CN103690972A - 18F-labeled quinazoline type EGFR (epidermal growth factor receptor) positron tracer, as well as preparation method and application thereof - Google Patents

Abstract

The invention discloses an 18F-labeled quinazoline type EGFR (epidermal growth factor receptor) positron tracer, as well as a preparation method and an application thereof and belongs to the field of chemical synthesis. The 18F-labeled quinazoline type EGFR positron tracer disclosed by the invention has a chemical structure as shown in a formula II. The synthesized 18F-labeled small molecular EGFR type positron tracer has clinical value of diagnosis and monitoring of treatment curative effect and particularly plays an important role in promoting personalized treatment. In addition, the invention further provides the method for full-automatic synthesis of the 18F-labeled quinazoline type EGFR positron tracer by one step, the method has the characteristics of multiple purposes, large yield, high efficiency, short synthesis time, low cost and the like, and the requirements of large-scale production can be further met.

Description

18quinazoline ditosylate salt EGFR positron tracer of F labelling and its preparation method and application

The cross reference of related application

The application's case requires application on January 5th, 2013, and application number is 201310002891.X, denomination of invention be " ¹⁸quinazoline ditosylate salt EGFR positron tracer of F labelling and its preparation method and application " the priority of Chinese patent application case, its description is to be all incorporated herein by reference.

Technical field

The present invention relates to that a kind of to fluoridize substitution reaction synthetic ¹⁸f labelling micromolecule aniline quinazoline class EGFR class positron tracer and its preparation method and application.The invention belongs to the field of chemical synthesis.

Background technology

The positron radionuclide that current clinical use medical cyclotron is produced ¹⁵o, ¹³n, ¹¹c, ¹⁸in F ¹⁸f has the half-life of 110 minutes and becomes the clinical positron radionuclide of paying attention to the most. ¹¹c was due to only 20 minutes half-life.So ¹¹the tracer of C labelling is little in clinic trial, and the tracer of most tracer labellings is only for preclinical phase and clinical research. ¹⁸the positron tracer of F labelling is clinical PET/CT, PET and the most frequently used positron radioactive tracer of coincidence circuit system, [ ¹⁸f] FDG, [ ¹⁸f] FLT, [ ¹⁸f] acetate, [ ¹⁸f] early diagnosis, the therapeutic scheme that have been widely used at present tumor, cardiovascular and nervous system disease as positive electricity radial pattern tracer such as choline formulate and curative effect evaluation.

EGF-R ELISA (EGFR) is the expression product of proto-oncogene c-erbB, belongs to receptor type tyrosine kinase (tyrosine kinase, TK).The postactivated intracellular region TK of EGFR and ligand binding, activates many signal paths, participates in tumor cell proliferation, apoptosis inhibition, invasion and attack, shifts and treat the processes such as resistance.EGFR cell after lonizing radiation opposing and irradiation accelerates in propagation significant again, can be used as the prediction important evidence of radiotherapy effect and the Effective target site of radiotherapy sensitization.EGFR targeted therapy is compared with traditional chemotherapy, because thering is better safety and toleration, in the treatment of the malignant tumor such as nonsmall-cell lung cancer (NSCLC), occupy more and more consequence, but medical expense is quite high, therefore the expression of clear and definite EGFR before treatment, has certain value to the treatment of tumor and prognosis judgement and medicine health economics.Along with the clinical practice widely of EGFR molecular targeted therapy, EGFR molecular imaging has also caused gradually pays close attention to and has obtained preliminary research.

The EGFR of take is the pith of tumor molecular targeted therapy as treating target spot, mainly contain monoclonal antibody and two kinds of modes of micromolecule tyrosine kinase antagonist, as Cetuximab (Cetuximab, Erbitux, Erbitux), Buddhist nun's trastuzumab (Nimotuzumab, Tai Xinsheng) and gefitinib (Gefitinib, Iressa, Iressa), Erlotinib (Erlotinib, Tarceva, Erlotinib) etc. shows good therapeutic effect in clinical experiment and clinical practice.Compare with antibody, micromolecule tyrosine kinase antagonist receives clinical concern because synthetic simple, patient's side effect is little.

