CN106902363B - Radioactive composition, its single fraction preparation method and use - Google Patents

Radioactive composition, its single fraction preparation method and use Download PDF

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CN106902363B
CN106902363B CN201710106158.0A CN201710106158A CN106902363B CN 106902363 B CN106902363 B CN 106902363B CN 201710106158 A CN201710106158 A CN 201710106158A CN 106902363 B CN106902363 B CN 106902363B
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唐刚华
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Guangdong Huixuan Medicine Technology Co ltd
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First Affiliated Hospital of Sun Yat Sen University
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
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    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
    • A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines

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Abstract

The present invention relates to contain a variety of radioactive compounds18F- fluorodeoxyglucose (18F‑FDG)、2‑18F- fluoropropionic acid (18) and/or (N-2- F-FPA18F- 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 drug is being prepared.Using mannose triflate and 2- ethyl bromide mixture, mannose triflate and (N-2- bromo propiono)-L- α-glutamate diethyl ester mixture or mannose triflate, 2- ethyl bromide and (N-2- bromo propiono)-L- α-glutamate diethyl ester mixture as precursor, drug containing PET can be obtained respectively 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

Radioactive composition, its single fraction preparation method and use
[technical field]
The present invention relates to the composition of radioactive compound, its single fraction synthetic method and its in preparation positron emission Application in tomography drug.The invention particularly relates to contain two kinds of PET drugs18F-FDG+18F-FPA and18F-FDG+18F- NFPGlu Radioactive composition and contain three kinds of PET drugs18F-FDG+18F-FPA+18F-NFPGlu Radioactive composition, list Secondary radiation synthetic method and its preparing the application in PET imaging agent.
[background technique]
18F- fluorodeoxyglucose (18It F-FDG is) most widely used in tumour, cardiovascular and cerebrovascular disease and psychoneural The antidiastole of disease and positron emission fault (PET) imaging agent (drug) of curative effect monitoring, but also will appear some false sun 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, special of imaging Property and accuracy.The imaging of different kinds of molecules probe is repeatedly imaged including divided doses and single-dose images simultaneously[1].Different kinds of molecules Probe divided doses, which repeatedly image, has been applied to clinical imaging research, shows preferable application prospect.Using O- (2- [18F] fluoro second Base)-l-tyrosine (18F-FET) with18F-FDG is administered twice imaging twice, helps to identify inflammation and tumour.Using11C- second Hydrochlorate with18F-FDG is administered twice imaging twice, and the sensitivity and accuracy of hepatoma diagnosis can be improved.Be used in combination (11C- Methyl)-L-cysteine (MCYS) and18The F-FDG monitoring therapeutic effect on glioma of PET imaging twice, as a result, it has been found that MCYS is obvious It is better than18F-FDG[2].Since the multiple imaging technique of multiple dosing is cumbersome, researcher is developed using different kinds of molecules probe single Administration while developing method.Foreign study person is by Parkinson's disease (PD) monkey model one injection99mA kind of Tc-TRODAT-1 (DOPA Amine transporter imaging agent) and123I-ADAM (serotonin transporter imaging agent) is imaged simultaneously, as a result, it has been found that double show Track agent can distinguish striatal dopamine transport protein and serotonin transporter, be while assessing PD monkey model intracerebral dopamine It can system and serotonergic system variation offer process useful[3].Also there is researcher to malignant tumor patient one injection18F- With18F-FDG mixture carries out a PET/CT scanning, can carry out bone metabolism to tumour patient simultaneously and glucose metabolism images, Patient care can be improved, reduce review time and number[4].However, different kinds of molecules probe imaging (single-dose simultaneously image and Divided doses repeatedly image) the multi-stage synthesis different kinds of molecules probe in one day or multiple days is needed, not only time-consuming cost and increase work Make personnel's exposure dose of radiation, and many centers PET are difficult to complete a variety of PET drug (molecular probe) production use in one day It is imaged simultaneously in single-dose.In addition, to overcome18The limitation of F-FDG imaging, the imaging of different kinds of molecules probe can make up18F- Certain deficiencies of FDG.But different kinds of molecules probe divided doses repeatedly image not only troublesome in poeration, time-consuming and increase patient with regard to consultation fee With, and patient and staff can obtain more radiating irradiation.Though and existing different kinds of molecules probe single-dose images simultaneously So certain defects that avoidable divided doses repeatedly image, but need while a variety of PET molecular probes being provided, and list can not be solved The problem of secondary production different kinds of molecules probe not can avoid radiochemistry staff yet and contact less radioactive possibility.
