies comprise: adopt ionic liquid as PTC, adopt zone heating reach heavy dose of synthetic and fast the synthetic purpose, use HPLC that high specific activity tracer agent or separator column are separated with further shortening product disengaging time, adopt microwave heating technique to improve combined coefficient and to adopt one-stop synthesis model to reach full-automatic single stage method synthetic metabolism class tracer agent 18The purpose of F positron radioactivity tracer agent.
(1) it is stable synthetic to adopt ionic liquid to solve as PTC 18F positron radioactivity tracer agent
From above-mentioned context analyzer data as can be seen ionic liquid have well water-solublely, it has very high stability in air, and advantages such as organic chemistry solvent are stablized, be can be used as to boiling point height, chemical property.So selecting ionic liquid is best selection as PTC.
(2) adopt zone heating to reach the purpose that satisfies the synthetic positron radioactivity tracer agent of clinical heavy dose
The volume of finding eluting liquid and water under study for action can not be greater than 80 μ l, otherwise combined coefficient will obviously reduce, to such an extent as to ionic liquid carries out as PTC 18F positron radioactivity tracer agent synthetic technology method does not reach the practicality purpose.For this reason, we adopt the zone heating technology well to solve heavy dose of synthesizing 18F positron radioactivity tracer agent purpose, and make ionic liquid enlarge the scope of mark positive electricity radioactive tracer as PTC.We adopt 65 degree of heating earlier, and then are heated to the synthetic needed temperature and time of different positron radioactivity tracer agents, have so just solved Kim, Moon B.S. etc. in the important technological problems that never solves.So it is synthetic that we adopt ionic liquid to carry out heavy dose as PTC smoothly 18F positron radioactivity tracer agent has obtained 18The F-acetate, 18F-FMZ, 18F-Fallypride, 18The F-choline, 18F-FDG, 18F-FLT, 18F-FET, 18F-FES, 18F-FMISO, 18Synthesizing of positron radioactivity tracer agents such as F-FHBG, Urogastron and matrix metalloproteinase.
(3) adopt HPLC that high specific activity tracer agent or separator column are carried out the product separation to metabolism class tracer agent
For metabolism class tracer agent such as 18F-FDG, 18F-FLT, 18F-FET, 18F-FMISO, 18F-choline and acetate etc. can adopt separator column to carry out sharp separation product tracer agent, adopt HPLC to reach high specific activity for enzyme, rii receptor tracer agent.
(4) adopt microwave heating technique to improve combined coefficient
Microwave not only has homogeneous heating, is rapidly heated and reduces the characteristics of temperature, and microwave heating obviously improves the ability of ionic liquid as PTC.We adopt microwave heating to obtain satisfied effect for the synthetic tracer agent of some trace.Such as: 18F-Fallypride, 18Enzyme and rii receptor tracer agents such as F-FMZ.
(5) it is synthetic to adopt one-stop synthesis model to reach full-automatic single stage method 18F positron radioactivity tracer agent
For reach this technology have practicality purpose we pay attention to reaching full-automatic single stage method synthetic purpose especially in design.Have only complete from change single stage method synthetic adopt make operator reduce x radiation x, fast finish building-up process, have highly advantage such as repeatability and stability.Because the transformation period of nucleic is very short, can not finish full-automatic one-step synthesis process, for the positron radioactivity tracer agent with regard to the problem of the practicality of not knowing where to begin.For this reason, we finish first in the whole world on the TracerLab of GE company FX fn chemosynthesis device and synthesize above-mentioned from changing single stage method entirely 18The positron radioactivity tracer agent of F mark.We redesign original sequence of control, and reach the effect of above-mentioned satisfaction.
The object of the present invention is achieved like this: adopt ionic liquid synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent, can carry out successively as follows:
1) will come from accelerator 18F ion and water pass to receiving bottle and import among the anion-exchange column QMA;
2) adopt strong base-weak acid salt, acetonitrile and ionic liquid among the described anion-exchange column QMA 18The F ion carries out wash-out and is sent to reaction flask, under the protection of rare gas element it is heated;
3) precursor being dissolved in acetonitrile (DMSO or DMF) and joining in the described reaction flask heats under the protection of rare gas element;
4) reduce temperature, to solution in the described reaction flask be hydrolyzed, purifying;
5) target product to step 4 gained solution separates, collects.
Above-mentioned strong base-weak acid salt can be selected one and select K for use 2CO 3, KHCO 3, Cs 2CO 3Or TBAB (tetrabutyl bicarbonate of ammonia).
Precursor of the present invention can be selected:
1,3,4,6-tetra-O-acetyl-2-O-trifluromethanesulfonyl-D-mannopyan ose, (5 '-O-(4 for 3-N-tert-Butoxycarbonyl-, the thymine of 4 '-dimethoxytripphenylmethyl)-2 '-deoxy-3 '-o-(4-nitrobenzenesulfonyl)-β-D-threopentofuranosyl), 1,2-bis (tosyloxy) ethane, 1-(2 '-nitro-l '-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediol, Ro 15-2344, ethyl 5,6-dihydro-5-methyl-8-nitro-6-oxo-4H-imidazo[1,5a] [1,4] benzodiazepine-3-carboxylate, (S)-N-[(1-allyl-2-pyrrolidinyl) methyl]-5-(3-tosyloxypropyl)-2,3-dimethoxybenzamide, N2-(p-anisyldiphenylmethyl)-9-[(4-(p-toluenesulfonyloxy))-and 3-p-anisyldiphenylmethoxymethylbutyl] guanine, 3-O-methoxymethyl-16,17-O-sulfuryl-16-epiesteriol or (2S)-O-(2 '-tosyloxyethyl)-N-trityl-tyrosine-tert-butyl ester.
Above-mentioned steps 5 of the present invention can adopt FDG basic hydrolysis purification column to carry out target product to separate, collect.
