CN109400605A - A kind of P2X7 receptor developer and preparation method thereof - Google Patents
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Abstract
The invention discloses a kind of P2X7 receptor developers of F-18 label, are compound shown in Formulas I18F- { (the chloro- 3- trifluorophenyl of 2-) (1- (pyrimidine -2-base) -6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) ketone }, P2X7 receptor developer of the invention can be used for antidiastole lung inflammation and tumour:
Description
Technical field
The invention belongs to radiodiagnosis drug fields, and in particular to a kind of P2X7 receptor developer of F-18 label and its
Preparation method.
Background technique
Nucleotide P2X receptor is the ion channel of atriphos (ATP) gate, is cloned in 7 in mammals
Hypotype (P2X1~7).Wherein P2X7 receptor is made of 595 amino acid, includes aminoterminal (N-terminal), c-terminus (C-terminal), born of the same parents
The transmembrane protein twice of internal area and conservative extracellular ring, N-terminal and C-terminal are formed on cell membrane by three homologous Asias intracellular
The polymer of type composition.Its N-terminal sequential structure is highly conserved, and C-terminal is its difference then with other P2X receptor subtypes without homology
In the mark of other hypotypes of family and the molecular basis of its unique physiological function.
Studies have shown that P2X7 receptor is because generating important function in the pathologic process of multiple system inflammation diseases, therefore
It is concerned in recent years.Its distribution in vivo is extremely wide, has table in tissues such as kidney, lung, bone, spleen, liver, pancreas, muscle
It reaches, is in addition expressed in macrophage and monocyte more.In the of short duration stimulation of low concentration ligand, P2X7 receptor may participate in inflammation
The pathogenic process of disease property disease: activation calcinerin/T cell activation nuclear factor (NFAT) leads to proinflammatory factor such as epoxy
The synthesis of synthase -2 (COX-2) etc..
The inflammation and inflammation damnification of lung tissue are to be related to the pathology of numerous inflammatory mediator wide participations such as IL-1 β and IL-18
Physiology course.The release of the inflammatory factors such as the receptor-mediated IL-1 β and IL-18 of P2X7, may participate in sarcoidosis, pulmonary tuberculosis, hyperoxia
Concentration causes the inflammation in respiratory system such as lung tissue inflammation and acute lung injury, air flue Chronic Obstructive Pulmonary Disease, bronchial asthma
The pathogenic process of disease.Document shows that P2X7 gene is located at chromosome 12q24, which includes multiple and Respiratory ft tive resistance
Relevant gene, this also indicates that P2X7 receptor may be related to inflammation in respiratory system disease.
Positron emission computerized tomography (Positron Emission Tomography, PET) is at present in In vivo detection
Tumour and the optimal images of disease development equipment are able to achieve the high-resolution image to cell metabolism and function, from point
The sub horizontal physiology to human body, noninvasive, the three-dimensional, dynamic studies of biochemical process progress.PET, which is checked, depends on spectrum or special
Property targeting pet imaging agent target organ metabolism, absorb.18F-FDG is the most common imaging agent of current PET, but
It is18F-FDG is poor in the presence of specificity, occurs false positive or false negative sometimes, cannot distinguish between the disadvantages of tumour and inflammation.Therefore18F-FDG is a kind of nonspecific imaging agent, about tumour and inflammation antidiastole and research also need to research and develop it is novel,
The imaging agent of specificity.
Radiolabeled P2X7 acceptor inhibitor is becoming one as the research of P2X7 receptor tracer in recent years
New hot spot prepares the research of pet imaging agent especially with C-11 and F-18 label.11C-GSK1482160 is due to right
P2X7 receptor has relatively good affinity and selectivity, and can penetrate blood-brain barrier, has research to attempt to be applied to brain inflammation
Disease imaging.In addition, also11C-JNJ54173717 and11Also some researches show that them can enter in animal experiments by C-SMW139
Animal pattern brain is in conjunction with P2X7 receptor.Have about 110 because of it compared to the C-11 that half-life period only has 20 minutes or so, F-18
The half-life period of minute and higher resolution ratio, the application in PET medicament research and development is more extensive, thus has and utilize PET/CT
Non-invasively to distinguish the research and development potentiality of inflammation and tumour.