Bibliography:
1. the more 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
[summary of the invention]
For in disease, there are different target spots, and the various single molecule probes with complementation are combined, preparation Single formulation containing a variety of single molecule probes, i.e. compound molecular probe (Radioactive composition).With compound molecular probe to disease Molecular imaging is carried out, i.e. compound molecular probe images.The object of the invention is that overcoming18The false positive of F-FDG imaging, false yin The limitations such as property, provide and are better than18The compound molecular probe (Radioactive composition) containing a variety of PET probes of F-FDG；And it can be complete Complete solution determine different kinds of molecules probe single production method problem, really radiochemistry personnel are solved from heavy radiation synthetic work It releases, and can be reduced radioactivity irradiation.
The present invention uses18F-FDG Fully automated synthesis instrument, with 1,3,4,6- tetra--O- acetyl group -2-O- trifyl - β-D- mannopyranose (abbreviation mannose triflate) and 2- ethyl bromide mixture are precursor, using simple, quick and high " the two step On-column hydrolysis " of effect can get through nucleophilic fluorination and hydrolysis two-step reaction and small column separating purification and contain two kinds of PET Drug18F-FDG+18F-FPA compound molecular probe.Equally, with mannose triflate+(N-2- bromo propiono)-L- α-glutamic acid Diethyl ester admixture is precursor, through nucleophilic fluorination and On-column hydrolysis and small column separating purification, can get and contains two kinds of PET medicines Object18F-FDG+(N-2-18F- fluorine propiono)-L- α-glutamic acid (18F-NFPGlu) compound molecular probe.With mannose triflate+2- Ethyl bromide+(N-2- bromo propiono)-L- α-glutamate diethyl ester mixture is precursor, through nucleophilic fluorination and in column water Solution and small column separating purification can get and contain three kinds of PET drugs18F-FDG+18F-FPA+18F-NFPGlu compound molecular probe (Radioactive composition).Radioactive composition of the present invention takes water as a solvent according to conventional, and the dosage of Radioactive composition and water is with suitable Cooperation is PET imaging agent；And be to be substituted into during the preparation process by raw material, it does not add separately.The application of the method solves two Footwork automated production contains18F marks the problem of a variety of probe compound molecular probes, is Fully automated synthesis compound18F mark molecule Probe provides universal method, and the synthesis for other compound radioactive molecule probes provides technical foundation.
The present invention relates to contain a variety of probes18F-FDG+18F-FPA+18The single synthesis side of F-NFPGlu compound molecular probe Method and its single simultaneously image in apply, have broad applicability, compound molecular probe single synthesis and its single can be opened up Research frontier is imaged simultaneously.Research contents of the present invention has following clear superiority: (1) proposing research and development compound molecule Probe new strategy solves the key technique problem of more targeted molecular probe preparations.To overcome18F-FDG single molecule probe is aobvious The limitation of picture, foreign study person have developed a variety of single molecule probe imagings of more targetings and more targeting coupled molecule probe imaging sides Method.But existing a variety of single molecule probe divided doses repeatedly image needs and repeatedly prepare different unimolecules spies within the not time Needle；Single-dose images needs simultaneously and repeatedly prepares different single molecule probes in one day using synthesis preparation method by several times；More targets It is that need to use more complex chemical modification using the single molecule probe imaging technique containing multiple ligand moleculars to the imaging of coupled molecule probe Method preparation is coupled multiple ligand probes.One pot of single synthesis method and more pots of synthesis preparing methods prepare compound molecular probe, overcome Divided doses repeatedly image and single-dose images the limitation in terms of preparing molecular probe simultaneously, can be within the same time The compound molecular probe of the probe containing different kinds of molecules is prepared simultaneously；The imaging of coupled molecule probe is also avoided to need using complicated chemical Method modifies the drawbacks of multiple ligands prepare coupled molecule probe, and especially overcoming each ligand in coupled molecule probe cannot be certainly By the limitation for combining its corresponding specific target spot.Existing monomer molecule probe synthesis condition is optimized and improved Single synthesis is completed to meet the requirements the compound molecular probe of proportion.Compound molecular probe single synthesis method is that research and development are better than18F- The important development strategy of FDG novel molecular probe also solves the problems, such as more targeted molecular probe synthesis indirectly.(2) containing a variety of Single molecule probe single dose injection contains a variety of single molecule probe single formulations (single dose), be a kind of innovative more targeting compounds Molecular probe, and formulate the important development direction of next-generation novel molecular probe.Compound molecular probe preparation is not a variety of The simple combination of single molecule probe, but a variety of single molecule probes with complementation are prepared through chemical synthesis and by one Certainty ratio building is combined into compound molecular probe, such as insensitive to hepatoma18F-FDG and the 2- sensitive to hepatoma18F- fluoropropionic acid (18F-FPA), designed, synthesized and building group is combined into compound molecular probe18F-FDG+18F-FPA single dose, It is substantially better than18F-FDG.And simultaneously although imaging technique is to use various of monomer molecular probe, but this simultaneously to existing single-dose Instead of compound molecular probe preparation, various of monomer molecular probe preparation are not equivalent to while injecting or taking orally a variety of medicines in matter Product.Various of monomer molecular probe preparation is several formulations, is equivalent to a variety of drugs；And compound molecular probe preparation (radioactivity group Close object) it is single dose, it is equivalent to compound drug.