As a kind of preferred version, FDG basic hydrolysis purification column of the present invention can comprise PS-H, PS-HCO3, ALOXN and HR-P filler, adopts millipore filtration when collecting.
In addition, above-mentioned steps 5 of the present invention adopts high pressure liquid chromatography (HPLC) post right 18F-FLT separates.
Step 5 of the present invention also can use separator column to separate except that adopting HPLC.
As another kind of preferred version, heating of the present invention also can be adopted microwave heating except that adopting the electrothermal oven mode.
Adopting ionic liquid to carry out nucleophilic as phase-transfer catalyst and zone heating technology and full-automatic single stage method, to fluoridize substitution reaction synthetic 18F mark positive electricity radioactive tracer technology and method have unique advantage, are very significant for the economic benefit and the social benefit that improve clinical position.
Need not synthetic for clinical position 18Carry out 38 minutes the dry work of synthesizer self before the F mark positive electricity radioactive tracer, the obvious like this working efficiency that improved; Need strict preservation facility (keep in dark place, water funk) be arranged to fluoridizing poly-ammonium when tradition adopts and to fluoridize poly-ammonium (kryptofix) as PTC, and ionic liquid has satisfactory stability as PTC, need not special preservation facility; Zone heating makes heavy dose of synthetic 18F mark positive electricity radioactive tracer becomes a reality; Obviously shorten building-up process,, adopt ionic liquid on average to shorten generated time more than 30% as PTC from each above-mentioned building-up process; Obviously simplify building-up process, adopt full-automatic single stage method synthetic method after adding precursor and reagent, to need not manual intervention and can automatization finish building-up process, obvious like this combined coefficient, synthesising stability and the repeatability of having improved; Can synthesize multiple positron radioactivity tracer agent, this shows that fully the employing ionic liquid is synthetic as PTC and full-automatic single stage method 18F mark positive electricity radioactive tracer agent method has multifunctionality.
Adopt ionic liquid synthetic as PTC and full-automatic single stage method 18F mark positive electricity radioactive tracer technology and method will 18Setup time had shortened 150% before F mark positive electricity radioactive tracer was synthetic; The synthetic success ratio of conventional art is brought up to 100%, 100% synthetic success ratio from 95% have a significant values (the each inspection of tumour patient all is very important) for clinical; Combined coefficient has on average been improved more than 30%, for 18F-FLT, 18F-FMZ, 18F-Fallypride, 18The F-choline, 18F-acetate combined coefficient has improved more than 40%.Improve combined coefficient for the positron radioactivity tracer agent and just mean that reducing input cost improves return rate, so this has important social benefit and economic benefit.In addition and since adopt full-automatic single stage method synthetic make clinical can be simply, stablize and obtain the result fast and accurately, the person grasps this technology and method fast also to be convenient to the clinical manipulation.We finish first in the whole world on the TracerLab of GE company FXfn chemosynthesis device and synthesize multiple from changing single stage method entirely 18The positron radioactivity tracer agent of F mark.
Conclusion is got up, and the present invention compared with prior art has following characteristics:
1, stable: as to adopt ionic liquid can under aqueous situation, finish as phase-transfer catalyst 18The positron radioactivity tracer agent of F mark is synthetic, so just can make clinical reach to stablize synthesize 18The positron radioactivity tracer agent synthetic method purpose of F mark.Need to select ionic liquid to carry out nucleophilic as PTC to fluoridize substitution reaction synthetic for this reason 18F mark positron radioactivity tracer agent.
2, satisfy routine clinical work: routine clinical production 18F amount between 1-4Ci, just need to improve for this reason from 18F post wash-out 18The ability of F promptly strengthens strong base-weak acid salt K 2CO 3, Cs 2CO 3, KHCO 3, or the concentration of TBAB wash-out and volume to improve 18F output.This is people's open questions such as Kim.People such as Kim find K 2CO 3Or the analogue volume can not be greater than 20 μ l, and the volume of water can not be greater than 60 μ l, and these are unpractical and can't accomplish in the routine clinical operation.Conventional K 2CO 3Volume also can surpass 100 μ l.
3, finish building-up process efficiently, fast: have only adopt the full-automatic synthetic technology of single stage method could finish entire synthesis process fast and improve combined coefficient ( 18Still there is decay in F positron radioactivity nucleic in building-up process).This technology provides and adopts HPLC or separator column isolation technique to shorten the time of separated product.
4, multi-usage: 18F-FDG and 18Two kinds of tracer agents of F-FLT can not meet clinical needs far away.Such as 18The F-choline be used for to prostate cancer diagnosis, 18The F-acetate be used for to diagnosing cancer of liver, 18F-FMZ be used for to epilepsy diagnosis, 18F-Fallypride is used for parkinsonian diagnosis.So, need synthetic line of design to satisfy multiple 18Synthesizing of the positron radioactivity tracer agent of F mark.
Description of drawings
The invention will be further described below in conjunction with drawings and Examples, but operational path of the present invention not only is confined to the following content of being explained.
Fig. 1 is a process flow sheet of the present invention.
Embodiment
(1) ionic liquid notion, classification reach and are using
1, ionic liquid notion and classification
Ionic liquid claims ionic liquid at room temperature (room temperature ionic liquid) or room temperature melting salt (room temperature molten salt) again, i.e. the liquid substance of being made up of ion fully under room temperature and adjacent temperature.Say that simply ionic liquid is exactly the ionic compound that is in liquid state.First normal temperature ionic liquid [EtNH 3] [NO 3] (mp.12 ℃) found in 1914, but new progress was only just arranged after 70 years last century.Ionic liquid is divided into three major types: AICI substantially 3Type ionic liquid, non-AICI 3Type ionic liquid and other special ion liquid.The main difference of preceding two class ionic liquid is the negative ion difference.Ion liquid positive ion mainly is three class quaternary ammoniums: imidazol ion, pyridinium ion, general quaternary ammonium ion etc.Ionic liquid has the unique characteristics such as stability that increase reactive activity, selectivity and catalyzer.