Summary of the invention
In order to overcome, the pet imaging agent specificity of the prior art is poor, false positive or false negative, Bu Nengxian easily occurs
The defect for distinguishing tumour and inflammation is write, provides the P2X7 receptor developer of a kind of high specificity, long half time, inventor is to P2X7
Receptor antagonist carries out systematic research and screening, has designed and synthesized a kind of P2X7 receptor indicator molecule of brand new,
It can be used as PET molecular probe and is used as P2X7 receptor developer.Specifically, the present invention includes following technical scheme.
A kind of P2X7 receptor developer of F-18 label, is compound shown in Formulas I18F- { (the chloro- 3- trifluorophenyl of 2-)
(1- (pyrimidine -2-base) -6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) ketone }, i.e.,18F-PTTP:
Above compound is prepared another object of the present invention is to provide a kind of18The method of F-PTTP, i.e.18F-PTTP's
Labeling method, mainly comprising the steps that makes compound shown in Formula II (the chloro- 3- iodophenyl of 2-) (1- (pyrimidine -2-base) -6,7-
Dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) ketone and chlorine methyl difluoroacetate ClCF2CO2Me, tetramethyl
Base ethylenediamine TMEDA, CuI, [18F]KF/K222Reaction, obtains compound shown in Formulas I18F-PTTP:
Wherein compound shown in Formula II is18The precursor of F-PTTP, also referred to herein simply as pre-PTTP or precursor.Therefore above-mentioned
Method is substantially the method that P2X7 receptor antagonist PTTP is marked using F-18.
More specifically, compound shown in Formulas I in the above method18F-PTTP can be synthesized by following step:
Make chlorine methyl difluoroacetate ClCF2CO2Me, tetramethylethylenediamine TMEDA, compound is dissolved in anhydrous DMF shown in Formula II
In, form B liquid；
Make CuI and dissolved [18F]KF/K222Acetonitrile MeCN solution mixing, in N2It heats under gas shielded by solvent acetonitrile
It removes, and by the H in system2O is all removed, and forms A liquid；
React B liquid about 20 minutes or so in about 150 DEG C with A liquid, reaction system is cooled to room temperature, and a small amount of water quenching is added to go out
Reaction；Mixture is separated through HPLC, obtains compound shown in Formulas I.
Preferably, it is above-mentioned for dissolve [18F]KF/K222Solvent acetonitrile and solvent for compound shown in dissolution type II
DMF is using preceding by (super dry) processing of absolute.Because the presence of minor amount of water will be greatly reduced product yield.
In one embodiment, above-mentioned HPLC separation condition are as follows: mobile phase H2O:MeCN=65:35,0.1% trifluoro
Acetic acid TFA.Precursor pre-PTTP and product when HPLC is separated18The appearance of F-PTTP is adjacent, but precursor is first eluted out.Product is put
Change purity (radiochemical purity) and is greater than 97%.
In one embodiment, compound shown in above-mentioned Formula II can be synthesized by following step: make formula III shownization
Close the iodo- chlorobenzoyl chloride of the chloro- 3- of compound 2- and triethylamine TEA (i.e. Et shown in object, formula IV3N) in solvents tetrahydrofurane (THF)
Reaction, obtains compound shown in Formula II:
More specifically, reaction solution stirs 30 minutes at 20 DEG C in the above method, H is added2O quenching reaction, uses dichloro
Methane DCM extraction is concentrated after organic phase is dry, obtains crude product.Crude product is chromatographed through column, obtains compound shown in Formula II.
In the above method, column chromatography condition is leacheate DCM:MeOH=1:0~10:1.
Another object of the present invention is to provide a kind of drug as PET imaging agent, and it includes compounds18F-PTTP conduct
Active pharmaceutical ingredient (API).
Said medicine can be used for identifying lung inflammation and tumour.
Compound shown in Formulas I of the invention18F-PTTP is a kind of metabolic stability, good with P2X7 receptor binding and synthesize
Simple and fast P2X7 receptor indicator molecule, it is possible to as pet imaging agent by PET/CT come non-invasively antidiastole
Inflammation and tumour.