(3) imaging of compound molecular probe is a kind of simple, practical and wide spectrum molecular imaging Method, Transformation Application will bring the deep revolution of molecular image and accurate medicine, 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 imaging, and develop and be better than indirectly18F- The important channel of FDG solves development and is better than18The problem of F-FDG molecular probe is that other compound molecular probes and compound target Theoretical and experiment basis has been established in the development of drug, opens compound molecular probe imaging frontier.(4) multi-mode compound molecule The development and Transformation Application of probe will open up the multi-mode compound molecular probe imaging new era, fundamentally solve long-standing problem The crucial technical problem that the practical challenges of molecular imaging doctor and technical staff, i.e. multi-mode molecular probe image simultaneously, Obstacle is removed for multi-mode polyfunctional molecule iconography Transformation Application.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 with there is high-resolution and combine compared with other image technologies of muting sensitivity, push molecular imaging to enter more The model molecule iconography new era.But single injects nucleic and magnetic signal group (or other signals group) label simultaneously Single molecule probe row multi-mode probe molecular imaging simultaneously will be huge challenge even not possible with.If will have different targets To the specific radiopharmaceutical and on-radiation molecular probe of effect, multi-mode compound molecular probe preparation, Jiu Huiqiao is made It is wonderful to solve the multi-mode molecular imaging important scientific problems that pendent multi-mode molecular probe images simultaneously always, it realizes multiple Conjunction molecular probe double mode PET-MRI, SPECT-MRI, PET- ultrasonoscopy, the imaging of PET- optics are possibly realized, and are opened up compound Molecular probe images the new era.
The invention is realized in this way.
Single molecule probe18F-FDG using mannose triflate as precursor, it is perfluorinated and column hydrolyze two-step method, it is complete in 25min At 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 column hydrolysis temperature；Using Sep-Pak Al2O3N Plus pillar, two Sep-Pak Plus C18 series connection pillar and the small column separating purification of Sep-Pak SCX and neutralized reaction product.
Single molecule probe18F-FPA using 2- ethyl bromide as precursor, it is perfluorinated and column hydrolyze two-step method, at 30 points Fully automated synthesis (formula 2) is completed in clock.Precursor 2- ethyl bromide optimum amount is 8-20mg, fluorination reaction temperature 110 DEG C, reaction time 10min；It is room temperature, reaction time 2-3min in column hydrolysis temperature；With18F-FDG is the same, using Sep-Pak Al2O3N Plus pillar, two Sep-Pak plus C18 series connection pillars and the small column separating purification of Sep-Pak SCX and neutralization produce Object.
Single molecule probe18F-NFPGlu using (N-2- bromo propiono)-L- α-glutamate diethyl ester as precursor, it is perfluorinated and Two-step method is hydrolyzed in column, completes Fully automated synthesis (formula 3) in 40min.Precursor (N-2- bromo 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 column hydrolysis temperature Temperature, reaction time 5-10min；With18F-FDG is the same, using Sep-Pak Al2O3N Plus pillar, two Sep-Pak plus C18 series connection pillar and the small column separating purification of Sep-Pak SCX and neutralized reaction product.
The present invention relates to bi-molecular probe PET drugs18F-FDG+18F-FPA compound molecular probe (Radioactive composition) Single full-automation radiation synthesis.Due to18F-FDG and18Similar method preparation can be used in F-FPA, thus the present invention is with trifluoro Mannose and 2- ethyl bromide mixture are precursor, and perfluorinated reaction generates 1,3,4,6- tetra--O- acetyl group -2 of intermediate -18F- β-D- mannopyranose+2-18F- fluoropropionic acid ethyl ester mixture.Add water release it is dilute after, pass through a Sep-Pak Al2O3N Plus pillar and two Sep-Pak plus C18 series connection pillars, radioactivity intermediate are captured in Sep-Pak plus C18 pillar In.Add 2M sodium hydroxide solution into pillar, in Sep-Pak plus C18 pillar hydrolysis occurs for intermediate.It is drenched with water The C18 pillar is washed, after leacheate further passes through the small column separating purification of Sep-Pak SCX and neutralizes, sterilised membrane filter is crossed and obtains18F- FDG+18F-FPA compound molecular probe.Bi-molecular probe single dose injection (Radioactive composition) synthetic route is as shown in Equation 4. But18F-FDG+18The single full-automation radiation synthesis of F-FPA compound molecular probe is not simply to apply18F-FDG or18F-FPA synthetic method, and must be in precursor mixture consumption proportion and solvent selection, fluorination reaction temperature and time, Yi Ji Optimized in terms of column hydrolysis time, 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 When than for 5:8~8:10, perfluorinated and hydrolysis two-step reaction and radioactivity HPLC detection can get contamination and respectively account for (50.0 ± 10.0) %'s18F-FDG+18F-FPA。18F-FDG+18F-FPA compound molecular probe optimum synthesis condition: precursor mixing Object dosage mannose triflate (5-8mg) and 2- ethyl bromide (8-10mg), fluorination reaction solvent are acetonitrile or the tertiary fourth of acetonitrile- Alcohol, (meaning in the present invention " about " is positive and negative five degree to about 100 DEG C of reaction temperature, primarily to balanced reaction.Similarly hereinafter), it reacts Time is 8-12min, optional 10min；It is room temperature 6-8min in column hydrolysis.