(1) micromolecule EGFR acceptor inhibitor and application thereof

1, micromolecule EGFR receptor and classification thereof

Epidermal growth factor (Epidermal Growth Factor, EGF) is a kind of of common somatomedin, promotes the growth of epidermis cell, epithelial cell and interstitial.EGF-R ELISA (Epidermal Growth Factor Receptor, EGFR) family comprises EGFR, ErbB2, ErbB3, 4 members such as ErbB4, its family receptors tyrosine kinase (Receptor Tyrosine Kinase, RTK) with monomeric form, exist, structurally by extracellular region, cross-film district, 3 parts of intracellular region form, extracellular region has 2 cysteine and enriches district, intracellular region has typical adenosine triphosphate (Adenosine Triphosphate, ATP) binding site and tyrosine kinase district, its tyrosine kinase activity has vital effect in regulating cell proliferation and differentiation.EGFR cross expressing and/or sudden change in many tumors, causes the out of control and malignization of Growth of Cells by signal transduction.In addition the unconventionality expression of EGFR also with the generation of new vessels, the invasion and attack of tumor and transfer, chemotherapy resistance and the prognosis of tumor are closely related.The tumor patient of EGFR high expressed, malignancy is high, easily shifts, and relapse rate is high, poor prognosis.

2, micromolecule EGFR inhibitor is in clinical practice

At present the micromolecule EGFR inhibitor of clinical the longest use have gefitinib and, Erlotinib.

Gefitinib (Gefitinib, ZD1839, Iressa): gefitinib is that a kind of can passing through blocked EGFR signal transduction pathway and the growth of inhibition tumor cell and the EGFR-TKIs of propagation.Within 2003, FDA Food and Drug Administration (FDA) approval gefitinib is for the previously advanced NSCLC patient's of chemotherapy failure treatment.Correlational study is found, even if patient once accepts repeatedly chemotherapeutics, treats, and gefitinib still can play a role, particularly the patients with lung adenocarcinoma to asian ancestry women, non-smoking.The similar result of study that Kim etc. do also shows, late in the second line treatment of NSCLC, gefitinib is compared with Docetaxel chemotherapy regimen, both therapeutic equivalences, but the former has better safety and toleration, these have determined the standard scheme that gefitinib can be used as advanced NSCLC second line treatment.Research in recent years finds that the curative effect of gefitinib and patient's race have much relations, is the earliest wherein to find that the female pulmonary adenocarcinoma patient of some non-smoking histories of Asia is responsive especially to it.Giaccone G in 2004 etc. studies confirm that the sudden change of this crowd's ubiquity EGFR gene.There are some researches show that the patient with EGFR gene mutation can reach 70%～80% to the responsive rate of EGFR-TKIs treatment, and the patient who accepts the rear EGFR gene mutation of EGFR-TKIs treatment compares Overall survival (overall survival, OS) and obviously extends with the normal patient of EGFR gene.

Erlotinib (Erlotinib, OSI-774, Tarceva): Erlotinib belongs to quinazoline compounds, a kind of selectivity and reversible EGFR-TK activity inhibitor of having concurrently, there is water solublity feature, can be through being positioned at the purine nucleosides triphosphoric acid (adenosine-triphosphate of the tyrosine kinase domain of EGFR molecule in cell membrane and Cytoplasm, ATP) specific binding, stop ATP to be combined with intracellular tyrosine kinases, suppress its phosphorylation, disabling signal conduction, thereby reversibly suppress EGFR tyrosine kinase activity, suppress the migration of lung carcinoma cell, adhere to, invasion and attack and angiogenesis, impel Increase Apoptosis of Lung Cancer Cells.A multiple center clinical study of Rosell in 2009 etc. is by detecting EGFR exons 1 9D746-750 disappearance and the exon 2 1L858R sudden change of NSCLC patient tumors specimen of routine IV phase of in April, 2005-2007 year December 2312, find wherein to have 307 routine patient EGFR sudden changes, and this part patient is adopted to Erlotinib treatment.Found that 165 routine complete datas and can the patient of Estimating curative effect in, 48 examples (29.1%) are male, 112 examples (67.9%) are non-smoker, 124 examples (75.2%) are adenocarcinoma.103 examples (62.8%) EGFR gene, 19 Exon deletion, 62 examples (37.6%) EGFR gene, 21 exons mutations, 89 examples (53.9%) are Erlotinib first-line treatment person, 76 examples (46.1%) are second line treatment person.193 routine patient's data of including analysis in show, total effective rate is 70.8%(128 example), remission rate 13.3%(24 example), its meta OS is 22 months, and wherein male is 17 months, and women is 28 months.The meta progression of disease time (TTP) is 12 months, and women also exists advantage.61～71 years old age group patients' effective percentage is 2 times of other age group patient, and the effective percentage that has exons 19 disappearance patients is 2 times of non-disappearance person.Exons 19 disappearances and L858R sudden change patient's average OS is respectively 27 months and 16 months, there are differences (P=0.03) between the two.In this research, observe 307 routine patient EGFR gene 19 or 21 exons mutations in 2312 examples, mutation rate is 13.3%, there are 19 Exon deletion in 62.8% patient wherein, and 37.6% patient exists 21 exons mutations, consistent lower than Asia ethnic group with known white people EGFR mutation rate.This result of study has pointed out EGFR sudden change patient from Erlotinib treatment, significantly to benefit, and it has also emphasized to detect EGFR gene mutation for the importance of realizing individualized treatment.

