CN106902363A - Radioactive composition, its single fraction preparation method and use - Google Patents
Radioactive composition, its single fraction preparation method and use Download PDFInfo
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Abstract
The present invention relates to contain various radioactive compounds18F fluorodeoxyglucoses (18F‑FDG)、2‑18F fluoropropionic acids (18F FPA) and/or (N 218F fluorine propiono) L α glutamic acid (18F NFPGlu) composition (compound molecular probe preparation), its single fraction synthetic method and its application in positron emission tomography medicine is prepared.With mannose triflate and 2 ethyl bromide mixtures, mannose triflate and (the bromo propionos of N 2) L α glutamate diethyl esters mixtures or mannose triflate, 2 ethyl bromides and (the bromo propionos of N 2) L α glutamate diethyl ester mixtures as precursor, medicine containing PET can be respectively obtained through nucleophilic fluorination and hydrolysis two-step reaction18F‑FDG+18F‑FPA、18F‑FDG+18F NFPGlu or18F‑FDG+18F‑FPA+18The composition of F NFPGlu.The present composition can be used for antidiastole and the curative effect evaluation of tumour, cardiovascular and cerebrovascular disease and neuropsychiatric disease, can overcome18The limitation of F FDG.
Description
【Technical field】
Composition, its single fraction synthetic method the present invention relates to radioactive compound and its preparing positron emission
Application in tomography medicine.The invention particularly relates to contain two kinds of PET medicines18F-FDG+18F-FPA and18F-FDG+18F-
NFPGlu Radioactive compositions and containing three kinds of PET medicines18F-FDG+18F-FPA+18F-NFPGlu Radioactive compositions, its list
Secondary radiation synthetic method and its application in PET developers are prepared.
【Background technology】
18F- fluorodeoxyglucoses (18F-FDG it is) most widely used in tumour, cardiovascular and cerebrovascular disease and psychoneural
The antidiastole of disease and positron emission fault (PET) developer (medicine) of curative effect monitoring, but some false sun also occur
Property and false negative result.The imaging of different kinds of molecules probe can make up18The deficiency of F-FDG, is remarkably improved the sensitivity of imaging, special
Property and accuracy.The imaging of different kinds of molecules probe includes that repeatedly imaging and single-dose are imaged divided doses simultaneously[1].Different kinds of molecules
Repeatedly imaging has been applied to clinical imaging research to probe divided doses, shows preferable application prospect.Using O- (2- [18F] fluoro second
Base)-TYR (18F-FET) with18F-FDG is administered twice imaging twice, helps to differentiate inflammation and tumour.Using11C- second
Hydrochlorate with18F-FDG is administered twice imaging twice, can improve sensitivity and the accuracy of hepatoma diagnosis.Be used in combination (11C-
Methyl)-Cys (MCYS) and18The F-FDG monitoring therapeutic effect on glioma of PET imagings twice, as a result finds that MCYS is obvious
It is better than18F-FDG[2].Because the multiple imaging technique of multiple dosing is cumbersome, researcher is developed using different kinds of molecules probe single
Administration is while developing method.Foreign study person is by Parkinson's (PD) monkey model shot99mA kind of Tc-TRODAT-1 (DOPA
Amine transporter developer) and123I-ADAM (serotonin transporter developer) is while imaged, as a result discovery is double to be shown
Track agent can distinguish striatal dopamine transport protein and serotonin transporter, be to assess PD monkey model intracerebral dopamines simultaneously
Can system and serotonergic system change offer process useful[3].Also there is researcher to a malignant tumor patient shot18F-
With18F-FDG mixtures carry out a PET/CT scannings, can carry out Bone m etabolism and glucose metabolism imaging to tumour patient simultaneously,
Patient care can be improved, review time and number of times is reduced[4].However, different kinds of molecules probe imaging (single-dose simultaneously image and
Divided doses are repeatedly imaged) the multi-stage synthesis different kinds of molecules probe in one day or multiple days is needed, not only take cost and increase work
Make personnel's exposure dose of radiation, and many PET centers are difficult to complete various PET medicines (molecular probe) production use in one day
Imaged simultaneously in single-dose.In addition, to overcome18The limitation of F-FDG imagings, different kinds of molecules probe imaging can make up18F-
Some of FDG are not enough.But different kinds of molecules probe divided doses repeatedly imaging not only troublesome poeration, it is time-consuming and increase patient with regard to consultation fee
With, and patient and staff can obtain more radiation exposures.Though and existing different kinds of molecules probe single-dose is imaged simultaneously
Some defects that can so avoid divided doses from repeatedly imaging, but need to provide various PET molecular probes simultaneously, and list cannot be solved
The problem of secondary production different kinds of molecules probe, cannot also avoid radiochemistry staff from contacting less radioactive possibility.
Bibliography：
1. many target molecule iconographies of Tang Gang China and its progress nuclear technology, 2011,34 (10):765-771.
2.Deng H,Tang X,Tang G,et al.S-[11C]methyl-L-cysteine, [11C]MCYS:A new
amino acid PET tracer for cancer imagimg.J Nucl Med,2011,52:287–293.
3.Lia IH,Huang WS,Yeh CB,et al.Dual-isotope single-photon emission
computed tomography for dopamine and serotonin transporters in normal and
parkinsonian monkey brains.Nucl Med Biol,2009,36:605–611
4.Iagaru A,Mi ttra E,Yaghoubi SS,et al.Novel strategy for a cocktail18F-fluorideand 18F-FDG PET/CT scan for evaluation of malignancy:Results of
the pilot-phase study.J Nucl Med,2009,50:501–505
【The content of the invention】
For there are different target spots in disease, the various single molecule probes with complementation being combined, prepared
Unitary agent containing various single molecule probes, i.e. compound molecular probe (Radioactive composition).With compound molecular probe to disease
Carry out molecular imaging, i.e. compound molecular probe imaging.The purpose of the present invention is that and overcomes18The false positive of F-FDG imagings, false the moon
The limitation such as property, there is provided be better than18The compound molecular probe (Radioactive composition) containing various PET probes of F-FDG；And can be complete
Complete solution determine different kinds of molecules probe single production method problem, really radiochemistry personnel from it is heavy radiation synthetic work in solve
Release, and radioactivity irradiation can be reduced.