The invention further relates to bi-molecular probe PET drugs18F-FDG+18(the radioactivity combination of F-NFPGlu compound molecular probe Object) single full-automation radiate synthesis.Due to18F-FDG and18Similar method preparation, thus this hair can be used in F-NFPGlu It is bright using mannose triflate and (N-2- bromo propiono)-L- α-glutamate diethyl ester mixture as precursor, perfluorinated reaction generation Tetra--O- acetyl group -2- of intermediate 1,3,4,6-18F- β-D- mannopyranose+(N-2-18F- fluorine propiono)-L- α-glutamic acid two Ethyl ester mixture.Add water release it is dilute after, pass through a Sep-Pak N Al2O3Plus pillar and two Sep-Pak plus C18 strings Join pillar, radioactivity intermediate captures in Sep-Pak plus C18 pillar.Add 2M sodium hydroxide solution into pillar, it is intermediate In Sep-Pak plus C18 pillar hydrolysis occurs for body.The C18 pillar is eluted with water, leacheate further passes through Sep- After the small column separating purification of Pak SCX and neutralization, crosses sterilised membrane filter and obtain18F-FDG+18F-NFPGlu compound molecular probe.This pair point Sub- probe compound molecular probe (Radioactive composition) synthetic route is as shown in Equation 5.18F-FDG+18F-NFPGlu compound molecule is visited Needle synthesis condition with18F-FDG and18F-FPA is different, wherein mannose triflate and (N-2- bromo propiono)-L- α-glutamic acid two When ethyl ester mass ratio is 5:8~8:15, perfluorinated and hydrolysis two-step reaction and radioactivity HPLC and radio thin layer are chromatographed (TLC) it detects, can get contamination and respectively account for (50.0 ± 10.0) %'s18F-FDG+18F-NFPGlu.Optimum synthesis condition: Precursor mixture dosage mannose triflate (5-8mg) and (N-2- bromo propiono)-L- α-glutamate diethyl ester (8-15mg), fluorine Changing reaction dissolvent is acetonitrile or acetonitrile-tert-butyl alcohol, and about 110 DEG C of reaction temperature, reaction time 12-18min, we are optional 15min；It is room temperature 3-4min in column hydrolysis.It can get in this way18F-FDG and18F-NFPGlu contamination respectively accounts for (50.0 ± 10.0) %'s18F-FDG+18F-FPA
The invention further relates to three molecular probe PET drugs18F-FDG+18F-FPA+18F-NFPGlu compound molecular probe (is put Penetrating property composition) single full-automation radiate synthesis.Due to18F-FDG、18F-FPA and18Similar side can be used in F-NFPGlu Method preparation, thus the present invention is with mannose triflate+2- ethyl bromide+(N-2- bromo propiono)-L- α-glutamic acid diethyl Ester admixture is precursor, and perfluorinated reaction generates 1,3,4,6- tetra--O- acetyl group -2- of intermediate18F- β-D- mannopyranose+2 -18F- fluoropropionic acid ethyl ester mixture+(N-2-18F- fluorine propiono)-L- α-glutamate diethyl ester mixture.Then it presses18F-FDG +18The single full-automation radiation of F-FPA compound molecular probe synthesizes similar method, obtains18F-FDG+18F-FPA+18F- NFPGlu compound 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 condition with18F-FDG、18F-FPA and18F-NFPGlu is different, Wherein as mannose triflate dosage 5-8mg+2- ethyl bromide 8-10mg+ (N-2- bromo propiono)-in precursor mixture L- α-glutamate diethyl ester 8-10mg, i.e. mannose triflate, 2- ethyl bromide and (N-2- bromo propiono)-L- α-paddy ammonia When diethyl phthalate mass ratio is 5:8:8~10:8~10, perfluorinated and hydrolysis two-step reaction and radioactivity HPLC and radioactivity TLC detection, can get 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 dosage Mannose triflate (5-8mg)+2- ethyl bromide (8-10mg)+(N-2- bromo 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, reaction time 12-18min, we Optional 15min；It is room temperature 8min in column hydrolysis.In this way, can get contamination18F-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 composition In colourless or faint yellow clear solution, pH value is between 5.0-8.0.With18F-For starting material,18F-FDG+18F-FPA、18F- FDG+18F-NFPGlu and18F-FDG+18F-FPA+18Non- putting of the correction for attenuation yield of F-NFPGlu is 20-35%, total Radiochemical purity Time is about 40min (every kind of compound molecular probe of production, n=5), and specific activity is not less than 3.7 × 1010Bq/mmol.Through radioactivity HPLC detection,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 time is consistent, and radiochemical purity is all larger than 95%.For into One step is distinguished18F-FDG、18F-FPA and18F-NFPGlu, detecting through radioactivity TLC confirms.
