CN109942550A - 11EGFR positive electron tracer of C flag and its preparation method and application - Google Patents
11EGFR positive electron tracer of C flag and its preparation method and application Download PDFInfo
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- CN109942550A CN109942550A CN201910299315.3A CN201910299315A CN109942550A CN 109942550 A CN109942550 A CN 109942550A CN 201910299315 A CN201910299315 A CN 201910299315A CN 109942550 A CN109942550 A CN 109942550A
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Abstract
The present invention relates to one kind11EGFR positive electron tracer of C flag and its preparation method and application, belongs to field of pharmaceutical chemistry technology.It should11The EGFR positive electron tracer of C flag is shown in formula I, the tracer can react the physiological and biochemical procedure of clinical application AZD9291 completely in cell tissue, utilize the Detectable effects of positron-emitting radionuclides, react drug metabolic process in tumour cell and tissue, to tumour Mechanism Study, Drug efficacy evaluation and Treatment monitoring have great importance.For positron emission tomography (PET/CT imaging),11C flag AZD9291 is a kind of imaging agent with very strong practical value.
Description
Technical field
The present invention relates to pharmaceutical chemistry and nuclear pharmacy, more particularly to one kind11The EGFR positive electron tracer of C flag and its
Preparation method and application.
Background technique
EGF-R ELISA (epidermal growth factor receptor, EGFR) tyrosine kinase inhibits
Agent (tyrosine kinase inhibitor, TKI) is the research hotspot of targeting cancer therapy drug in recent years.EGFR-TKIs
The mechanism of targeted therapy acts on tumour cell with being such molecule property of can choose, with EGFR tyrosine kinase domain intracellular
In conjunction with, the phosphorylation of tyrosine kinase is prevented or reduces, it is final to realize the proliferation function for inhibiting tumour.
Although EGFR-TKIs targeted therapy has good therapeutic effect, and not all patient is suitable for using the strategy
It is treated.For example, although the patient with EGFR activated mutant can reach the response ratio of EGFR-TKIs targeted drug
70%, but to the tumour of target feminine gender, therapeutic effect is often very poor, or even not as good as cytotoxic chemotherapy agents.Targeted drug
It is expensive, and the treatment of multiple courses for the treatment of must be carried out, burden of patients is larger.Also, patient uses a period of time EGFR-TKIs
Afterwards, often there is drug resistance phenomenon, need replacing other targeted drugs and treated.
Based on the above situation, people are marked drug using positron-emitting radionuclides, utilize positron radioactivity
Nucleic can produce gamma-rays, the Detectable effects (such as PET/CT imaging) for the EGFR-TKIs that can be marked by positron radionuclide,
Clinical drug effect is monitored, the mechanism of action of drug is studied, there is good application value.Especially sent out in positive electron
It penetrates in tomography and is concerned.
Going through at present, it is luxuriant and rich with fragrance for Buddhist nun to list the Ji for having the first generation for the targeted therapy EGFR-TKIs of tumour
(Gefitinib), Tarceva (Erlotinib), Conmana (Icotinib)；The Afatinib of the second generation
(Afatinib), all morals replace Buddhist nun (Vandetanib), reach and can replace Buddhist nun (Dacomitinib)；Third generation EGFR-TKIs has been at present
Or market is gradually released, such as AZD9291, Rociletinib, HM61713, wherein AZD9291 is listed in China.It corresponds to
Marketed drug positive electron tracer has11C-Gefitinib、18F-Gefitinib、11C-Erlotinib、18F-Afatinib etc. is
There are relevant research and report.Other numerous EGFR-TKIs for positron radionuclide label, chemical structure and clinical application
Drug is not identical: or be only analogue, or the chemical structure of drug is changed during label, therefore not
The practical drug effect and metabolic condition of clinical medicine can be directly reacted, this kind of positive electron label has:11C-PD153035、11C-
M03、18F-PEG6-IPQA、18F-ML04、18F-Lapatinib、18F-FEA-Erlotinib etc..
AZD9291, that is, Osimertinib mesylate (domestic goods name: Tai Ruisha), is by Astrazeneca AB, Britain
The third generation epidermal growth factor receptor inhibitor of research and development lists for 2015 in the U.S., and 2017 in Discussion on Chinese Listed.It is a kind of use
In the antineoplastic for the treatment of EGFR T790M mutation positive Locally Advanced or Metastatic Nsclc.Its is significant in efficacy,
Tolerance is preferable, and side effect is easier to be received compared with the first and second generation EGFR-TKIs.To received other EGFR-TKIs treatment and go out
Existing drug resistant patient, Austria is uncommon can to bring new selection for Buddhist nun for such patient, have good clinical value.