The present invention is used18F-FDG Fully automated synthesis instrument, with 1,3,4,6- tetra--O- acetyl group -2-O- trifyls -
β-D- mannopyranoses (abbreviation mannose triflate) and 2- ethyl bromides mixture are precursor, using simple, quick and high
" the two step On-column hydrolysis " of effect, through nucleophilic fluorination and hydrolysis two-step reaction and small column separating purification, can obtain containing two kinds of PET
Medicine18F-FDG+18F-FPA compound molecular probes.Equally, with mannose triflate+(N-2- bromos propiono)-L- α-glutamic acid
Diethyl ester admixture is precursor, through nucleophilic fluorination and On-column hydrolysis and small column separating purification, can be obtained containing two kinds of PET medicines
Thing18F-FDG+(N-2-18F- fluorine propiono)-L- α-glutamic acid (18F-NFPGlu) compound molecular probe.With mannose triflate+2-
Ethyl bromide+(N-2- bromos propiono)-L- α-glutamate diethyl ester mixture is precursor, through nucleophilic fluorination and in post water
Solution and small column separating purification, can obtain containing three kinds of PET medicines18F-FDG+18F-FPA+18F-NFPGlu compound molecular probes
(Radioactive composition)., according to routine with water as solvent, the consumption of Radioactive composition and water is with suitable for Radioactive composition of the present invention
It is PET developers to cooperate；And tie up in preparation process and substituted into by raw material, do not add separately.The application of the method solves two
Footwork automated production contains18F marks the problem of various probe compound molecular probes, is Fully automated synthesis compound18F mark molecules
Probe provides universal method, for the synthesis of other compound Geigers probes provides technical foundation.
The present invention relates to contain various probes18F-FDG+18F-FPA+18The single synthesis side of F-NFPGlu compound molecular probes
Method and its single simultaneously image in apply, with broad applicability, can open up compound molecular probe single synthesis and its single
Research frontier is imaged simultaneously.Research contents of the present invention has following clear superiority：(1) research and development compound molecule is proposed
Probe new strategy, solves guardian technique problem prepared by many targeted molecular probes.To overcome18F-FDG single molecule probes show
The limitation of picture, foreign study person have developed the various single molecule probe imagings of many targetings and many targeting coupled molecule probe imaging sides
Method.But, existing various single molecule probe divided doses repeatedly image needs and different unimolecules spies are repeatedly prepared within the not time
Pin；Single-dose is imaged simultaneously to be needed repeatedly to prepare different single molecule probes in one day using synthesis preparation method by several times；Many targets
It is that, using the single molecule probe imaging technique containing multiple ligand moleculars, need to be modified with compared with complicated chemical to the imaging of coupled molecule probe
Method prepares the multiple part probes of coupling.One pot of single synthetic method and many pots of synthesis preparing methods prepare compound molecular probe, overcome
Divided doses repeatedly image the limitation imaged simultaneously with single-dose in terms of molecular probe is prepared, can be within the same time
The compound molecular probe containing different kinds of molecules probe is prepared simultaneously；It also avoid the imaging of coupled molecule probe needs to use complicated chemical
The drawbacks of multiple parts of method modification prepare coupled molecule probe, each part can not be certainly in particularly overcoming coupled molecule probe
By the limitation for combining its corresponding specificity target spot.Existing monomer molecule probe synthesis condition is optimized and improved, you can
Complete the compound molecular probe that single synthesizes the proportioning that meets the requirements.Compound molecular probe single synthetic method is that research and development are better than18F-
The important development strategy of FDG novel molecular probes, also solves the problem of many targeted molecular probe synthesis indirectly.(2) containing various
Single molecule probe single dose parenteral solution, i.e., be to target compound a kind of novelty containing various single molecule probe unitary agents (single dose) more
Molecular probe, is also the important development direction of initiative novel molecular probe of future generation.Compound molecular probe preparation is not various
The simple combination of single molecule probe, but the various single molecule probes with complementation are prepared and by one through chemical synthesis
Certainty ratio builds and is combined into compound molecular probe, as insensitive to hepatoma18The F-FDG and 2- sensitive to hepatoma18F- fluoropropionic acids (18F-FPA), designed, synthesized and structure is combined as compound molecular probe18F-FDG+18F-FPA single doses,
It is substantially better than18F-FDG.And existing single-dose is while although imaging technique is to use various of monomer molecular probe, but this simultaneously
It is not compound molecular probe preparation in matter, but various of monomer molecular probe preparation, equivalent to injection simultaneously or oral various medicines
Product.Various of monomer molecular probe preparation is several formulations, equivalent to various medicines；And compound molecular probe preparation (radioactivity group
Compound) it is single dose, equivalent to compound medicine.(3) compound molecular probe imaging is a kind of simple, practical and wide spectrum molecular imaging
Method, its Transformation Application will bring the deep revolution of molecular image and accurate medical science, open up the molecular imaging new situation.Compound molecule
Probe is (such as18F-FDG+18F-FPA etc.) imaging be expected better than and substituted monomer18F-FDG is imaged, and is also to develop to be better than indirectly18F-
The important channel of FDG, solves development and is better than18The problem of F-FDG molecular probes, is other compound molecular probes and compound targeting
Theoretical and experiment basis have been established in the development of medicine, open compound molecular probe imaging frontier.(4) multi-mode compound molecule
The development of probe and Transformation Application, will open up the multi-mode compound molecular probe imaging New Times, fundamentally solve long-standing problem
The crucial technical problem that molecular imaging doctor and the practical challenges of technical staff, i.e. multi-mode molecular probe are imaged simultaneously,
For multi-mode polyfunctional molecule iconography Transformation Application removes obstacle.Multi-mode molecular imaging (such as PET-x computer on line tomography
CT, PET- Magnetic Resonance Imaging MRI, single photon emission computed tomography SPECT-CT etc.) super-sensitive nuclear medicine is shown
As technology combines with high-resolution and compared with other image technologies of muting sensitivity, molecular imaging is promoted to enter into many
The model molecule iconography New Times.But, single injects nucleic and magnetic signal group (or other signal groups) mark simultaneously
Single molecule probe row multi-mode probe molecular imaging simultaneously will be huge challenge even not possible with.If will be with different targets
To the specific radiopharmaceutical and on-radiation molecular probe of effect, multi-mode compound molecular probe preparation, Jiu Huiqiao are made
It is wonderful to solve the multi-mode molecular imaging important scientific problems that pendent multi-mode molecular probe is imaged simultaneously always, realize multiple
Close double mode PET-MRI, SPECT-MRI, PET- ultrasonoscopy of molecular probe, the imaging of PET- optics to be possibly realized, open up compound
Molecular probe images the New Times.