AICI 3The type ionic liquid is such as AlCl 3(III) and the mixture of chlorination 1-methyl-3-ethyl imidazol(e) salt, it contains several different ionization seriess, and their fusing point and character depend on composition, [C commonly used 2Mim] Cl-AlCl 3Represent this complex compound.Main research is by AlCl before 1992 3Deng the ionic liquid of forming, but AICI 3The type ionic liquid is to water, atmosphere instability, so that studied few in recent years.
Non-AICI 3The type ionic liquid is to study focus and emphasis at present.Non-AICI 3The type ionic liquid is made up of organic cation and negatively charged ion, and organic cation generally includes derivative of quaternary ammonium cation, season phosphonium salt positively charged ion, heterocyclic aromatic compounds and natural product etc.And ion liquid to water, atmospheric good stability based on the positive ion of quaternary ammonium ion, so the ionic liquid of mentioning at present mainly is meant non-AlCl 3The ionic liquid of class.Quaternary ammonium ion is that main positive ion mainly comprises general quaternary ammonium ion (notation: be designated as N as dimethyl ethyl butyl ammonium 1124 +) and imidazol ion (be designated as im +), pyridinium ion (is designated as Py +) etc.Two N atoms of imidazol ion are identical, N, and the imidazol ion that N ' (or 1,3) replaces is designated as (R 1R 3Im) +, as N-ethyl-N ' Methylimidazole ion be designated as (emim)+, if 2 go up to also have substituting groups then to be designated as (R 1R 2R 3Im) +There is substituent R then to be designated as (RPy) on the N atom of pyridinium ion +N, the Pyrrolidine positive ion that the N-methylethyl replaces is designated as P 12 +Study more ion liquid negative ion in addition BF is arranged 4 -, PF 6 -, also have OTf -(CF 3SO 3 -), NTf 2 -(N (CF 3SO 2) 2 -), CTf 3 -(C (CF 3SO 2) 3 -), CF 3COO -, C 3F 7COO -, C 4F 9SO 3 -, N (C 2F 5SO 2) 2 -, and PO 4 -, NO 3 -Deng.
Other special ion liquid are meant some performances, use special ionic liquid.Br or BF such as N-alkyl-N vinyl-2-Pyrrolidone 4The ionic liquid of salt.
Ion liquid advantage comprises: be in liquid state in the temperature range (100-200 ℃) of broadness; Almost there is not vapour pressure; There is not combustibility, no point of ignition; High thermostability is still stable more than 400 ℃; The ionic conductivity height, decomposition voltage is big, and it is many to reach 4V; Thermal capacity is big; Lower viscosity; Reclaim easily etc.Reclaim just because of ionic liquid has so many advantage and is easy to, and claimed to become " green solvent ".
2, ionic liquid is used
Ionic liquid has in fields such as chemical industry, pharmacy industries widely to be used.Below mainly introduce its main application.
(1) reactions such as transition metal-catalyzed hydrogenation in ionic liquid and coupling
Ionic liquid is made the existing a large amount of reports of transition metal-catalyzed hydrogenation of solvent, it makes solvent on the one hand, makes promotor (cocatalyst) again, compares with other ordinary organic solvents with water, ionic liquid is that catalyzer is again good solvent, and it makes catalytic activity stable.
(2) application of ionic liquid in extracting and separating
With the ionic liquid is extraction phase, and then ionic liquid should be immiscible with extracting phase, and present research all is extraction organic or inorganic thing from the aqueous solution, and the different selected ionic liquids of extract also should be different.These comprise the organic research of extraction, use supercritical CO 2From ionic liquid, extract organism, with ionic liquid from water the extracting metals ion, introduce ligating atom extracting metals ion etc. at ionic liquid.
(3) ionic liquid during nucleophilic substitution reaction and aromatic hydrocarbons replace
The aliphatics nucleophilic substitution reaction utilizes phase transition (PTC) method better, usually to use methylene dichloride, toluene and chlorobenzene and make solvent, because the use of halohydrocarbon more and more is restricted, ionic liquid makes solvent and the catalysis nucleophilic substitution reaction comes into one's own naturally, it is the energy activated anionic on the one hand, and ion liquid cationic moiety is effective catalyzer as PTC, as reaction of benzyl chloride and prussiate etc.
Recently, relevant aromatic diazo salt is substituted in the ionic liquid by fluorine and carries out, and has obtained sizable progress, and easy and simple to handle, and productive rate is almost quantitative, the recyclable several of ionic liquid.Nitrated in ionic liquid also change classical nitrifying method effectively, overcome the disadvantage of classical inverse strong acidic liquid after the neutralization reaction.
Ionic liquid not only can be used as fine PTC, but also can play important katalysis.At present, adopt ionic liquid as phase-transfer catalyst at the main nucleophilic substitution reaction of using 18During F positron radioactivity tracer agent is synthetic, obtained very big progress.
(2) ionic liquid exists 18Application during F mark positron radioactivity tracer agent is synthetic
1、 18F-FDG
18F-FDG is synthetic can simply to be divided into tradition 18Two kinds of F-FDG synthetic method and employing ionic liquid methods.
(1) tradition 18F-FDG is synthetic
Tradition 18The synthetic synthetic method of F-FDG roughly is divided into three phases: synthetic tradition 18The F-FDG design phase (before 1976); Right 18F-FDG synthetic technology and methodology are improved, the raising stage (1976-1986); 18The F-FDG synthesis phase (1986-so far).Mainly concentrate on design in first stage 18On the F-FDG synthetic method.Successfully synthetic since 1976 18After the F-FDG, in nearly 30 years of development processes, 18The F-FDG synthetic method is updated, is improved and improved.Particularly the commercialization full-automatic method is synthetic 18After the F-FDG success, 18F-FDG is synthetic to be greatly developed with clinical application.