Summary of the invention
Based on this, it is necessary in view of the above-mentioned problems, providing one kind11The EGFR positive electron tracer of C flag, the tracer needle
AZD9291 is designed, can be the basic research and clinical research of AZD9291, especially positron emission tomography provides one kind
Investigational agent.
Shown in a kind of Formulas I11The EGFR positive electron tracer or its pharmaceutically acceptable salt of C flag:
Wherein: R1, R2, R3, R4, R5For methyl, and wherein optional at least one is11The methyl of C flag.
It is described in one of the embodiments,11The EGFR positive electron tracer of C flag is selected from shown in Formula II or formula III
Compound:
The invention also discloses above-mentioned11The preparation method of the EGFR positive electron tracer of C flag, comprising the following steps:
S1: it is prepared with cyclotron11CO2；
S2: will be above-mentioned11CO2It is converted into11The methylating reagent of C flag；
S3: S2 step is prepared into gained methylating reagent and precursor compound carries out nucleophilic substitution, is obtained11C flag
EGFR positive electron tracer crude product；
S4: it is obtained after crude product is purified11The EGFR positive electron tracer of C flag.
The precursor compound is selected from formula IV compound represented in one of the embodiments:
Wherein: R6, R7, R8, R9, R10In optionally at least one be leaving group.
The leaving group is selected from one of the embodiments: hydrogen.
Methyl in AZD9291 structure is replaced with leaving group by being designed as of above-mentioned precursor compound,11C-CH3I
Or11Under the attack of C-Methyl triflate (trifluoromethayl sulfonic acid methyl esters) etc., nucleophilic substitution occurs, to make11C-
Methyl replaces the leaving group, obtains11C flag AZD9291.
The precursor compound is selected from Formula V or Formula IV compound represented in one of the embodiments:
The present inventor has found after experimental study, and above-mentioned precursor compound is selected to be reacted, and has reaction condition letter
It is single, the advantage that reaction process is controllable, side reaction is few and yield is high.
It is anti-through core using oxygen and nitrogen mixed gas as target gas in one of the embodiments, in the S1 step
It answers14N (p, α)11C produces to obtain with cyclotron11C-CO2。
It preferably, is 1%O with percentage by volume2And 99%N2Mixed gas is that target gas is reacted.
It is described in one of the embodiments,11The methylating reagent of C flag is11C-CH3I or11C- trifluoromethayl sulfonic acid
Methyl esters；
It is described11C-CH3I's the preparation method comprises the following steps:11C-CO2Under Ni catalysis, with H2It is reacted, reduction generates11C-CH4,
Again will11C-CH4In with I2Reaction generates11C-CH3I；
It is described11C- trifluoromethayl sulfonic acid methyl esters the preparation method comprises the following steps: will11C-CH3I and silver trifluoromethanesulfonate (AgOTf) are anti-
It should generate11C- trifluoromethayl sulfonic acid methyl esters (11C-Methyl triflate)。
Preferably,11C-CO2Under Ni catalysis, in 400 DEG C and H2It is reacted, reduction generates11C-CH4, then will11C-CH4
In 720 DEG C and I2Reaction generates11C-CH3I,11C-CH3I sends out Ying Shengcheng with AgOTf at 200 DEG C11C-Methyl triflate。
In one of the embodiments, in the S3 step, the precursor compound is dissolved in organic solvent, then by first
Base reagent is passed through in organic solvent solution, is carried out nucleophilic substitution, is obtained11The EGFR positive electron tracer of C flag.It can be with
Understand, the organic solvent can be selected from acetone, acetonitrile, dimethyl sulfoxide etc..Reaction obtains at this time11The EGFR positive electron of C flag
Tracer crude product.
In one of the embodiments, in the S4 step, is purified with preparing liquid phase, be bonded with octadecylsilane
Silicagel column is stationary phase, the methanol solution containing 0.2% ammonium hydroxide be mobile phase eluted, collect target chromatographic peak to get.It is above-mentioned
Ammonium hydroxide, that is, commercially available ammonia content is the aqueous solution of 25wt%~28wt%.
The invention also discloses above-mentioned11The EGFR positive electron tracer of C flag is aobvious in positron emission tomography
As the application in drug AZD9291 therapeutic evaluation, Treatment monitoring and mechanism study reagent as in.