What the present invention was realized in.
Single molecule probe18F-FDG with mannose triflate as precursor, it is perfluorinated and post hydrolyze two-step method, it is complete in 25min
Into Fully automated synthesis (formula 1).Precursor mannose triflate optimum amount is 15-30mg, and fluorination reaction temperature is 80-90 DEG C, reaction
Time 2-5min；It is room temperature reaction 2min in post hydrolysis temperature；Using Sep-Pak Al2O3N Plus pillars, two Sep-Pak
Plus C18 series connection pillar and the small column separating purifications of Sep-Pak SCX and neutralized reaction product.
Single molecule probe18F-FPA with 2- ethyl bromides as precursor, it is perfluorinated and post hydrolyze two-step method, at 30 points
Fully automated synthesis (formula 2) are completed in clock.Precursor 2- ethyl bromides optimum amount is 8-20mg, and fluorination reaction temperature is 110
DEG C, reaction time 10min；It is room temperature, reaction time 2-3min in post hydrolysis temperature；With18F-FDG is the same, using Sep-Pak
Al2O3N Plus pillars, two Sep-Pak plus C18 series connection pillars and the small column separating purifications of Sep-Pak SCX and neutralization are produced
Thing.
Single molecule probe18F-NFPGlu with (N-2- bromos propiono)-L- α-glutamate diethyl ester be precursor, it is perfluorinated and
Two-step method is hydrolyzed in post, Fully automated synthesis (formula 3) are completed in 40min.Precursor (N-2- bromos propiono)-L- α-glutamic acid two
Ethyl ester optimum amount is 5-20mg, and fluorination reaction temperature is 110-115 DEG C, reaction time 15min；It is room in post hydrolysis temperature
Temperature, reaction time 5-10min；With18F-FDG is the same, using Sep-Pak Al2O3N Plus pillars, two Sep-Pak plus
C18 series connection pillar and the small column separating purifications of Sep-Pak SCX and neutralized reaction product.
The present invention relates to bi-molecular probe PET medicines18F-FDG+18F-FPA compounds molecular probe (Radioactive composition)
The full-automatic radiation synthesis of single.Due to18F-FDG and18F-FPA can be prepared using similar method, thus the present invention is with trifluoro
Mannose and 2- ethyl bromides mixture are precursor, and perfluorinated reaction generates the-O- acetyl group -2 of intermediate 1,3,4,6- tetra-
-18F- β-D- mannopyranoses+2-18F- fluoropropionic acid ethyl ester mixtures.Add water release it is dilute after, by a Sep-Pak Al2O3N
Plus pillars and two Sep-Pak plus C18 series connection pillars, radioactivity intermediate are captured in Sep-Pak plus C18 pillars
In.Plus in 2M sodium hydroxide solutions to pillar, there is hydrolysis in intermediate in Sep-Pak plus C18 pillars.Drenched with water
The C18 pillars are washed, leacheate is further by after the small column separating purifications of Sep-Pak SCX and neutralization, crossing sterilised membrane filter and obtaining18F-
FDG+18F-FPA compound molecular probes.Bi-molecular probe single dose parenteral solution (Radioactive composition) synthetic route is as shown in Equation 4.
But,18F-FDG+18The full-automatic radiation synthesis of the single of F-FPA compound molecular probes is not simply to apply mechanically18F-FDG or18F-FPA synthetic methods, and must be in precursor mixture consumption proportion and solvent selection, fluorination reaction temperature and time, Yi Ji
Post hydrolysis time aspect optimizes improvements, could obtain properly putting yield radiochemicsl purity and each component probe put
Penetrating property content respectively accounts for (50.0 ± 10.0) %'s18F-FDG+18F-FPA.Wherein mannose triflate and 2- ethyl bromide quality
Than being 5：8~8：When 10, perfluorinated and hydrolysis two-step reaction and radioactivity HPLC are detected, can be obtained contamination and respectively be accounted for
(50.0 ± 10.0) %'s18F-FDG+18F-FPA。18F-FDG+18F-FPA compound molecular probe optimum synthesis conditions：Precursor mixes
Thing consumption mannose triflate (5-8mg) and 2- ethyl bromides (8-10mg), fluorination reaction solvent are acetonitrile or acetonitrile-tertiary fourth
Alcohol, (meaning of " about " is positive and negative five degree to about 100 DEG C of reaction temperature in the present invention, primarily to balanced reaction.Similarly hereinafter), react
Time is 8-12min, optional 10min；It is room temperature 6-8min in post hydrolysis.