In early days 18The FDG of F-mark is synthetic by being 18F 2Gas and 3,4,6-tri-O-acetyl-D-glucal adopts close electric fluoro labelling method as precursor.Fluoro reagent is in the electric fluoro mark of parent 18F-acetyl time fluorochemical. 18F-acetyl time fluorochemical be by 18F 2Molecule prepares by acetate.The nucleophilic fluoro 18The FDG of F-mark is synthetic by being 18F -Ion and 1,3,4,6-tetra-O-acetyl-2-O-trifluromethanesulfonyl-D-mannopyan ose (TATM) precursor is synthetic.Although there are many scholars that fluoro cationoid reaction method afford is improved, because 18The electric fluoro marking method of FDG parent of F-mark needs at first to produce 18F 2Gas, and gas 18F 2Produce to need special ion source and gas, and full-automatic synthetic method complexity, cost height, radio-protective is complicated and replaced by nucleophilic fluoro marking method.Nucleophilic fluoro labelling method is compared with the electric fluoro labelling method of parent 18F ionic production process is simple and convenient, is convenient to clinical popularizing.Particularly 18F ionic production ratio 18F 2Ionic production has better cost performance, meets the maximization of environmental protection and resource, is subjected to extensive welcome, and obtains popularizing and development.
The substitution reaction of nucleophilic fluoro needs nucleophilic fluoro-reaction reagent, nucleophilic fluoro-reaction medium.
The nucleophilic fluoro reagent: 18Chemical reaction can not directly take place with the precursor of organic phase and generate final product in the F ion. 18The F ion as effective nucleophilic fluoro reagent must with 18The pairing of F ionic condition and phase-transfer catalyst positively charged ion, and in the solvent of anhydrous, non-hydrogen bond, just can carry out nucleophilic reaction.Phase-transfer catalyst commonly used is usually to fluoridize tetra-allkylammonium (M + 18F -) form or fluoridize poly-ammonium (kryptofix/K + 18F -) form be dissolved in the solution, be fit to carry out the nucleophilic fluoro-reaction like this.Quaternary ammonium salt commonly used has tetramethyl-, tetraethyl-, tetra-n-butyl ammonium.The kryptofix/K that present nucleophilic fluoro labelling method generally uses + 18F -Mixture, it is effective organic cation, inorganic anion salt, kryptofix/K + 18F -In the complex molecule, potassium ion plays shielding effect in the middle of being enclosed in molecule.But also there are many scholars to adopt tetra-allkylammonium as phase-transfer catalyst (M + 18F -) carry out the mark of enzyme, acceptor, polypeptide.But adopt and to fluoridize tetra-allkylammonium and may have some production of by-products as phase-transfer catalyst in reaction process, this notes at design nucleophilic fluoro-reaction process need, and labeling effciency is low makes this technology use to be restricted.
The medium of nucleophilic reaction: the solvent that the medium of nucleophilic reaction can be selected for use has dimethyl formamide, dimethyl sulfoxide (DMSO), acetone, acetonitrile etc.What routine work was commonly used is acetonitrile, mainly is that acetonitrile has the following advantages: form lower boiling azeotrope, the unsettled fluoride salt of dry heat effectively with water; Reaction is fast, height produces effects; Under reflux state, do not decompose substrate; Boiling point is low, can steam effectively after reaction finishes and remove.
Nucleophilic fluoro-reaction: the common nucleophilic fluoro-reaction that has on the aromatic nucleus; Indirect fluoro-reaction in the molecule on N, O, the S element etc.
FDG is PET/CT and the PET positron radioactivity tracer agent of normal use.Adopt 18The F ion as effectively nucleophilic fluoro reagent, kryptofix as PTC, acetonitrile as medium and 1,3,4,6-tetra-O-acetyl-2-O-trifluromethanesulfonyl-D-mannopyan ose (TATM) comprises five steps as the synthetic F-18FDG of precursor: labeling process comprises dehydration, mark, takes off acetonitrile, hydrolysis and purifying.What generally adopt at present is that nucleophilic substitution reaction is synthetic 18F-FDG.But nucleophilic substitution reaction need make by the azeotropic drying step 18F is ion-activated.This step is time-consuming, but is the step that must finish.If the more important thing is in this step dehydration and not exclusively will cause synthetic failure.If can cancel this step of dehydration, also synthesizing the drying process that does not need strictness with regard to meaning person.So just can make 18The synthetic simplification of F-FDG, building-up process stabilization.Also there is report to adopt and fluoridizes tetra-allkylammonium (M + 18F -) synthetic as the PTC automatization 18F-FDG, although radiochemical purity is very high, the radiological chemistry productive rate still is lower than the method for kryptofix as PTC of using.
Two kinds of tradition of table 1 18The F-FDG marking method relatively
The electric fluoro labelling method of parent Nucleophilic fluoro labelling method
Participate in reactive species 18F 2Molecule 18The F ion
Fluoro reagent 18F-acetyl time fluorochemical Usually to fluoridize tetra-allkylammonium (M + 18F -) form or fluoridize poly-ammonium (kryptofix/K + 18F -)
Reaction medium Glacial acetic acid Acetonitrile
Fluoro-reaction Directly carry out mark Direct substitution or indirect fluoro replaces
Separation and purification Simply Relative complex
(2) adopt quick, the stable nucleophilic fluoro-reaction that carries out of ionic liquid
Kim etc. use Potassium monofluoride and ion liquid fluorination process significance to strengthen fluorination reaction process at report in 2002, and have improved selectivity.Kim etc. find that some salt and first sulfo group alkane can be at [bmim] [BF 4] quicken the nucleophilic fluoridation of KF under the different situations that exist.Such as first sulfo group and KF at organic solvent such as CH 3CN reacted after 24 hours even at 100 ℃, equally at ionic liquid [bmim] [BF 4] finished reaction when existing at 1.5 hours.This shows that ionic liquid not only can tolerate the existence of water, and obviously accelerated speed of response.