Compared with prior art, the invention has the following advantages:
One kind of the invention11The EGFR positive electron tracer of C flag is designed for AZD9291, therefore obtain11C mark
The design feature of AZD9291 has been fully retained in note AZD9291 tracer, with clinical application molecular structure, element composition, configuration,
Conformation is identical.Thus the tracer can react the physiological and biochemical procedure of clinical application AZD9291 completely in cell tissue,
Using the Detectable effects of positron-emitting radionuclides, drug metabolic process in tumour cell and tissue is reacted, to tumour mechanism
Research, Drug efficacy evaluation and Treatment monitoring have great importance.For positron emission tomography,11C mark
Remember that AZD9291 is a kind of imaging agent with very strong practical value.
One kind of the invention11The preparation method of the EGFR positive electron tracer of C flag, before this method uses designed, designed
The preparation of body compound11Positron medicine Fully automated synthesis at present on the market can be used in the positron radioactive tracer of C flag
Device (the TracerLab FX-FC synthesizer of General Corporation), is automatically synthesized by preset control program, avoids grasping
Make personnel and directly contact radionuclide, is conducive to radiation protection.And of the invention preparation method reaction step is few, preparation time
It is short, easy to operate, yield is high, can effectively meet because positron radionuclide half-life short (11C half-life short is 20 minutes) to system
Standby rate request, has good production efficiency and practical application.
It is above-mentioned11The EGFR positive electron tracer of C flag, the clinical drug effect that can be used for AZD9291 are monitored and act on machine
In reason research, there is good application value.
Detailed description of the invention
Fig. 1 is the chromatogram that preparation liquid phase obtains in embodiment 1；
Wherein: A: ultraviolet chromatogram；B: radiochromatogram；
Fig. 2 is in embodiment 211C-AZD9291 and standard items AZD9291 analyzes liquid chromatogram；
Wherein: A:11C-AZD9291 radiochromatogram；B:11The ultraviolet chromatogram of C-AZD9291；C:12C-AZD9291 is purple
Outer chromatogram.
Specific embodiment
To facilitate the understanding of the present invention, a more comprehensive description of the invention is given in the following sections with reference to the relevant attached drawings.In attached drawing
Give presently preferred embodiments of the present invention.But the invention can be realized in many different forms, however it is not limited to this paper institute
The embodiment of description.On the contrary, purpose of providing these embodiments is keeps the understanding to the disclosure more thorough
Comprehensively.
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention
The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.
It is raw materials used in following embodiment, it is commercially available if not otherwise indicated.
Embodiment 1
It is a kind of11C flag EGFR positive electron tracer (11C-AZD9291), it is prepared by the following method to obtain:
S1: being 1%O with percentage by volume2And 99%N2Mixed gas is target gas, through nuclear reaction14N (p, α)11C is used back
Rotation accelerator produces to obtain 200mCi's11C-CO2, will be above-mentioned11C-CO2It is adsorbed inIn molecular sieve, high-purity N is used2Purging removes
Other impurities gas.
By heating molecular sieve, high-purity N is used2It will11C-CO2It carries into synthesizer (the TracerLab FX- of General Corporation
FC module) in.
S2: in the combiner,11C-CO2Under W metal catalysis, in 400 DEG C and H2It is reacted, reduction generates11C-
CH4。11C-CH4In 720 DEG C and I2Reaction generates11C-CH3I,11C-CH3I sends out Ying Shengcheng with AgOTf at 200 DEG C11C-Methyl
triflate。
S3: by precursor AZD7550 (N- (4-methoxy-2- (methyl (2- (methylamino) ethyl) amino)-
5- ((4-- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide) it is dissolved in 1mL
Acetonitrile solution is placed in micro-reaction bottle.It will11C-Methyl triflate is passed through in reaction flask, and 85 DEG C are stirred to react 5 minutes,
It is reacted as follows:
S4: above-mentioned reacting coarse product is purified with preparing liquid phase, is to fix with octadecylsilane chemically bonded silica column
Phase (German Macherey-Nagel company VP 250/10NUCLEOSIL 100-5C18 Nautilus chromatographic column), is contained with volume
Amount is that the methanol of 0.2% ammonium hydroxide (aqueous solution i.e. containing ammonia 25%~28%) is mobile phase, is eluted with flow velocity 4mL/min,
Radioactivity chromatographic peak when collecting 5.5 minutes, as shown in Figure 1,11C-AZD9291。
Embodiment 2
Embodiment 1 is prepared11C-AZD9291 carries out structural identification.