The invention further relates to bi-molecular probe PET medicines18F-FDG+18(radioactivity is combined F-NFPGlu compounds molecular probe
Thing) the full-automatic radiation synthesis of single.Due to18F-FDG and18F-NFPGlu can be prepared using similar method, thus this hair
It is bright with mannose triflate and (N-2- bromos propiono)-L- α-glutamate diethyl ester mixture as precursor, perfluorinated reaction is generated
- O- acetyl group-the 2- of intermediate 1,3,4,6- tetra-18F- β-D- mannopyranoses+(N-2-18F- fluorine propiono)-L- α-glutamic acid two
Ethyl ester mixture.Add water release it is dilute after, by a Sep-Pak N Al2O3Plus pillars and two Sep-Pak plus C18 strings
Connection pillar, radioactivity intermediate is captured in Sep-Pak plus C18 pillars.Plus in 2M sodium hydroxide solutions to pillar, it is middle
There is hydrolysis in Sep-Pak plus C18 pillars in body.With the water wash C18 pillars, leacheate is further by Sep-
After the small column separating purifications of Pak SCX and neutralization, cross sterilised membrane filter and obtain18F-FDG+18F-NFPGlu compound molecular probes.This pair point
Sub- probe compound molecular probe (Radioactive composition) synthetic route is as shown in Equation 5.18F-FDG+18F-NFPGlu compounds molecule is visited
Pin synthesis condition with18F-FDG and18F-FPA is different, wherein mannose triflate and (N-2- bromos propiono)-L- α-glutamic acid two
Ethyl ester mass ratio is 5:8~8:When 15, perfluorinated and hydrolysis two-step reaction and radioactivity HPLC and radio thin layer are chromatographed
(TLC) detect, contamination can be obtained and respectively account for (50.0 ± 10.0) %'s18F-FDG+18F-NFPGlu.Optimum synthesis condition：
Precursor mixture consumption mannose triflate (5-8mg) and (N-2- bromos propiono)-L- α-glutamate diethyl ester (8-15mg), fluorine
Change reaction dissolvent for acetonitrile or acetonitrile-tert-butyl alcohol, about 110 DEG C of reaction temperature, the reaction time is 12-18min, and we are optional
15min；It is room temperature 3-4min in post hydrolysis.Can so obtain18F-FDG and18F-NFPGlu contaminations are respectively accounted for
(50.0 ± 10.0) %'s18F-FDG+18F-FPA
The invention further relates to three molecular probe PET medicines18F-FDG+18F-FPA+18F-NFPGlu compound molecular probes (are put
Penetrating property composition) the full-automatic radiation synthesis of single.Due to18F-FDG、18F-FPA and18F-NFPGlu can use similar side
Prepared by method, thus the present invention is with mannose triflate+2- ethyl bromides+(N-2- bromos propiono)-L- α-glutamic acid diethyl
Ester admixture is precursor, perfluorinated reaction generation intermediate 1,3,4,6- tetra--O- acetyl group -2-18F- β-D- mannopyranoses+2
-18F- fluoropropionic acids ethyl ester mixture+(N-2-18F- fluorine propiono)-L- α-glutamate diethyl ester mixture.Then press18F-FDG
+18The single of the F-FPA compound molecular probes similar method of full-automatic radiation synthesis, obtains18F-FDG+18F-FPA+18F-
NFPGlu compounds molecular probe (Radioactive composition).The three molecular probes compound molecular probe synthetic route is as shown in Equation 6.18F-FDG+18F-FPA+18F-NFPGlu compound molecular probe synthesis conditions with18F-FDG、18F-FPA and18F-NFPGlu is different,
Wherein when mannose triflate consumption 5-8mg+2- ethyl bromides 8-10mg+ (N-2- bromos propiono) in precursor mixture-
L- α-glutamate diethyl ester 8-10mg, i.e. mannose triflate, 2- ethyl bromides and (N-2- bromos propiono)-L- α-paddy ammonia
Diethyl phthalate mass ratio is 5:8:8~10:When 8~10, perfluorinated and hydrolysis two-step reaction and radioactivity HPLC and radioactivity
TLC detections, can obtain contamination18F-FDG account for (30.0 ± 5.0) %,18F-FPA account for (30.0 ± 5.0) % and18F-
NFPGlu accounts for (40.0 ± 10.0) %'s18F-FDG+18F-FPA+18F-NFPGlu.Optimum synthesis condition：Precursor mixture consumption
Mannose triflate (5-8mg)+2- ethyl bromides (8-10mg)+(N-2- bromos propiono)-L- α-glutamate diethyl ester (8-
10mg), fluorination reaction solvent be acetonitrile or acetonitrile-tert-butyl alcohol, about 110 DEG C of reaction temperature, the reaction time is 12-18min, we
Optional 15min；It is room temperature 8min in post hydrolysis.So, contamination can be obtained18F-FDG accounts for (30.0 ± 5.0) %
、18F-FPA account for (30.0 ± 5.0) % and18F-NFPGlu accounts for (40.0 ± 10.0) %'s18F-FDG+18F-FPA+18F-NFPGlu。
18F-FDG+18F-FPA、18F-FDG+18F-NFPGlu and18F-FDG+18F-FPA+18F-NFPGlu Radioactive compositions
In colourless or faint yellow settled solution, pH value is between 5.0-8.0.With18F-It is initiation material,18F-FDG+18F-FPA、18F-
FDG+18F-NFPGlu and18F-FDG+18F-FPA+18Non- putting of the correction for attenuation yields of F-NFPGlu are 20-35%, total Radiochemical purity
Time is about 40min (the every kind of compound molecular probe of production, n=5), and specific activity is not less than 3.7 × 1010Bq/mmol.Through radioactivity
HPLC detections,18F-Retention time (Rt) is about 2.5min,18F-FDG+18F-FPA、18F-FDG+18F-NFPGlu and18F-FDG+18F-FPA+18The retention time (Rt) of F-NFPGlu is 3.5-4.0min, with its standard items19F-FDG+19F-FPA、19F-FDG+19F-NFPGlu and19F-FDG+19F-FPA+19F-NFPGlu retention times are consistent, and its radiochemical purity is all higher than 95%.To enter
One step is distinguished18F-FDG、18F-FPA and18F-NFPGlu, being detected through radioactivity TLC confirms.