The present invention relates to18F-FDG、18F-FPA and18It is mixed that corresponding precursor can also be used in the Radioactive composition of F-NFPGlu The solid phase fluorination reaction and soda acid liquid phase hydrolysis two-stage process for closing object complete its Fully automated synthesis.Therefore, it is mixed in precursor It object consumption proportion and solvent selection, fluorination reaction temperature and time and is optimized in terms of column hydrolysis time, It can also realize18F-FDG、18F-FPA and18F-NFPGlu is bis-/tri- kinds of tracer compound molecular probe single fractions synthesis.As it can be seen that18F-FDG、18F-FPA and18F-NFPGlu is bis-/tri- kinds of tracer compound molecular probe single fraction synthetic methods, it is not limited to liquid Phase fluorination and in column method for hydrolysis, solid phase fluorination and soda acid liquid phase method for hydrolysis are equally applicable.
[Detailed description of the invention]
Fig. 1 self-control18F-FDG synthesizer schematic diagram.
Fig. 2 is used18The preparation of F-FDG synthesizer18F-FDG+18F-FPA、18F-FDG+18F-NFPGlu or18F-FDG+18F-FPA +18The Fully automated synthesis process flow chart of F-NFPGlu compound molecular probe；
Fig. 3 compound molecular probe18F-FDG+18The F-FPA single figure of PET imaging simultaneously.Upper figure is coronal-plane PET-CT fusion Image, the following figure are PET image.
Fig. 4 compound molecular probe18F-FDG+18The F-NFPGlu single figure of PET imaging simultaneously.Upper figure is horizontal shape face PET figure Picture, the following figure are coronal-plane PET image.
Fig. 5 compound molecular probe18F-FDG+18F-FPA+18PET images coronal-plane figure to F-NFPGlu single simultaneously.
[specific embodiment]
1 dual tracer of embodiment18F-FDG+18The Fully automated synthesis of F-FPA compound molecular probe
Using18F-FDG Fully automated synthesis instrument (Fig. 1) and the preparation of two step On-column hydrolysis contain two kinds of PET drugs18F-FDG+18F-FPA compound molecular probe, is completed under the control of the computer18F-FDG+18F-FPA compound molecular probe automated production, Synthesis technology process is shown in Fig. 2.Specifically include that (1)18F-F-Trapping.Passed through by cyclotron18O(p,n)18F nuclear reaction is raw It produces18F-F-, in N2Airborne leukorrhagia, 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 evaporates.In N2Under effect, in headpin Containing K2CO3It, will with the acetonitrile solution (1.0-1.5mL) of catalyst K22218F-F-It elutes in confined reaction bottle, heating mixing For solution to 95 DEG C, evaporated under reduced pressure obtains dry compound [K/K222]+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 bromide in No. 3 bottles (8-10mg) acetonitrile (or acetonitrile-tert-butyl alcohol) solution (1mL) is pressed into reaction flask, and 5-15min is reacted in 90-105 DEG C of heating.Fluorine Change after the reaction was completed, is concentrated under reduced pressure, it is cooling.(4) it is trapped in column.In N2Under airflow function, H in No. 2 bottles2O (4.0-8.0mL) adds Enter in reaction flask, two kinds18F- fluorinated intermediates and H2O mixed liquor is 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 pillar.With No. 4 H in bottle2O (8.0-15mL) washs pillar, uses N2Drying, the waste collection of the water containing acetonitrile is in waste bottle.(5) in column basic hydrolysis. NaOH solution (1.0mL) is pressed into reaction flask in kingpin, and is loaded into two Sep Pak plus C18 pillars, hydrolysis Reaction time is about 2-5min.(6) it neutralizes and isolates and purifies.It is produced in water (4.0-15.0mL) elution C18 pillar in No. 6 bottles Product, by the way that in Sep-Pak SCX pillar and aqueous slkali, leacheate is in N2Under atmospheric pressure effect, collected after sterilised membrane filter is handled In sterile product bottle, obtain18F-FDG+18F-FPA compound molecular probe, each component probe radiation content respectively account for (50.0 ± 10.0) %18F-FDG+18F-FPA。
Above-mentioned fluorination reaction can also carry out in solid phase, hydrolysis can also in room temperature NaOH (or KOH) aqueous slkali or It is completed in heating hydrochloric acid solution.