(3) adopt ionic liquid synthetic fast, easily 18F-FDG
After adopting ionic liquid as nucleophilic fluoro-reaction reagent, synthetic 18The F-FDG process does not need dehydrating step.There has been report to adopt ionic liquid recently, direct activation as medium 18The F ion.After Kim adopts ionic liquid as fluoro-reaction reagent, synthetic 18The F-FDG time is no more than 15 minutes, and traditional 18The F-FDG generated time is about 30 minutes.Save half the time like this.In addition, adopt the ionic liquid technology simple, do not need confined reaction bottle and substep dry technology, greatly facilitate clinical everyday work like this equipment requirements.
In order to improve combined coefficient, TABF, K are adopted in suggestion such as Kim 2CO 3Salt or other carbonate and acetonitrile mixing liquid are gone up drip washing from anion-exchange column QMA 18The F ion, and find Cs 2CO 3From the QMA wash-out 18The F ionic is most effective.Ion liquid concentration is right 18The F-FDG combined coefficient also has tangible influence, needs best ionic liquid concentration could obtain the highest combined coefficient.It is generally acknowledged that high ionic liquid concentration and long reaction times can obtain high combined coefficient.In addition, employing such as Lemaire has obviously improved in low polarity solid phase column basic hydrolysis 18The F-FDG resultant velocity.
Adopt ionic liquid as solvent and catalyzer,, quicken building-up process, improve having water to exist to save under the situation drying step of anhydrating 18The productive rate of F-FDG and the stability of building-up process.But, tetrabutyl bicarbonate of ammonia (TBAB) wash-out that Kim adopts 18The F ion, and only can the wash-out low dose 18The F ion makes this method lose practicality.
2, 18Other positron radioactivity tracer agent of F mark
Piyush Kumar etc. has reported PET β-starch patch developer 18F-FESB's is synthetic.Synthesize under the situation that water exists, obviously simplified building-up process, combined coefficient improves 2-3 doubly.Moon Byung Seok etc. introduce and adopt the ionic liquid technology under the situation that water exists, and research is synthetic 18The top condition of F-FLT.When adopting ionic liquid [bmim] [Otf], top condition is to adopt ionic liquid, 5 μ l 1M KHCO 3With 5mg precursor (productive rate 61.5 ± 4.3%N=10).Comprise the HPLC purifying, total time is 70 minutes.Omitted the distillation drying step, can synthesize fast [ 18F] FLT, radiological chemistry productive rate and purity are respectively 30 ± 5% and＞95%.
We adopt the brand-new technology scheme to finish multiple 18Synthesizing of the positron radioactivity tracer agent of F mark.
Embodiment 1:
18The synthesis step of F-FDG:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, (1,3,4,6-tetra-O-acetyl-2-O-trifluromethanesulfonyl-D-mannopyan ose (TATM) 25mg) is dissolved in the 0.7mL acetonitrile, fully joins reaction flask again behind the mixing with precursor; Heating 100 degree are 5 minutes under the protection of nitrogen or helium;
5, temperature is reduced to 90 ℃, adds 2ml water in reaction flask, is cooled to 33 ℃, adds 1M 1mL NaOH hydrolysis in 1.5 minutes removing acetyl protection base (AcO then -);
6, with solution by a special-purpose FDG basic hydrolysis (comprising PS-H, PS-HCO3, ALOXN, four kinds of fillers of HR-P) purification column, discard solution; , carry and to collect in the product bottle by 0.2 μ m millipore filtration product wash-out on the pillar with 14ml water, obtaining can be for injection 18F-FDG solution;
Combined coefficient is more than 65%, and radiochemical purity is greater than 98%;
When 7, adopting 70W microwave heating, all can shorten 1-2 minute heat-up time, and combined coefficient can reach 70-75%, and radio chemistry purity is greater than 98%;
8, can be synthetic from changing single stage method entirely on the TracerLab of GE company FX fn chemosynthesis device 18F-FDG;
Embodiment 2:
18The synthesis step of F-FLT:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, ((5 '-O-(4 for 3-N-tert-Butoxycarbonyl-with precursor, the thymine of 4 '-dimethoxytripphenylmethyl)-2 '-deoxy-3 '-o-(4-nitrobenzenesulfonyl)-β-D-threopentofuranosyl), 30mg) be dissolved in the 0.7mL acetonitrile, fully join reaction flask again behind the mixing; Heating 130 degree are 15 minutes under the protection of nitrogen or helium;
5, temperature is reduced to 100 ℃, adds 1N HCI 1.2mL reaction 2 minutes in reaction flask, is cooled to 33 ℃, adds 1M 1mL NaOH then;
6, solution is undertaken by a HPLC 18F-FLT separates.Leacheate is 90% water: 10% ethanol, obtain can for the injection 18F-FLT solution; The separator column that also can adopt WATER company or other company to provide separates 18F-FLT;
Combined coefficient is more than 30%, and radiochemical purity is greater than 98%;
When 7, adopting 70W microwave heating, all can shorten 3-5 minute heat-up time, and combined coefficient can reach more than 40%, and radio chemistry purity is greater than 98%;
8, can be synthetic from changing single stage method entirely on the TracerLab of GE company FX fn chemosynthesis device 18F-FLT;
Embodiment 3:
18The synthesis step of F-monoethyl choline:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, with precursor (1,2-bis (tosyloxy) ethane, 20mg) molten to the 0.7mL acetonitrile, fully join reaction flask again behind the mixing; Heating 100 degree are 15 minutes under the protection of nitrogen or helium;