The present invention relates to18F-FDG、18F-FPA and18The Radioactive composition of F-NFPGlu, also can be mixed using corresponding precursor
The solid phase fluorination reaction and soda acid liquid phase hydrolysis two-stage process of compound complete its Fully automated synthesis.Therefore, mix in precursor
Thing consumption proportion and solvent selection, fluorination reaction temperature and time and improvement is optimized in terms of post hydrolysis time,
Also can realize18F-FDG、18F-FPA and18F-NFPGlu pairs/tri- kinds tracer compound molecular probe single fractions synthesis.It can be seen that,18F-FDG、18F-FPA and18F-NFPGlu pairs/tri- kinds of tracer compound molecular probe single fraction synthetic methods, it is not limited to liquid
Phase fluorination and in post method for hydrolysis, solid phase fluorination and soda acid liquid phase method for hydrolysis are equally applicable.
【Brief description of the drawings】
Fig. 1 makes by oneself18F-FDG synthesizer schematic diagrames.
Fig. 2 is used18It is prepared by F-FDG synthesizers18F-FDG+18F-FPA、18F-FDG+18F-NFPGlu or18F-FDG+18F-FPA
+18The Fully automated synthesis process chart of F-NFPGlu compound molecular probes；
Fig. 3 compound molecular probes18F-FDG+18The F-FPA singles figure of PET imagings simultaneously.Upper figure is coronal-plane PET-CT fusions
Image, figure below is PET image.
Fig. 4 compound molecular probes18F-FDG+18The F-NFPGlu singles figure of PET imagings simultaneously.Upper figure is horizontal shape face PET figures
Picture, figure below is coronal-plane PET image.
Fig. 5 compound molecular probes18F-FDG+18F-FPA+18The F-NFPGlu singles coronal-plane figure of PET imagings simultaneously.
【Specific embodiment】
The dual tracer of embodiment 118F-FDG+18The Fully automated synthesis of F-FPA compound molecular probes
Using18F-FDG Fully automated synthesis instrument (Fig. 1) and two step On-column hydrolysis are prepared and contain two kinds of PET medicines18F-FDG+18F-FPA compound molecular probes, complete under the control of the computer18F-FDG+18F-FPA compound molecular probe automated productions, its
Synthesis technique flow is shown in Fig. 2.Mainly include：(1)18F-F-Trapping.Passed through by cyclotron18O(p,n)18F nuclear reactions are given birth to
Produce18F-F-, in N2Airborne under band, by the pretreatment Sep-Pak l ight QMA anion being placed in radioactive activity measuring meter
Pillar,18F-F-It is trapped in pillar,18O- water is collected in returnable bottle.(2) solvent evaporation.In N2Under effect, in headpin
Containing K2CO3With the acetonitrile solution (1.0-1.5mL) of catalyst K222, incite somebody to action18F-F-Elute in confined reaction bottle, heating mixes
To 95 DEG C, evaporated under reduced pressure obtains dry compound [K/K222] to solution+18F-, waste liquid absorbs by the cold-trap that is placed in liquid nitrogen.
(3) fluorination reaction.In N2Under gas effect, precursor mixture mannose triflate (5-8mg) and 2- ethyl bromides in No. 3 bottles
(8-10mg) acetonitrile (or acetonitrile-tert-butyl alcohol) solution (1mL) is pressed into reaction bulb, 90-105 DEG C of heating response 5-15min.Fluorine
Change after the completion of reaction, be concentrated under reduced pressure, cooling.(4) trapped in post.In N2Under airflow function, H in No. 2 bottles2O (4.0-8.0mL) adds
In entering reaction bulb, two kinds18F- fluorinated intermediates and H2O mixed liquors are transmitted over a Sep-Pak plus Al2O3Pillar and
In two Sep-Pak plus C18 pillars,18F- fluorinated intermediates mixture is trapped by Sep-Pakplus C18 pillars.With No. 4
H in bottle2O (8.0-15mL) washs pillar, uses N2Drying, the waste collection containing acetonitrile water is in waste bottle.(5) in post basic hydrolysis.
NaOH solution (1.0mL) is pressed into reaction bulb in kingpin, and is loaded into two Sep Pak plus C18 pillars, hydrolysis
Reaction time is about 2-5min.(6) neutralize and isolate and purify.Produced in water (4.0-15.0mL) wash-out C18 pillars in No. 6 bottles
Product, by the way that in Sep-Pak SCX pillars and aqueous slkali, leacheate is in N2Under atmospheric pressure effect, collected after being processed through sterilised membrane filter
In sterile product bottle, obtain18F-FDG+18F-FPA compound molecular probes, each component probe radiation content respectively account for (50.0 ±
10.0) %18F-FDG+18F-FPA。
Above-mentioned fluorination reaction can also be carried out in solid phase, hydrolysis also can in room temperature NaOH (or KOH) aqueous slkalis or
Completed in heating hydrochloric acid solution.