It is identified using analytic type high performance liquid chromatography.
1, testing conditions
Stationary phase: Thermo Synoronis C18 column
Mobile phase: 0.2% ammonium hydroxide methanol: water=90:10 (v:v)；
Flow velocity: 1mL/min；
UV detector Detection wavelength: 254nm；
Gamma activity detector: Bioscan FC-3600.
2, result
Fig. 1 is11C-AZD9291 and standard items AZD9291 high-efficient liquid phase chromatogram, in which: A:11C-AZD9291 radioactivity
Chromatogram；B:11The ultraviolet chromatogram of C-AZD9291；C: standard items12The ultraviolet chromatogram of C-AZD9291.
As the result is shown:11C-AZD9291 retention time is 8.9min, with standard items12C-AZD9291 retention time is consistent.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (10)
1. shown in a kind of Formulas I11The EGFR positive electron tracer or its pharmaceutically acceptable salt of C flag:
Wherein: R1, R2, R3, R4, R5For methyl, and wherein optional at least one is11The methyl of C flag.
2. according to claim 111The EGFR positive electron tracer of C flag, which is characterized in that described11The EGFR of C flag
Positive electron tracer is selected from Formula II or formula III compound represented:
3. of any of claims 1 or 211The preparation method of the EGFR positive electron tracer of C flag, which is characterized in that including with
Lower step:
S1: it is prepared with cyclotron11CO2；
S2: will be above-mentioned11CO2It is converted into11The methylating reagent of C flag；
S3: S2 step is prepared into gained methylating reagent and precursor compound carries out nucleophilic substitution, is obtained11C flag
EGFR positive electron tracer crude product；
S4: it is obtained after crude product is purified11The EGFR positive electron tracer of C flag.
4. according to claim 311The EGFR positive electron tracer preparation method of C flag, which is characterized in that the S3 step
In rapid, the precursor compound is selected from formula IV compound represented:
Wherein: R6, R7, R8, R9, R10In optionally at least one be leaving group.
5. according to claim 411The EGFR positive electron tracer preparation method of C flag, which is characterized in that the S3 step
In rapid, the precursor compound is selected from Formula V or Formula IV compound represented:
6. described in any item according to claim 3-511The EGFR positive electron tracer preparation method of C flag, which is characterized in that
In the S1 step, using oxygen and nitrogen mixed gas as target gas, through nuclear reaction14N (p, α)11C is produced with cyclotron
It obtains11C-CO2。
7. described in any item according to claim 3-511The EGFR positive electron tracer preparation method of C flag, which is characterized in that
It is described11The methylating reagent of C flag is11C-CH3I or11C- trifluoromethayl sulfonic acid methyl esters；
It is described11C-CH3I's the preparation method comprises the following steps:11C-CO2Under Ni catalysis, in 350-450 DEG C and H2It is reacted, it is also primary
At11C-CH4, then will11C-CH4In 700-740 DEG C and I2Reaction generates11C-CH3I；
It is described11C- trifluoromethayl sulfonic acid methyl esters the preparation method comprises the following steps: will11C-CH3I and trifluoromethanesulfonic acid silver reaction generate11C- tri-
Fluoromethane methylmesylate.
8. described in any item according to claim 3-511The EGFR positive electron tracer preparation method of C flag, which is characterized in that
In the S3 step, the precursor compound is dissolved in organic solvent, then methylating reagent is passed through in organic solvent solution,
Nucleophilic substitution is carried out, is obtained11The EGFR positive electron tracer of C flag.
9. described in any item according to claim 3-511The EGFR positive electron tracer preparation method of C flag, which is characterized in that
It in the S4 step, is purified with preparing liquid phase, using octadecylsilane chemically bonded silica column as stationary phase, contains 0.2% ammonium hydroxide
Methanol solution be mobile phase eluted, collect target chromatographic peak to get.
10. of any of claims 1 or 211The EGFR positive electron tracer of C flag is in Positron Emission Computed Tomography
As the application in drug AZD9291 therapeutic evaluation, Treatment monitoring and mechanism study reagent.
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| CN115925687A (en) * | 2022-12-29 | 2023-04-07 | 广东省人民医院 | EGFR (epidermal growth factor receptor) -targeting compound, PET (polyethylene terephthalate) molecular probe and preparation method and application thereof |
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Application publication date: 20190628 |