(2) detect at present method and the limitation thereof whether EGFR suddenlys change, screens micromolecule EGFR inhibitor beneficiaries and monitor therapy curative effect

At present, the biological markers that may predict EGFR targeted therapy curative effect comprises Research of predicting markers of EGFR albumen or mRNA high expressed, EGFR gene copy number, EGFR gene mutation, K-RAS gene mutation, EGFR downstream signal system etc.But there is no enough evidence-based medical exemplary application biological markers and determine whether applying TKIs treatment.

Conventional DNA sequencing, after round pcr amplification EGFR gene, though DNA analysis, fluorescence RT-PCR, high performance liquid chromatography can judge EGFR gene mutation, analyzes from technological layer, all exists limitation.1. live body is drawn materials: belong in vitro, have the inspection of wound property, increase the risk that pathological changes shifts after operation; 2. tissue sampling requirement is high, affected by composition and experiment condition larger; Can the 3. pathologic specimen of drawing materials much when making a definite diagnosis of at present research, represent that patient accepts the tumor situation of recurrence before TKI treatment and needs further research; 4. complicated operation, consuming time many, randomness is larger; 5. instrument required in detecting is expensive, efficiency is lower, and at present domestic only have several units that this gene tester can be provided, therefore be difficult to large scale application, 1/5th the patient of only having an appointment at present can find suitable tissue specimen to detect; 6. up-to-date research has people to attempt detecting EGFR sudden change from hydrothorax and serum, but the EGFR sample size obtaining due to this mode and small, and recall rate, concordance and accuracy rate are lower; 7. also there is many uncertain factors in traditional Imaging Technology in monitoring EGFR targeted therapy curative effect, there is no the curative effect that clear and definite iconography means can judge EGFR targeted therapy.In NSCLC patient, identify most possible patient benefited from EGFR targeted therapy, be still a difficult problem that determines EGFR targeted therapy ^[22].Therefore, seek a kind of more simply, more directly perceived, and same responsive, accurately, and can be at live body real-time estimate micromolecule EGFR inhibitor for treating sensitive patients, instruct this type of medicine medication, the detection method of monitor therapy curative effect becomes at present another study hotspot problem of research both at home and abroad.

(3) molecular image is the ideal style that detects EGFR state--- ¹⁸the application of F labelling micromolecule aniline quinazoline class EGFR class positron tracer

Molecular image be on live body from Molecular level study cell function, metabolism to reach the uncharted field of medical diagnosis on disease, efficacy determination and new drug development.Molecular image utilizes molecular probe in conjunction with certain target molecules in born of the same parents, live body adopts the detection imagings such as PET, PET/CT, MRI, SPECT and optical imaging apparatus, there is high specific, high sensitivity and high-resolution, can non-invasive location, the quantitative and qualitative analysis data of providing.

¹¹c-PD153035 is the earliest for the PET tracer of EGFR inhibitor imaging.But, due to ¹¹only 20 minutes C half-life, and ¹¹c-PD153035 has huge uptake thereby and is not suitable for the PET tracer as EGFR at normal liver.For this reason, explore ¹⁸the synthetic method of F labelling micromolecule quinazoline ditosylate salt EGFR class PET tracer just becomes the focus and emphasis of basis and clinical research.From the selection of precursor, acknowledged is adopts the serve as a mark framework compound of precursor of 4-anilinoquinazoline.Adopt ¹⁸f all adopts multistep method to complete for the labelling of framework compound and its derivant.According to ¹⁸the difference of F labelling 4-anilinoquinazoline derivatives position, is divided into two classes substantially by labeling method.Be marked at 4-anilino-and quinazoline derivant.