5, temperature is reduced to 33 ℃, adds the 2mL leacheate in reaction flask;
6, solution enters high pressure liquid chromatography (HPLC) post at last by 2 series connection anion-exchange columns (characteristic of post, hydroxyl type).High pressure liquid chromatography is pressed following conditional operation: permaphase ODS-silica gel (post model), 250 millimeters long, 10 millimeters of diameters; Solution (moving phase), 50 mmoles/rise phosphoric acid+1 mmole/rise 2-naphthene sulfonic acid; Flow velocity, 5 ml/min; Temperature, room temperature; Or directly adopt separator column to carry out;
7, 18The F-monoethyl choline with respect to 18Putting productive rate behind the F-decay correction is 46.3%, and radiochemical purity is greater than 98%;
When 8, adopting 70W microwave heating, all can shorten 3-5 minute heat-up time, and combined coefficient can reach more than 50%, and radio chemistry purity is greater than 98%;
9, can be synthetic from changing single stage method entirely on the TracerLab of GE company FX fn chemosynthesis device 18The F-monoethyl choline;
Embodiment 4:
18The synthesis step of F-FMISO:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, with precursor (1-(2 '-nitro-1 '-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediol, NITTP 5mg) is dissolved in 0.7mL DMSO, fully joins reaction flask again behind the mixing; Heating 100 degree are 8 minutes under the protection of nitrogen or helium;
5, reaction flask add HCl (1N, 1ml) solution enters reaction flask, 100 ℃ of heating 3 minutes are hydrolyzed.Then reaction flask add sodium acetate solution (30% aqueous solution 0.5ml) enters reaction flask, in and mixed solution.
6, thick product enters the HPLC separation module and is further purified (elutriant H 2O/C 2H 5OH95/5, v/v, flow velocity 8ml/min, ultraviolet 220nm, radioactivity and ultraviolet ray are monitored simultaneously).After system detects the radiocounting of HPLC place and reaches setting threshold, begin automatically to collect, obtain final product; Also can adopt the separator column separated product;
Obtain product at last 18F-FMISO, putting productive rate 60%.If use 10mg, can obtain productive rate 86% under the similarity condition
When 7, adopting 70W microwave heating, all can shorten 1-2 minute heat-up time, and combined coefficient can reach (precursor 5mg) more than 65%, and radio chemistry purity is greater than 98%;
8, can be synthetic from changing single stage method entirely on the TracerLab of GE company FX fn chemosynthesis device 18F-FMISO;
Embodiment 5:
18The synthesis step of F-acetate:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, precursor (10mg) is molten to the 0.7mL acetonitrile, fully join reaction flask again behind the mixing; Heating 100 degree are 10 minutes under the protection of nitrogen or helium;
5, in reaction flask, add 2ml 1M NaOH, 60 ℃ of hydrolysis 5min.Add 1ml1M HCl neutralization.
6, thick product enters the HPLC separation module and is further purified (elutriant H 2O/C 2H 5OH90/10, v/v, flow velocity 5ml/min, ultraviolet 200nm, radioactivity and ultraviolet ray are monitored simultaneously).After system detects the radiocounting of HPLC place and reaches setting threshold, begin automatically to collect, obtain final product.Also can adopt the separator column separated product;
Obtain product at last 18The F-acetate, putting productive rate 40%, radiochemical purity 98%;
When 7, adopting 70W microwave heating, all can shorten 1-2 minute heat-up time, and combined coefficient can reach (precursor 5mg) more than 45%, and radio chemistry purity is greater than 98%;
8, can be synthetic from changing single stage method entirely on the Trac of GE company erLab FX fn chemosynthesis device 18The F-acetate;
Embodiment 6:
18The synthesis step of F-Flumazenil:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, with precursor (Ro 15-2344, ethyl 5,6-dihydro-5-methyl-8-nitro-6-oxo-4H-imidazo[1,5a] [1,4] benzodiazepine-3-carboxylate, 10mg) molten to the 0.7mL acetonitrile, fully join reaction flask again behind the mixing; Heating 160 degree are 30 minutes under the protection of nitrogen or helium;
5, add the 2mL leacheate at reaction flask;
6, product is with HPLC purifying, analysis (flow velocity 5ml/min, ultraviolet 254nm, radioactivity and ultraviolet ray are monitored simultaneously for elutriant EtOH/3%NaCl=70/30, v/v).Also can adopt separator column to separate;
Obtain product at last 18F-FMZ, putting productive rate 50%, radiochemical purity 98%;
When 7, adopting 70W microwave heating, all can shorten 1-2 minute heat-up time, and combined coefficient can reach more than 60%, and radio chemistry purity is greater than 98%;
8, can be synthetic from changing single stage method entirely on the TracerLab of GE company FX fn chemosynthesis device 18F-Flumazenil;
Embodiment 7:
18The synthesis step of F-Fallypride:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, with precursor ((S)-N-[(1-allyl-2-pyrrolidinyl) methyl]-5-(3-tosyloxypropyl)-2,3-dimethoxybenzamide, 10mg) molten to the 0.7mL acetonitrile, fully join reaction flask again behind the mixing; Heating 90 degree are 18 minutes under the protection of nitrogen or helium;
5, add the 2mL leacheate at reaction flask;
6, product is with HPLC purifying, analysis (ultraviolet 280nm, radioactivity and ultraviolet ray are monitored simultaneously for elutriant 0.01M phosphoric acid/acetonitrile=6/4, flow velocity 3ml/min).Be further purified with Sep-Pak C18 post after collecting product.Combined coefficient is greater than 30%, and radio chemistry purity is greater than 98%; Also can directly adopt the separator column of WATER company or other company directly to separate;