2 dual tracer of embodiment18F-FDG+18The Fully automated synthesis of F-NFPGlu compound molecular probe
Using18F-FDG Fully automated synthesis instrument (Fig. 1) and the preparation of two step On-column hydrolysis contain two kinds of PET drugs18F-FDG+18F-NFPGlu compound molecular probe, is completed under the control of the computer18F-FDG+18The automatic metaplasia of F-NFPGlu compound molecular probe It produces, synthesis technology process is shown in Fig. 2.Specifically include that (1)18F-F-Trapping.Passed through by cyclotron18O(p,n)18F core is anti- It should produce18F-F-, in N2Airborne leukorrhagia, by the pretreatment Sep-Pak l ight QMA yin 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 evaporates.In N2Under effect, No. 1 Contain K in bottle2CO3It, will with the acetonitrile solution (1.0-1.5mL) of catalyst K22218F-F-It elutes in confined reaction bottle, heats For mixed solution to 95 DEG C, evaporated under reduced pressure obtains dry compound [K/K222]+18F-, waste liquid inhaled by the cold-trap that is placed in liquid nitrogen It receives.(3) fluorination reaction.In N2Under gas effect, precursor mixture mannose triflate (5-8mg) and (N-2- bromo 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 flask, 100- 10-15min is reacted in 115 DEG C of heating.After the completion of fluorination reaction, it is concentrated under reduced pressure, it is cooling.(4) it is trapped in column.In N2Airflow function Under, H in No. 2 bottles2O (4.0-8.0mL) is added in reaction flask, and two kinds18F- fluorinated intermediates and H2O mixed liquor is transmitted over one A Sep-Pak plus Al2O3In pillar and two Sep-Pak plus C18 pillars,18F- fluorinated intermediates mixture quilt The trapping of Sep-Pakplus C18 pillar.With H in No. 4 bottles2O (8.0-15mL) washs pillar, uses N2Drying, the waste liquid of the water containing acetonitrile It collects in waste bottle.(5) in column basic hydrolysis.NaOH solution (1.0mL) is pressed into reaction flask in kingpin, and is loaded into two In a Sep Pak plus C18 pillar, hydrolysis time is about 5-10min.(6) it neutralizes and isolates and purifies.In No. 6 bottles Water (4.0-15.0mL) elutes product in C18 pillar, by the way that in Sep-Pak SCX pillar and aqueous slkali, leacheate is in N2Air pressure Under power effect, collects in sterile product bottle, obtain after sterilised membrane filter is handled18F-FDG+18F-NFPGlu compound molecular probe. In this way, can get18F-FDG and18F-NFPGlu contamination respectively accounts for (50.0 ± 10.0) %'s18F-FDG+18F-NFPGlu。
Above-mentioned fluorination reaction can also carry out in solid phase, hydrolysis can also in room temperature NaOH (or KOH) aqueous slkali or It is completed in heating hydrochloric acid solution.
3 three tracer of embodiment18F-FDG+18F-FPA+18The Fully automated synthesis of F-NFPGlu compound molecular probe
Using18F-FDG Fully automated synthesis instrument (Fig. 1) and two step On-column hydrolysis prepare three kinds of PET drugs18F-FDG+18F- FPA+18F-NFPGlu compound molecular probe, completes its automated production under the control of the computer, and synthesis technology process is shown in figure 2.Specifically include that (1)18F-F-Trapping.Passed through by cyclotron18O(p,n)18F nuclear reaction production18F-F-, in N2Airborne band Under, by the pretreatment Sep-Pak l ight QMA anion pillar being placed in radioactive activity measuring meter,18F-F-It is trapped in small In column,18O- water is collected in returnable bottle.(2) solvent evaporates.In N2Under effect, K is contained in headpin2CO3With catalyst K222's Acetonitrile solution (1.0-1.5mL), will18F-F-It eluting in confined reaction bottle, heating mixed solution is 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 effect Under, precursor mixture mannose triflate (5-8mg)+2- ethyl bromide (8-10mg)+(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 flask, 100- 10-15min is reacted in 115 DEG C of heating.After the completion of fluorination reaction, it is concentrated under reduced pressure, it is cooling.(4) it is trapped in column.In N2Airflow function Under, H in No. 2 bottles2O (4.0-8.0mL) is added in reaction flask, and three kinds18F- fluorinated intermediates and H2O mixed liquor is transmitted over one A Sep-Pak plus Al2O3In pillar and two Sep-Pak plus C18 pillars,18F- fluorinated intermediates mixture quilt The trapping of Sep-Pakplus C18 pillar.With H in No. 4 bottles2O (8.0-20mL) washs pillar, uses N2Drying, the waste liquid of the water containing acetonitrile It collects in waste bottle.(5) in column basic hydrolysis.NaOH solution (1.0mL) is pressed into reaction flask in kingpin, and is loaded into two In a Sep Pak plus C18 pillar, hydrolysis time is about 5-10min.(6) it neutralizes and isolates and purifies.In No. 6 bottles Water (4.0-15.0mL) elutes product in C18 pillar, by the way that in Sep-Pak SCX pillar and aqueous slkali, leacheate is in N2Air pressure Under power effect, collects in sterile product bottle, obtain after sterilised membrane filter is handled18F-FDG+18F-FPA+18F-NFPGlu compound point Sub- probe.In this way, can get 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。
Above-mentioned fluorination reaction can also carry out in solid phase, hydrolysis can room temperature NaOH (or KOH) aqueous slkali or add It is completed in hot hydrochloric acid solution.