First use ¹⁸f labelling anilino-, then will ¹⁸f labelled compound is connected with quinazoline or derivant.Most typical be BonaseraThomas A and Abourbeh Galith report [ ¹⁸f]-ML01 and [ ¹⁸f]-ML04 adopts in this way synthetic.But [ ¹⁸f]-ML01 and [ ¹⁸f]-ML04 still has very high picked-up at liver, and the picked-up in tumor does not reach satisfied effect.Particularly adopt such labeling method generated time generally to need 120 minutes, mark rate is all less than 15%.So this method lacks Clinical practicability.

Labelling quinazoline or derivatives thereof, then connects in aniline or derivatives thereof.The people such as Chen Yurong report employing the method recently.First use [ ¹⁸f] labelling ethyl, then incite somebody to action [ ¹⁸f] 6 groups of-ethyl and quinazoline are connected.And then being connected mark rate 20% left and right (after proofreading and correct) of last synthetic end product with aniline, synthetic total time approaches 120 minutes.The result of author's reports such as this and Kobus K is basically identical.

At present ¹⁸f labelling micromolecule class positron tracer in clinical practice seldom, particularly clinical ¹⁸the positron tracer of F labelling mainly utilizes fluoridizes polyammonium (kryptofix/K ^{+ 18}f ^-) as phase transfer catalyst (phase transfer catalysis, PTC), labeling process relative complex, even if utilize the positron radioactive tracer synthesis system of state-of-the-art full-automation, also wants multistep reaction just can complete ¹⁸f labelling micromolecule quinazoline ditosylate salt EGFR class positron tracer.So not only extend the labelling time (generally needing 90-120 minute), and can reduce mark rate, cause lacking Clinical practicability with these methods.The method that research tumor has the synthetic EGFR class positron tracer of full-automation, the one-step method of high picked-up (high-affinity) becomes molecular image research urgent problem.

Summary of the invention

For the problem of current existence, that one of technical problem to be solved by this invention is to provide is a kind of [ ¹⁸f] labelling EGFR positron tracer;

Two of technical problem to be solved by this invention be to provide a kind of one-step method synthetic [ ¹⁸f] labelling EGFR positron tracer method, the feature such as the method has multipurpose, output is large, efficiency is high, method is stable, generated time is short and cost is low.

In order to reach to design, can meet multipurpose, high yield, stable, efficiently and fast and synthetic cheaply ¹⁸the method of F labelling EGFR positron tracer, the present invention utilizes following key core technology to reach the technical solution of requirement of the present invention in design.These core technologies comprise: design unique precursor; Precursor adopts trifluoromethanesulfonic acid fat as leaving group; 7 at precursor increase by 4 PEG, to improve the water solublity of tracer; Utilization heating reaches heavy dose of synthetic and quick synthetic object; Use HPLC or detached dowel to carry out separation further to shorten the product separation time to tracer; Utilize microwave heating technique to improve combined coefficient; Finally reach full-automatic, one-step method synthetic ¹⁸the object of F labelling micromolecule EGFR class positron tracer.

(1) in precursor (shown in formula I), adopt trifluoromethanesulfonic acid fat synthetic as leaving group one-step method ¹⁸f labelling EGFR positron tracer

Trifluoromethanesulfonic acid is desirable leaving group.7 in the present invention on precursor adopt trifluoromethanesulfonic acid as leaving group, can improve mark rate like this.In addition, at 7 introducing 4 PEG groups (raising hydrophilic) of precursor, and connect trifluoromethanesulfonic acid fat at the end of PEG group; .

(2) 7 at precursor connect 4 PEG, to improve tracer hydrophilic, reduce the uptake ratio of liver, improve tumor uptake rate.Traditional ¹¹the EGFR positron tracer of C labelling has a large amount of dense gathering at liver, has obviously affected its clinical practice.The present invention enters 4 PEG groups at 7 and has obviously reduced its ester dissolubility.

(3) utilize heating to shorten building-up process, to meet the object of the synthetic positron radioactive tracer of clinical heavy dose.