When 7, adopting 70W microwave heating, all can shorten 1-2 minute heat-up time, and combined coefficient can reach more than 60%, and radio chemistry purity is greater than 98%;
8, can be synthetic from changing single stage method entirely on the TracerLab of GE company FX fn chemosynthesis device 18F-Fallypride;
Embodiment 8:
18The synthesis step of F-FHBG:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, with precursor (N2-(p-anisyldiphenylmethyl)-9-[(4-(p-toluenesulfonyloxy))-3-p-anisyldiphenylmethoxymethylbutyl] guanine, 5mg) molten to the 0.7mL acetonitrile, fully join reaction flask again behind the mixing; Heating 150 degree are 15 minutes under the protection of nitrogen or helium;
5, HCl (1N, 0.4ml) solution enters reaction flask, 110 ℃ the heating 3 minutes, be hydrolyzed;
6, NaOH (1N 0.18ml) enters reaction flask, in and mixed solution;
7, thick product dilutes with 1.3ml HPLC leacheate.Head product enters the HPLC separation module, be further purified (elutriant NH4OAc (50mmol/L)/C2H5OH 93/7, v/v, flow velocity 5ml/min, ultraviolet 254nm, radioactivity and ultraviolet ray are monitored simultaneously).After system detects the radiocounting of HPLC place and reaches setting threshold, begin automatically to collect, obtain final product.Obtain product at last 18F-FHBG, putting productive rate 15% (not proofreading and correct).Also can adopt the separator column separated product;
When 8, adopting 70W microwave heating, all can shorten 1-2 minute heat-up time, and combined coefficient can reach more than 25%, and radio chemistry purity is greater than 98%;
9, can be synthetic from changing single stage method entirely on the TracerLab of GE company FX fn chemosynthesis device 18F-FHBG;
Embodiment 9:
18The synthesis step of F-FES:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, (3mg) the molten 0.7mL acetonitrile that arrives fully joins reaction flask behind the mixing again for 3-O-methoxymethyl-16,17-O-sulfuryl-16-epiesteriol with precursor; Heating 100 degree are 10 minutes under the protection of nitrogen or helium;
5, the 1.5ml 0.1M HCl of reaction mixture adding.With 100 ℃ of heating of mixture 3 minutes, remove blocking group.Product is with HPLC purifying, analysis (ultraviolet 280nm, radioactivity and ultraviolet ray are monitored simultaneously for elutriant 50%EtOH, flow velocity 7ml/min).Gleanings dilutes with physiological saline, aseptic membrane filtration.Obtain product at last 18F-FES, putting productive rate 30%, radiochemical purity 98%; Also can adopt the separator column separated product;
When 6, adopting 70W microwave heating, all can shorten 1-2 minute heat-up time, and combined coefficient can reach more than 38%, and radio chemistry purity is greater than 98%;
7, can be synthetic from changing single stage method entirely on the TracerLab of GE company FX fn chemosynthesis device 18F-FES.
Embodiment 10:
18The synthesis step of F-FET:
1, will transmit from accelerator 18F ion and water pass to receiving bottle (1-4Ci);
2, will 18F ion and water pass to anion-exchange column QMA;
3, adopt 0.15mL K 2CO 3(0.9mg)+0.2mL acetonitrile+0.3mL ionic liquid (BMI) is from QMA post wash-out 18The F ion also is sent to reaction flask; Heating 65 degree are 3.5 minutes under the protection of nitrogen or helium;
4, with precursor ((2S)-O-(and 2 '-tosyloxyethyl)-N-trityl-tyrosine-tert-butyl ester, 10mg) molten to the 0.7mL acetonitrile, fully join reaction flask again behind the mixing; Heating 85 degree are 5 minutes under the protection of nitrogen or helium;
5, the 0.5ml 0.1M HCl of reaction mixture adding.With 100 ℃ of heating of mixture 5 minutes, remove blocking group.After the cooling, NaOH (1N, 0.5ml) neutralization reaction liquid.Head product enters the HPLC separation module, be further purified (elutriant is 0.1% phosphoric acid buffer (pH5.7), contains 2% ethanol, 10mM NaH2PO4, and flow velocity 4ml/min, ultraviolet 254nm, radioactivity and ultraviolet ray are monitored simultaneously).After system detects the radiocounting of HPLC place and reaches setting threshold, begin automatically to collect, obtain final product.Also can adopt the separator column separated product;
Obtain product at last 18F-FET, putting productive rate 50%, radiochemicsl purity＞98%.
When 6, adopting 70W microwave heating, all can shorten 1-2 minute heat-up time, and combined coefficient can reach more than 38%, and radio chemistry purity is greater than 98%;
7, can be synthetic from changing single stage method entirely on the TracerLab of GE company FX fn chemosynthesis device 18F-FES.

Claims (14)

1, adopt ionic liquid synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that, carries out successively as follows:
1) will come from medical cyclotron 18F ion and water pass to receiving bottle and import among the anion-exchange column QMA;
2) adopt strong base-weak acid salt, acetonitrile and ionic liquid among the described anion-exchange column QMA 18The F ion carries out wash-out and is sent to reaction flask, under the protection of rare gas element it is heated;
3) different precursors being dissolved in acetonitrile, DMSO or DMF and joining in the described reaction flask heats under the protection of rare gas element;
4) reduce temperature, to solution in the described reaction flask be hydrolyzed, purifying;
5) target product to step 4) gained solution separates, collects.