The measurement of 4 product purity of embodiment
It is measured 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 probe.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 probe is injected together Into HPLC, or point sample row TLC together, to determine whether its retention time is consistent, and confirmation prepares the authenticity of injection, warp It measures its radiochemical purity and is all larger than 95%.
HPLC analysis condition: analytical column is ZORBAX Ecl ipse XDB-C18 column, and mobile phase is the acetonitrile of 0.1%TFA Solution: the aqueous solution of 0.1%TFA, row gradient elution: when 0min, acetonitrile solution/0.1%TFA containing 0.1%TFA is water-soluble Liquid: 2/98；When being gradually raised to 8min, acetonitrile solution/0.1%TFA aqueous solution of 0.1%TFA: 10/90；It is raised again to 20min When, acetonitrile solution/0.1%TFA aqueous solution 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 compound point Sub- probe, it is still necessary to TLC methods to be used further to confirm to contain18F-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), gently put and at one 1mL of distance, it is dried up with hair dryer together on silica gel plate.It is chromatographed, is opened up in chromatography cylinder Opening agent is acetonitrile: water=95:5 (V/V), is dried up after chromatography with hot-air, carries out thin layer scanning using TLC scanner.After scanning, TLC plate is uniformly sprayed on iodine staining, or with 2N sulfuric acid, and 110 degree lower to dry 10min dyeing, detection molecules probe sample and standard The Rf value Rf of product.
Compound molecular probe is detected by radioactivity HPLC and radioactivity TLC18F-FDG+18F-FPA、18F-FDG+18F- NFPGlu and18F-FDG+18F-FPA+18F-NFPGlu preparation each component monomer probe radiation percentage composition.
The imaging of 5 lotus knurl model small animal position emission tomography (PET) of embodiment
Lotus SPC-A-1 tumor nude mice model, is injected respectively by tail vein by every group 318F-FDG+18F-FPA、18F-FDG+18F- NFPGlu and18F-FDG+18F-FPA+18F-NFPGlu compound molecular probe (0.2mL, about 3.7-5.5MBq) is to nude mice model body It is interior.10min anaesthetizes nude mice through intraperitoneal injection 5% chloraldurate (6mL/kg) before imaging, and is placed on fixed plate adhesive tape and fixes, and uses Heating cushion keeps body temperature.After CT scan, PET data is collected in injection imaging agent different time points, with software (Inevon Research Workplace 4.1) after row correction for attenuation, iterative approximation image.Sketch the contours of the tissues such as tumour and brain, muscle Area-of-interest (ROIs) measures the radiocounting and volume of region of interest tissue, calculates per gram of tissue injection dosage percentage Than (%ID/g), and calculate the radioactive uptakes relative ratios such as tumour/brain, tumour/muscle.Representative single synthesis compound molecule For lotus knurl model single, image results are shown probe 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 higher intake in tumor tissues, respectively higher than18F-FDG、18F-FPA and18F-NFPGlu (Fig. 5).The model18F-FPA and18F-NFPGlu detection is more sensitive, and18F-FDG Detect more insensitive, compound molecular probe18F-FDG+18F-FPA and18F-FDG+18F-NFPGlu detection can reach with18F- FPA and18The same detection effect of F-NFPGlu, and be better than18F-FDG.Equally, it makes18F-FDG it is sensitive and18F-FPA and18F- NFPGlu insensitive tumor model, compound molecular probe18F-FDG+18F-FPA and18F-FDG+18F-NFPGlu detection can be excellent In18F-FPA and18F-NFPGlu, and can reach with18F-FDG peer-level.Compound molecular probe, which can detect that, compares monomer molecule The more lesions of probe.