(4) utilize HPLC to carry out separation to product to obtain high specific activity tracer, or adopt detached dowel to carry out separation to reduce synthetic cost to product.

For needing product separation after micromolecule EGFR class positron tracer one-step synthesis, the invention provides HPLC and the two kinds of methods of column isolation technics of adopting.Adopt HPLC obviously to improve the specific activity of product, adopt column isolation technics obviously to reduce synthetic cost.

(5) utilize microwave heating technique to improve combined coefficient

Microwave not only has homogeneous heating, is rapidly heated and reduces the feature of temperature, and microwave heating has obviously improved combined coefficient.

(6) utilize that one-stop synthesis model reaches full-automatic, one-step method synthetic ¹⁸f positron tracer

Object the present invention's special attention in design in order to reach this technology with practicality reaches the synthetic object of full-automatic one-step method.Only have entirely and make operator reduce x radiation x, complete building-up process fast, there is the highly advantage such as repeatability and stability from changing the synthetic utilization of one-step method.For positron radioactive tracer, because the half-life of nucleic is very short, can not complete full-automatic one-step synthesis process, with regard to the problem of the practicality of not knowing where to begin.For this reason, on the TracerLab FX fn chemosynthesis device of our GE company, in the whole world, complete first entirely and synthesize above-mentioned from changing one-step method ¹⁸the positron radioactive tracer of F labelling.

Of the present invention a kind of ¹⁸the quinazoline ditosylate salt EGFR positron tracer of F labelling, is characterized in that described positron tracer has the chemical constitution shown in formula II:

Further, the invention allows for a kind of one-step method synthesizes ¹⁸the method of F labelling quinazoline ditosylate salt EGFR positron tracer, is characterized in that comprising the following steps:

1) accelerator will be come from ¹⁸f ion and water pass to receiving bottle and import in anion-exchange column;

2) utilize strong base-weak acid salt and acetonitrile by described anion-exchange column ¹⁸f ion carries out eluting and is sent to reaction bulb;

3) precursor be dissolved in to acetonitrile, DMSO or DMF and join in described reaction bulb and heat under the protection of noble gas, wherein, the chemical structural formula of described precursor is suc as formula shown in I:

4) reduce temperature, crude product in described reaction bulb is hydrolyzed;

5) target product of step 4) gained solution is carried out to separation, collection.

In method of the present invention, preferred, step 2) in the mixed liquor of strong base-weak acid salt and acetonitrile, add ionic liquid [BMIm] ⁺[OTf] ^-.

In method of the present invention, preferred, described strong base-weak acid salt is K ₂cO ₃, KHCO ₃, Cs ₂cO ₃or a kind of in TBAC.

In method of the present invention, preferred, in step 5), utilize high performance liquid chromatography or purification column or detached dowel to carry out separation, collection to target product.

In method of the present invention, preferred, the mode of described heating is microwave heating or muffle electric furnace heating.

Further, the invention allows for described ¹⁸the quinazoline ditosylate salt EGFR positron tracer of F labelling detects the application in EGF-R ELISA (EGFR) expression reagent in preparation.And

Described ¹⁸the application of the quinazoline ditosylate salt EGFR positron tracer of F labelling in preparation screening micromolecule epidermal growth factor receptor inhibitor reagent.

The utilization that the present invention creates ¹⁸the micromolecule EGFR class positron tracer method of F labelling all has important value for the evaluation of pulmonary carcinoma early diagnosis, lung cancer therapy solution formulation, curative effect.

Be summed up, the present invention compared with prior art has following features:

1, stable: to utilize ¹⁸the micromolecule EGFR class positron tracer full-automation of F labelling, one-step method synthetic method, combined coefficient is high, and stable.The method has obviously overcome that the generated time that multistep synthetic method exists is long, efficiency is low, be not easy the inherent shortcomings such as grasp.

2, meet routine clinical work: routine clinical production ¹⁸f amount between 1-4Ci, just need to improve for this reason from ¹⁸f post eluting ¹⁸the ability of F, strengthens strong base-weak acid salt K ₂cO ₃, Cs ₂cO ₃, KHCO ₃or the concentration of TBAC eluting and volume are to improve ¹⁸f output.This is the highest so far synthetic output.