2, employing ionic liquid according to claim 1 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent, it is characterized in that: described precursor is 1,3,4,6-tetra-O-acetyl-2-O-trifluromethanesulfonyl-D-mannopyan ose, (5 '-O-(4 for 3-N-tert-Butoxycarbonyl-, the thymine of 4 '-dimethoxytripphenylmethyl)-2 '-deoxy-3 '-o-(4-nitrobenzenesulfonyl)-β-D-threopentofuranosyl), 1,2-bis (tosyloxy) ethane, 1-(2 '-nitro-1 '-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediol, Ro 15-2344, ethyl 5,6-dihydro-5-methyl-8-nitro-6-oxo-4H-imidazo[1,5a] [1,4] benzodiazepine-3-carboxylate, (S)-N-[(1-allyl-2-pyrrolidinyl) methyl]-5-(3-tosyloxypropyl)-2,3-dimethoxybenzamide, N2-(p-anisyldiphenylmethyl)-9-[(4-(p-toluenesulfonyloxy))-and 3-p-anisyldiphenylmethoxymethylbutyl] guanine, 3-O-methoxymethyl-16,17-O-sulfuryl-16-epiesteriol or (2S)-O-(2 '-tosyloxyethyl)-N-trityl-tyrosine-tert-butyl ester.
3, employing ionic liquid according to claim 1 and 2 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described step 5 adopts FDG basic hydrolysis purification column that target product is separated, collects.
4, employing ionic liquid according to claim 3 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described FDG basic hydrolysis purification column comprises PS-H, PS-HCO3, ALOX N and HR-P filler, adopts millipore filtration when collecting.
5, employing ionic liquid according to claim 1 and 2 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described step 5 adopts high pressure liquid chromatography (HPLC) post right 18F-FLT or 18F-FMISO etc. separate.
6, employing ionic liquid according to claim 1 and 2 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described step 5 adopts anion-exchange column and high pressure liquid chromatography (HPLC) post to target product 18The F-monoethyl choline, 18The F-acetate, 18F-FMZ, 18F-Fallypride, 18F-FHBG, 18F-FET separates.
7, employing ionic liquid according to claim 1 and 2 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described step 5 can use separator column to separate.
8, employing ionic liquid according to claim 1 and 2 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described type of heating is microwave heating.
9, employing ionic liquid according to claim 3 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described type of heating is microwave heating.
10, employing ionic liquid according to claim 4 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described type of heating is microwave heating.
11, employing ionic liquid according to claim 5 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described type of heating is microwave heating.
12, employing ionic liquid according to claim 1 and 2 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described type of heating also can adopt the electrothermal oven heating.
13, employing ionic liquid according to claim 3 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described type of heating also can adopt the electrothermal oven heating.
14, employing ionic liquid according to claim 1 and 2 is synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent is characterized in that: described strong base-weak acid salt can be selected one and select K for use 2CO 3, KHCO 3, Cs 2CO 3Or TBAB.
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WO2008101305A1 (en) * 2007-02-21 2008-08-28 Trasis S.A. Method for the elution of 18f fluoride trapped on an anion-exchange phase in a form suitable for efficient radiolabeling without any evaporation step
CN100560549C (en) * 2006-06-23 2009-11-18 郭启勇 Utilize ionic liquid synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent
CN101168554B (en) * 2007-11-28 2011-03-02 中国人民解放军总医院 Method for preparing 18F-FLT
CN102329359A (en) * 2011-07-15 2012-01-25 无锡江原安迪科分子核医学研究发展有限公司 Process for preparing 18F-FLT and self-contained reagent kit
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CN101967149B (en) * 2009-07-28 2013-01-16 北京师范大学 18F substituted nitro-labeled pyrazolo [1,5-a] pyrimidines and their preparation and application
CN103608337A (en) * 2011-05-13 2014-02-26 Futurechem株式会社 <18>F-marked precursor of PET radioactive medical supplies, and preparation method thereof
US9023316B2 (en) 2010-04-08 2015-05-05 Siemens Medical Solutions Usa, Inc. Synthesis of 18F-labeled tracers in hydrous organic solvents
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
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CN100560549C (en) * 2006-06-23 2009-11-18 郭启勇 Utilize ionic liquid synthetic as phase-transfer catalyst 18The method of F mark positron radioactivity tracer agent
WO2008101305A1 (en) * 2007-02-21 2008-08-28 Trasis S.A. Method for the elution of 18f fluoride trapped on an anion-exchange phase in a form suitable for efficient radiolabeling without any evaporation step
KR101528140B1 (en) * 2007-02-21 2015-06-29 트라시스 에스.에이. Method for the elution of 18f fluoride trapped on an anion-exchange phase in a form suitable for efficient radiolabeling without any evaporation step
US8366934B2 (en) 2007-02-21 2013-02-05 Trasis S.A. Method for the elution of 18F fluoride trapped on an anion-exchange phase in a form suitable for efficient radiolabeling without any evaporation step
EP2017359A3 (en) * 2007-06-11 2009-08-05 Trasis S.A. Method for the elution of 18F fluoride trapped on an anion-exchange resin in a form suitable for efficient radiolabeling without any evaporation step
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CN101967149B (en) * 2009-07-28 2013-01-16 北京师范大学 18F substituted nitro-labeled pyrazolo [1,5-a] pyrimidines and their preparation and application
US9023316B2 (en) 2010-04-08 2015-05-05 Siemens Medical Solutions Usa, Inc. Synthesis of 18F-labeled tracers in hydrous organic solvents
CN103608337A (en) * 2011-05-13 2014-02-26 Futurechem株式会社 <18>F-marked precursor of PET radioactive medical supplies, and preparation method thereof
CN103608337B (en) * 2011-05-13 2016-07-06 Futurechem株式会社 18F-labelled precursor of PET radioactivity medical supplies and preparation method thereof
CN102336678A (en) * 2011-07-13 2012-02-01 中国人民解放军总医院 Method for preparing 18F-FET
CN102329359A (en) * 2011-07-15 2012-01-25 无锡江原安迪科分子核医学研究发展有限公司 Process for preparing 18F-FLT and self-contained reagent kit
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
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