Claims (9)

1. a kind of Radioactive composition of single fraction synthetic method preparation, wherein the composition of each drug are as follows:18F- fluorodeoxy Glucose18F-FDG, 2-18F- fluoropropionic acid18F-FPA and/or (N-2-18F- fluorine propiono)-L- α-paddy ammonia Acid18F-NFPGlu, radioactive dosage percentage range shared by each component are as follows:
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 Radioactive composition described in claim 1, including with mannose triflate and 2- bromo Ethyl propionate mixture, mannose triflate and (N-2- bromo propiono)-L- α-glutamate diethyl ester mixture or Before mannose triflate, 2- ethyl bromide and (N-2- bromo propiono)-L- α-glutamate diethyl ester mixture are Body obtains drug containing PET through nucleophilic fluorination and hydrolysis two-step reaction respectively18F-FDG+18F-FPA,18F-FDG+18F- NFPGlu or18F-FDG+18F-FPA+18F-NFPGlu Radioactive composition, wherein nucleophilic fluorination reagent is [K/K222]+ 18F。
3. the single fraction synthetic method of Radioactive composition according to claim 2, it is characterised in that described18F- FDG+18F-FPA compound molecular probe radiates synthetic method, before being with mannose triflate and 2- ethyl bromide mixture Body, perfluorinated reaction generate 1,3,4,6- tetra--O- acetyl group -2- of intermediate18F- β-D- mannopyranose+2-18F- fluoropropionic acid ethyl ester mixture；Add water release it is dilute after, pass through a Sep-PakAl2O3NPlus pillar and two Sep- PakplusC18 series connection pillar, radioactivity intermediate capture in Sep-PakplusC18 pillar；
Into pillar, in Sep-PakplusC18 pillar hydrolysis occurs adding sodium hydroxide solution for intermediate；It is eluted with water The C18 pillar after leacheate further passes through the small column separating purification of Sep-PakSCX and neutralizes, is crossed sterilised membrane filter and is obtained18F-FDG +18F-FPA Radioactive composition；Wherein mannose triflate and 2- ethyl bromide mass ratio are 5:8~8:10.
4. the single fraction synthetic method of Radioactive composition according to claim 2, it is characterised in that described18F- FDG+18F-NFPGlu preparation radiates synthetic method, with mannose triflate and (N-2- bromo propiono)-L- α-glutamic acid Diethyl ester admixture is precursor, and perfluorinated reaction generates 1,3,4,6- tetra--O- acetyl group -2- of intermediate18F- β-D- Mannopyranose+(N-2-18F- fluorine propiono)-L- α-glutamate diethyl ester mixture；Add water release it is dilute after, pass through one Sep-PakNAl2O3Plus pillar and two Sep-PakplusC18 series connection pillars, radioactivity intermediate are captured in Sep- In PakplusC18 pillar；Into pillar, intermediate hydrolyzes adding sodium hydroxide solution in Sep-PakplusC18 pillar Reaction；The C18 pillar is eluted with water, it is excessively sterile after leacheate further passes through the small column separating purification of Sep-PakSCX and neutralizes Filter membrane obtains18F-FDG+18F-NFPGlu Radioactive composition；Wherein mannose triflate and (N-2- bromo propiono)-L- α-glutamate diethyl ester mass ratio 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 compound molecular probe radiates synthetic method, with mannose triflate, 2- ethyl bromide (N-2- bromo propiono)-L- α-glutamate diethyl ester mixture is precursor, and perfluorinated reaction generates intermediate 1,3, 4,6- tetra--O- acetyl group -2-18F- β-D- mannopyranose+2-18F- fluoropropionic acid ethyl ester mixture+(N- 2-18F- fluorine propiono)-L- α-glutamate diethyl ester mixture, add water release it is dilute after, pass through a Sep- PakAl2O3NPlus pillar and two Sep-PakplusC18 series connection pillars, radioactivity intermediate are captured in Sep- In PakplusC18 pillar；Into pillar, intermediate hydrolyzes adding sodium hydroxide solution in Sep-PakplusC18 pillar Reaction；The C18 pillar is eluted with water, it is excessively sterile after leacheate further passes through the small column separating purification of Sep-PakSCX and neutralizes Filter membrane obtains18F-FDG+18F-FPA+18F-NFPGlu Radioactive composition；Wherein mannose triflate, 2- ethyl bromide (N-2- bromo propiono)-L- α-glutamate diethyl ester mass ratio is 5:8:8~10:8~10.
6. the Radioactive composition of single fraction synthetic method preparation described in claim 1 is preparing answering in PET imaging agent With.
7. the Radioactive composition of single fraction synthetic method preparation according to claim 6 is in preparation PET imaging agent Application, it is characterised in that18F-FDG+18F-FPA Radioactive composition is for tumour, cardiovascular and cerebrovascular disease and nerve essence The antidiastole of refreshing disease and curative effect evaluation PET imaging agent.
8. the Radioactive composition of single fraction synthetic method preparation according to claim 6 is in preparation PET imaging agent Application, it is characterised in that18F-FDG+18F-NFPGlu Radioactive composition is used for tumour, cardiovascular and cerebrovascular disease and nerve The antidiastole of mental disease and curative effect evaluation PET imaging agent.
9. the Radioactive composition of single fraction synthetic method preparation according to claim 6 is in preparation PET imaging agent Application, it is characterised in that18F-FDG+18F-FPA+18F-NFPGlu Radioactive composition is used for tumour, cardiovascular and cerebrovascular disease And antidiastole and the curative effect evaluation PET imaging agent of neuropsychiatric disease.
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