3, simply, facilitate building-up process: obviously simplified synthesis flow, and set up a brand-new utilization ¹⁸the micromolecule EGFR class positron tracer class new technological process of F labelling.

4,, as prioritization scheme, experimental results show that and adopt ionic liquid [BMIm] ⁺[OTf] ^-as obviously having improved productive rate after auxiliary phase transfer catalyst.

5, multipurpose: synthetic ¹⁸the micromolecule EGFR class positron tracer of F labelling has the clinical value of diagnosis and guiding treatment, particularly for promoting personalized treatment, will play an important role.

Accompanying drawing explanation

Fig. 1 is method flow diagram of the present invention.

Abbreviation annotation:

Boc Di-tert-butyldicarbonate

Dde 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl

DMF N,N-dimethyl formamide

DMSO Dimethylsulfoxide

DMTEAN 1-{6-[(2-(p-toluolslfonyloxy) ethyl) (methyl) amino]-2naphthyl}ethylidene) malononitrile or 2-(1-{6-[(2-hydroxy) ethyl) (methyl) amino]-2naphthyl}ethylidene) malononitrile)

EGFR Epidermal Growth Factor Receptor

[ ¹⁸F]ML04 [ ¹⁸F]-N-{4-[(4,5-Dichloro-2-fluorophenyl)amino]quinazoline-6-yl}-dimethylamine-butylamide

PEG Polyethyleneglycol

TBAC Tetrabutylammonium bicarbonate

Tso- 4-methylbenzenesulfonate

Trt Trityl

Fig. 2 be each cell line with [ ¹⁸f] FH42 hatches the radioactivity measured after the different time and takes in quantity.

The specific embodiment

Below by experiment, also the present invention will be further described in conjunction with the embodiments, it should be understood that these embodiment, only for the object of illustration, never limit the scope of the invention.

Embodiment 1:[ ¹⁸f] synthetic (shown in the formula II) of FH42

Synthesis step:

1, precursor (N-(3-chloro-4-fluorophenyl)-7-(Tso-PEG (4))-6-(3-morpholin-4-ylpropoxy) quinazolin-4-amine, N-(the chloro-4-fluorophenyl of 3-)-7-(p-toluenesulfonyl-Polyethylene Glycol 4)-6-(3-morpholine-4-propoxyl group) quinazoline-4-amine, shown in formula I), it is synthetic that this compound is delivered Jiangsu Hua Yi company limited;

2, will transmit from medical cyclotron ¹⁸f ion and water pass to receiving bottle (1-4Ci);

2, will ¹⁸f ion and water pass to anion-exchange column QMA;

3, utilize 0.15mL K ₂cO ₃(0.9mg)+0.5mL acetonitrile is from QMA post eluting ¹⁸f ion is also sent to reaction bulb, and the mixture that 5mg precursor is dissolved in to 0.5mL DMSO joins reaction bulb; Under the protection of nitrogen or helium, 65 ℃ are heated 3.5 minutes, and at 90 ℃ of temperature, microwave heating is 10 minutes;

4, temperature is cooled to 33 ℃, then adds leacheate to enter reaction bulb; Leacheate is CH ₃oH and 1%Et ₃n aqueous solution (is used H ₃pO ₄regulate pH to 7.4) formulated according to volume ratio 65:35 (v/v).

6, by solution by HPLC(C18 post) carry out separation, purified product.Obtain can for injection [ ¹⁸f] FH42 solution; Also can utilize the detached dowel that WATERS company or other company provide separated [ ¹⁸f] FH42; Combined coefficient is more than 25%, and radiochemical purity is greater than 98%;

Can be entirely from changing synthetic [18F] FH42(N-(3-chloro-4-fluorophenyl)-7-(18F-fluoro-PEG (4))-6-(3-morpholin-4-ylpropoxy) quinazolin-4-amine of one-step method on the TracerLab FX fn chemosynthesis device of above step GE company, N-(the chloro-4-fluorophenyl of 3-) the fluoro-Polyethylene Glycol 4 of-7-(18F-)-6-(3-morpholine-4-propoxyl group) quinazoline-4-amine), its chemical structural formula is suc as formula shown in II.

Possibility:

While 1, utilizing 70W microwave heating, all can shorten 1-2 minute heat time heating time, and combined coefficient can reach 35%, and radio chemistry purity is greater than 98%.