The dual tracer of embodiment 218F-FDG+18The Fully automated synthesis of F-NFPGlu compound molecular probes
Using18F-FDG Fully automated synthesis instrument (Fig. 1) and two step On-column hydrolysis are prepared and contain two kinds of PET medicines18F-FDG+18F-NFPGlu compound molecular probes, complete under the control of the computer18F-FDG+18The automatic metaplasia of F-NFPGlu compound molecular probes
Produce, its synthesis technique flow is shown in Fig. 2.Mainly include：(1)18F-F-Trapping.Passed through by cyclotron18O(p,n)18F cores are anti-
Should produce18F-F-, in N2Airborne under band, it is cloudy by the pretreatment Sep-Pak l ight QMA being placed in radioactive activity measuring meter
Ion pillar,18F-F-It is trapped in pillar,18O- water is collected in returnable bottle.(2) solvent evaporation.In N2Under effect, No. 1
Contain K in bottle2CO3With the acetonitrile solution (1.0-1.5mL) of catalyst K222, incite somebody to action18F-F-Elute in confined reaction bottle, heat
To 95 DEG C, evaporated under reduced pressure obtains dry compound [K/K222] to mixed solution+18F-, waste liquid inhaled by the cold-trap that is placed in liquid nitrogen
Receive.(3) fluorination reaction.In N2Under gas effect, precursor mixture mannose triflate (5-8mg) and (N-2- bromos third in No. 3 bottles
Acyl group)-L- α-glutamate diethyl ester (8-15mg) acetonitrile (or acetonitrile-tert-butyl alcohol) solution (1mL) is pressed into reaction bulb, 100-
115 DEG C of heating response 10-15min.After the completion of fluorination reaction, it is concentrated under reduced pressure, cooling.(4) trapped in post.In N2Airflow function
Under, H in No. 2 bottles2O (4.0-8.0mL) is added in reaction bulb, two kinds18F- fluorinated intermediates and H2O mixed liquors are transmitted over one
Individual Sep-Pak plus Al2O3In pillar and two Sep-Pak plus C18 pillars,18F- fluorinated intermediates mixture quilts
Sep-Pakplus C18 pillars are trapped.With H in No. 4 bottles2O (8.0-15mL) washs pillar, uses N2Drying, the waste liquid containing acetonitrile water
Collect in waste bottle.(5) in post basic hydrolysis.NaOH solution (1.0mL) is pressed into reaction bulb in kingpin, and is loaded into two
In individual Sep Pak plus C18 pillars, hydrolysis time is about 5-10min.(6) neutralize and isolate and purify.In No. 6 bottles
Product in water (4.0-15.0mL) wash-out C18 pillars, by the way that in Sep-Pak SCX pillars and aqueous slkali, leacheate is in N2Air pressure
Under power effect, collected after being processed through sterilised membrane filter in sterile product bottle, obtained18F-FDG+18F-NFPGlu compound molecular probes.
So, can obtain18F-FDG and18F-NFPGlu contaminations respectively account for (50.0 ± 10.0) %'s18F-FDG+18F-NFPGlu。
Above-mentioned fluorination reaction can also be carried out in solid phase, hydrolysis also can in room temperature NaOH (or KOH) aqueous slkalis or
Completed in heating hydrochloric acid solution.
The tracer of embodiment 3 three18F-FDG+18F-FPA+18The Fully automated synthesis of F-NFPGlu compound molecular probes
Using18F-FDG Fully automated synthesis instrument (Fig. 1) and two step On-column hydrolysis prepare three kinds of PET medicines18F-FDG+18F-
FPA+18F-NFPGlu compound molecular probes, complete its automated production under the control of the computer, and its synthesis technique flow is shown in figure
2.Mainly include：(1)18F-F-Trapping.Passed through by cyclotron18O(p,n)18F nuclear reactions production18F-F-, in N2Airborne band
Under, by the pretreatment Sep-Pak l ight QMA anion pillars being placed in radioactive activity measuring meter,18F-F-It is trapped in small
In post,18O- water is collected in returnable bottle.(2) solvent evaporation.In N2Under effect, K is contained in headpin2CO3With catalyst K222's
Acetonitrile solution (1.0-1.5mL), will18F-F-In eluting confined reaction bottle, heating mixed solution to 95 DEG C, evaporated under reduced pressure,
Obtain dry compound [K/K222]+18F-, waste liquid absorbs by the cold-trap that is placed in liquid nitrogen.(3) fluorination reaction.In N2Gas is acted on
Under, precursor mixture mannose triflate (5-8mg)+2- ethyl bromides (8-10mg)+(the N-2- bromo propionyl in No. 3 bottles
Base)-L- α-glutamate diethyl ester (8-10mg) acetonitrile (or acetonitrile-tert-butyl alcohol) solution (1mL) is pressed into reaction bulb, 100-
115 DEG C of heating response 10-15min.After the completion of fluorination reaction, it is concentrated under reduced pressure, cooling.(4) trapped in post.In N2Airflow function
Under, H in No. 2 bottles2O (4.0-8.0mL) is added in reaction bulb, three kinds18F- fluorinated intermediates and H2O mixed liquors are transmitted over one
Individual Sep-Pak plus Al2O3In pillar and two Sep-Pak plus C18 pillars,18F- fluorinated intermediates mixture quilts
Sep-Pakplus C18 pillars are trapped.With H in No. 4 bottles2O (8.0-20mL) washs pillar, uses N2Drying, the waste liquid containing acetonitrile water
Collect in waste bottle.(5) in post basic hydrolysis.NaOH solution (1.0mL) is pressed into reaction bulb in kingpin, and is loaded into two
In individual Sep Pak plus C18 pillars, hydrolysis time is about 5-10min.(6) neutralize and isolate and purify.In No. 6 bottles
Product in water (4.0-15.0mL) wash-out C18 pillars, by the way that in Sep-Pak SCX pillars and aqueous slkali, leacheate is in N2Air pressure
Under power effect, collected after being processed through sterilised membrane filter in sterile product bottle, obtained18F-FDG+18F-FPA+18F-NFPGlu compounds point
Sub- probe.So, contamination can be obtained18F-FDG account for (30.0 ± 5.0) %,18F-FPA account for (30.0 ± 5.0) % and18F-
NFPGlu accounts for (40.0 ± 10.0) %'s18F-FDG+18F-FPA+18F-NFPGlu。
Above-mentioned fluorination reaction can also be carried out in solid phase, hydrolysis can room temperature NaOH (or KOH) aqueous slkalis or add
Completed in hot hydrochloric acid solution.
The measure of the product purity of embodiment 4
Determined with radioactivity high performance liquid chromatography (HPLC) and thin-layered chromatography (TLC)18F-FDG+18F-FPA、18F-FDG
+18F-NFPGlu and18F-FDG+18F-FPA+18The radiochemical purity of F-NFPGlu compound molecular probes.With the mark for determining structure
Quasi- product19F-FDG+19F-FPA、19F-FDG+19F-NFPGlu and19F-FDG+19F-FPA+19F-NFPGlu, respectively with it is corresponding18F-FDG+18F-FPA、18F-FDG+18F-NFPGlu and18F-FDG+18F-FPA+18F-NFPGlu compound molecular probes are together injected
To in HPLC, or together point sample row TLC, to determine whether its retention time is consistent, and confirmation prepares the authenticity of parenteral solution, warp
Determine its radiochemical purity and be all higher than 95%.
HPLC analysis conditions：Analytical column is ZORBAX Ecl ipse XDB-C18 posts, and mobile phase is the acetonitrile of 0.1%TFA
Solution：The aqueous solution of 0.1%TFA, row gradient elution：During 0min, the acetonitrile solution/0.1%TFA's containing 0.1%TFA is water-soluble
Liquid：2/98；When being gradually raised to 8min, the aqueous solution of the acetonitrile solution/0.1%TFA of 0.1%TFA：10/90；It is raised again to 20min
When, the aqueous solution of the acetonitrile solution/0.1%TFA of 0.1%TFA：80/20.Flow velocity is 1mL/min, ultraviolet detection wavelength 210nm
And 254nm.
For18F-FDG+18F-FPA、18F-FDG+18F-NFPGlu and18F-FDG+18F-FPA+ 18F-NFPGlu compounds point
Sub- probe, TLC methods to be used of still needing are further characterized by containing18F-FDG、18F-FPA and18F-NFPGlu.A silica gel plate is taken, is put into
On panel sub-assembling platform behind lead glass, a small amount of probe sample containing different kinds of molecules and its standard items (concentration 0.5mg/ are drawn with capillary
ML), together gently put and at one 1mL of distance, it is dried up with hair dryer on silica gel plate.Chromatographed in chromatography cylinder, opened up
Agent is opened for acetonitrile：Water=95:5 (V/V), are dried up after chromatography with hot-air, and thin layer scanning is carried out using TLC scanners.After scanning,
With iodine staining, or TLC plates are uniformly sprayed on 2N sulfuric acid, 110 degree lower to dry 10min dyeing, detection molecules probe sample and standard
The Rf value Rf of product.
By radioactivity HPLC and radioactivity TLC detection compound molecular probes18F-FDG+18F-FPA、18F-FDG+18F-
NFPGlu and18F-FDG+18F-FPA+18F-NFPGlu preparation each component monomer probe radiation percentage compositions.
The lotus knurl model small animal position emission tomography (PET) of embodiment 5 is imaged
Lotus SPC-A-1 knurl nude mice models, are injected respectively by tail vein by every group 318F-FDG+18F-FPA、18F-FDG+18F-
NFPGlu and18F-FDG+18F-FPA+18F-NFPGlu compounds molecular probe (0.2mL, about 3.7-5.5MBq) is to nude mice model body
It is interior.Nude mice is anaesthetized through the chloraldurate of intraperitoneal injection 5% (6mL/kg) in 10min before imaging, fixed plate adhesive tape is placed on and is fixed, used
Heating cushion keeps body temperature.After through CT scan, PET data is collected in injection developer different time points, with software (Inevon
Research Workplace 4.1) after row correction for attenuation, iterative approximation image.Sketch the contours of the tissue such as tumour and brain, muscle
Area-of-interest (ROIs), measures radiocounting and the volume of region of interest tissue, calculates per gram of tissue injection dosage percentage
Than (%ID/g), and calculate the radioactive uptake relative ratios such as tumour/brain, tumour/muscle.Representative single synthesizes compound molecule
Probe is used for lotus knurl model single, and image results show simultaneously, tumor uptake compound molecular probe18F-FDG+18F-FPA is higher than18F-FDG, with18F-FPA similar (Fig. 3)；Tumor uptake compound molecular probe18F-FDG+18F-NFPGlu is higher than18F-FDG, with18F-NFPGlu similar (Fig. 4)；18F-FDG+18F-FPA+18F-NFPGlu has intake higher in tumor tissues, respectively higher than18F-FDG、18F-FPA and18F-NFPGlu (Fig. 5).The model18F-FPA and18F-NFPGlu detections are more sensitive, and18F-FDG
Detect more insensitive, compound molecular probe18F-FDG+18F-FPA and18F-FDG+18F-NFPGlu detection can reach with18F-
FPA and18The equal Detection results of F-NFPGlu, and be better than18F-FDG.Equally, make18F-FDG it is sensitive and18F-FPA and18F-
NFPGlu insensitive tumor model, compound molecular probe18F-FDG+18F-FPA and18F-FDG+18F-NFPGlu detections can be excellent
In18F-FPA and18F-NFPGlu, and can reach with18F-FDG peer-levels.Compound molecular probe can detect that and compare monomer molecule
The more focuses of probe.
Claims (9)
1. the Radioactive composition that prepared by a kind of single fraction synthetic method, wherein the composition of each medicine is：18F- fluorodeoxies Portugal
Grape sugar18F-FDG、2-18F- fluoropropionic acids18F-FPA and/or (N-2-18F- fluorine propiono)-L- α-glutamic acid18F-NFPGlu, respectively
Radioactive dosage percentage range is shared by component：
1)18F-FDG+18F-FPA,18F–FDG：18F-FPA=60:40~40:60；Or
2)18F-FDG+18F-NFPGlu,18F–FDG：18F-NFPGlu=60:40~40:60；Or
3)18F-FDG+18F-FPA+18F-NFPGlu,18F–FDG：18F–FPA：18F-NFPGlu=25~35:25~35：30~
50, Radioactive composition is soluble in water.