Embodiment 2[ ¹⁸f] shown in FH42(formula II) application in detecting expression of epidermal growth factor receptor level

Experimental technique:

1. four of different EGFR expressions kinds of cell lines are respectively with 5x10 ⁵individual being laid in 12 orifice plates, adherent

24 hours standby, and four kinds of described cell lines are respectively;

The cell line PC9(molecular targeted therapy sensitive cell line of EGFR19 Exon deletion sudden change);

EGFRL858R and T790M mutational cell line H1975(molecular targeted therapy medicine-resistant cell line);

Wild type EGFR cell line H358;

The low express cell of EGFR is H520.

Above cell line is all bought from US mode strain and is collected center (ATCC).

2. contain 18.5kBq[ ¹⁸f] the 0.5ml serum-free medium of FH42 is added among each hole;

[ ¹⁸f] FH42 adds and hatches altogether 15min, and 30min, after 60min and 120min, removes cultivation

Liquid;

4. the adherent cell in each hole rinses once with the cold PBS of 1ml;

5. each hole adds after 200ul pancreatin, at 37 ℃, hatches 5min;

6. each hole digests the cell getting off and moves on in counting vial, in gamma calculating instrument, counts.

Experimental result:

According to result judge different EGFR expression cell line to [ ¹⁸f] the picked-up quantity of FH42, result is as shown in table 1 and Fig. 2.That result shows is of the present invention [ ¹⁸f] FH42 can have combination in various degree from the EGFR in the cell line of different EGFR expressions and state, and the result of study PC9 cell line that showed to express sudden change EGFR to [ ¹⁸f] FH42 uptake ratio is the highest, thereby proof [ ¹⁸f] FH42 is targeting sudden change EGFR, and can arrive by living imaging equipment Inspection, thereby illustrated [ ¹⁸f] FH42 can be for clinical EGFR targeted imaging and treatment curative effect monitoring.

Each cell line of table 1 with [ ¹⁸f] FH42 hatches the radioactivity measured after the different time and takes in quantity (representing to account for the percent (%) of gross activity intake)

The foregoing is only the preferred embodiments of the present invention, is only illustrative for the purpose of the present invention, and nonrestrictive; Those of ordinary skills understand, and in the spirit and scope that limit, can carry out many changes to it in the claims in the present invention, revise, and even equivalence change, but all will fall within the scope of protection of the present invention.

Claims (8)

1. one kind ¹⁸the quinazoline ditosylate salt EGFR positron tracer of F labelling, is characterized in that described positron tracer has the chemical constitution shown in formula II:

2. an one-step method is synthetic ¹⁸the method of F labelling quinazoline ditosylate salt EGFR positron tracer, is characterized in that comprising the following steps:

1) accelerator will be come from ¹⁸f ion and water pass to receiving bottle and import in anion-exchange column;

2) utilize strong base-weak acid salt and acetonitrile by described anion-exchange column ¹⁸f ion carries out eluting and is sent to reaction bulb;

3) precursor be dissolved in to acetonitrile, DMSO or DMF and join in described reaction bulb and heat under the protection of noble gas, wherein, the chemical structural formula of described precursor is suc as formula shown in I:

4) reduce temperature, crude product in described reaction bulb is hydrolyzed;

5) target product of step 4) gained solution is carried out to separation, collection.

3. method according to claim 2, is characterized in that step 2) in the mixed liquor of strong base-weak acid salt and acetonitrile, add ionic liquid [BMIm] ⁺[OTf] ^-.

4. method according to claim 2, is characterized in that: described strong base-weak acid salt is K ₂cO ₃, KHCO ₃, Cs ₂cO ₃or a kind of in TBAC.

5. method according to claim 2, is characterized in that: in step 5), utilize high performance liquid chromatography or purification column or detached dowel to carry out separation, collection to target product.

6. method according to claim 2, is characterized in that: the mode of described heating is microwave heating or muffle electric furnace heating.

7. claimed in claim 1 ¹⁸the quinazoline ditosylate salt EGFR positron tracer of F labelling detects the application in the horizontal reagent of expression of epidermal growth factor receptor in preparation.

8. claimed in claim 1 ¹⁸the application of the quinazoline ditosylate salt EGFR positron tracer of F labelling in preparation screening micromolecule epidermal growth factor receptor inhibitor reagent.

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