2. the single fraction synthetic method of the Radioactive composition described in claim 1, including with mannose triflate and 2- bromos
Ethyl propionate mixture, mannose triflate and (N-2- bromos propiono)-L- α-glutamate diethyl ester mixture or trifluoro are sweet
Dew sugar, 2- ethyl bromides and (N-2- bromos propiono)-L- α-glutamate diethyl ester mixture are precursor, through nucleophilic fluorination
Medicine containing PET is obtained respectively with hydrolysis two-step reaction18F-FDG+18F-FPA、18F-FDG+18F-NFPGlu or18F-FDG+18F-
FPA+18F-NFPGlu Radioactive compositions, wherein nucleophilic fluorination reagent are [K/K222]+18F-Its reaction equation is：
3. the single fraction synthetic method of Radioactive composition according to claim 2, it is characterised in that described18F-
FDG+18F-FPA compounds molecular probe radiates synthetic method, with mannose triflate and 2- ethyl bromide mixtures as precursor,
Perfluorinated-O- acetyl group-the 2- of reaction generation intermediate 1,3,4,6- tetra-18F- β-D- mannopyranoses+2-18F- fluoropropionic acid second
Ester admixture；Add water release it is dilute after, by a Sep-Pak Al2O3N Plus pillars and two Sep-Pak plus C18 series connection
Pillar, radioactivity intermediate is captured in Sep-Pak plus C18 pillars；In hydrogenation sodium hydroxide solution to pillar, intermediate exists
There is hydrolysis in Sep-Pak plus C18 pillars；With the water wash C18 pillars, leacheate is further by Sep-Pak
After the small column separating purifications of SCX and neutralization, cross sterilised membrane filter and obtain18F-FDG+18F-FPA Radioactive compositions；Wherein mannose triflate
It is 5 with 2- ethyl bromides mass ratio：8~8：10.
4. the single fraction synthetic method of Radioactive composition according to claim 2, it is characterised in that described18F-
FDG+18F-NFPGlu preparations radiate synthetic method, with mannose triflate and (N-2- bromos propiono)-L- α-glutamate diethyl ester
Mixture is precursor, perfluorinated reaction generation intermediate 1,3,4,6- tetra--O- acetyl group -2-18F- β-D- mannopyranoses+(N-
2-18F- fluorine propiono)-L- α-glutamate diethyl ester mixture；Add water release it is dilute after, by a Sep-Pak N Al2O3Plus
Pillar and two Sep-Pak plus C18 series connection pillars, radioactivity intermediate are captured in Sep-Pak plus C18 pillars；
In hydrogenation sodium hydroxide solution to pillar, there is hydrolysis in intermediate in Sep-Pak plus C18 pillars；Should with water wash
C18 pillars, leacheate is further by after the small column separating purifications of Sep-Pak SCX and neutralization, crossing sterilised membrane filter and obtaining18F-FDG+18F-NFPGlu Radioactive compositions.Wherein mannose triflate and (N-2- bromos propiono)-L- α-glutamate diethyl ester mass ratio
It is 5:8~8:15.
5. the single fraction synthetic method of Radioactive composition according to claim 2, it is characterised in that described18F-
FDG+18F-FPA+18F-NFPGlu compounds molecular probe radiate synthetic method, with mannose triflate, 2- ethyl bromides and
(N-2- bromos propiono)-L- α-glutamate diethyl ester mixture is precursor, perfluorinated reaction generation intermediate 1,3,4,6- tetra--
O- acetyl group -2-18F- β-D- mannopyranoses+2-18F- fluoropropionic acids ethyl ester mixture+(N-2-18F- fluorine propiono)-L- α-
Glutamate diethyl ester mixture, add water release it is dilute after, by a Sep-Pak Al2O3N Plus pillars and two Sep-Pak
Plus C18 series connection pillars, radioactivity intermediate is captured in Sep-Pak plus C18 pillars；Hydrogenation sodium hydroxide solution is to small
In post, there is hydrolysis in intermediate in Sep-Pak plus C18 pillars；With the water wash C18 pillars, leacheate enters one
Step is by after the small column separating purifications of Sep-Pak SCX and neutralization, crossing sterilised membrane filter and obtaining18F-FDG+18F-FPA+18F-NFPGlu is put
Penetrating property composition；Wherein mannose triflate, 2- ethyl bromides and (N-2- bromos propiono)-L- α-glutamate diethyl ester matter
Amount is than being 5:8:8~10:8~10.
6. the Radioactive composition that prepared by the single fraction synthetic method described in claim 1 answering in PET developers are prepared
With.
7. the Radioactive composition that prepared by single fraction synthetic method according to claim 6 is in PET developers are prepared
Application, it is characterised in that18F-FDG+18F-FPA Radioactive compositions are used for tumour, cardiovascular and cerebrovascular disease and psychoneural
The antidiastole of disease and curative effect evaluation PET developers.
8. the Radioactive composition that prepared by single fraction synthetic method according to claim 6 is in PET developers are prepared
Application, it is characterised in that18F-FDG+18F-NFPGlu Radioactive compositions are used for tumour, cardiovascular and cerebrovascular disease and nerve essence
The antidiastole of refreshing disease and curative effect evaluation PET developers.
9. the Radioactive composition that prepared by single fraction synthetic method according to claim 6 is in PET developers are prepared
Application, it is characterised in that18F-FDG+18F-FPA+18F-NFPGlu Radioactive compositions be used for tumour, cardiovascular and cerebrovascular disease with
And antidiastole and the curative effect evaluation PET developers of neuropsychiatric disease.
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| 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 |
| CN114700006A (en) * | 2022-06-07 | 2022-07-05 | 北京先通国际医药科技股份有限公司 | Production equipment of liquid composition and preparation method and application thereof |
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