Detailed description of the invention
Fig. 1 is18The blood concentration-time curve of F-PTTP；
Fig. 2 is18The combination saturation curve of F-PTTP and P2X7 receptor；
Fig. 3 is18F-PTTP is injected into 8 weeks male model mouses and carries out PET/CT dynamic imaging 1 hour PET/CT image.Figure
As display, work as injection18After F-PTTP, the inflammation part of mouse can be detected obviously at 5 minutes (min)18F-PTTP's deposits
?.
Specific embodiment
The present invention is further explained by the following examples.It should be understood that these embodiments are only used for illustrating purpose, and
It is not limitation of the present invention.Those skilled in the art conceive the various changes or adjustment made to it according to the present invention, should all
It falls within the scope of protection of the present invention.
Additive amount, content and the concentration of many kinds of substance is referred to herein, wherein the percentage composition, except special instruction
Outside, all refer to mass percentage.
It in the embodiments herein, is illustrated if do not made for reaction temperature or operation temperature, the temperature is logical
Often refer to room temperature (15-30 DEG C).
The present invention is simply reacted by single stepping, and being marked using F-18 can be divided in conjunction with P2X7 receptor-specific
Son.In view of containing-a CF3 in the chemical structure of the P2X7 receptor antagonist PTTP reported, we are to precursor pre-
PTTP, which is introduced into the reaction of-CF3, above-mentioned purpose can be realized with flag F -18.Aryl iodide, can under the catalysis of CuI
It reacts to obtain the corresponding trifluoromethyl aromatic compound of F-18 label with difluorocarbene and F-18 fluorine ion, finally obtains target
Molecule18F-PTTP。
The present invention marks P2X7 receptor antagonist with F-18, forms radioactively labelled substance, can be used as the internal P2X7 of detection by
The radiological imaging agent of body, living animal experiment show difference according to P2X7 receptor expression quantity in inflammation and tumour, can be at
Material gain non-invasively distinguishes inflammation and tumour with PET/CT.
Embodiment
Reagent: reactant and catalyst used in the embodiment of the present invention are that chemistry is pure, be can be used directly or according to need
To pass through simple purification；Organic solvent etc. is that analysis is pure, is directly used.Reagent is purchased from Chinese Medicine (group) Shanghai chemistry
Reagent Company.
Predominantly detect instrument:
Nuclear Magnetic Resonance model: (Bruker 400MHz)
Mass spectrograph (LC-MS (LCMS)), model: (Shimadzu, LCMS-2020).
The synthesis of 1 precursor pre-PTTP of embodiment
To the iodo- benzoyl chlorination of the chloro- 3- of compound 2- shown in compound shown in formula III (500mg, 2.47mmol) and formula IV
It closes and TEA (i.e. Et is added in object (743.25mg, 2.47mmol) THF solution (10mL)3N) (499.88mg, 4.94mmol), mixing
Object stirs 0.5h at 20 DEG C, and LCMS detection reaction terminates, generates target product (pre-PTTP).It is added into reaction mixture
H2O (100mL) quenching reaction, DCM extract (50mL × 3).Organic phase is dry after merging, is concentrated to get crude product, crude product warp
After column chromatographs (DCM:MeOH=1:0~10:1) separation, obtaining white solid is compound products shown in Formula II
(510.00mg), yield 44%.The hydrogen spectrum and mass spectrometric data of precursor pre-PTTP is as follows:
1H NMR:ES6134-17-P1A(CDCl3,400MHz)δ8.89-8.85(dd,J1=4.8Hz, J2=13.6Hz,
2H),7.96-7.92(m,1H),7.43-7.39(m,1H),7.30-7.27(m,1H),7.07-7.04(m,1H),5.17-5.02
(m,1H),4.60-4.46(m,1H),4.23-4.07(m,1H),3.60-3.56(m,1H),3.44-3.43(m,1H),3.41-
3.21(m,1H).
MS(ESI):467.0([M+H]+, 100%).
2 compound of embodiment18The synthesis of F-PTTP
A bottles, B bottles are divided to prepare respectively reaction raw materials before synthetic reaction.
B bottles: chlorine methyl difluoroacetate ClCF2CO2Me (6 μ L, 57 μm of ol), tetramethylethylenediamine TMEDA (10 μ L, 63 μ
Mol), precursor pre-PTTP (7mg), super dry DMF (500 μ L, it is ensured that absolute).
A bottles: it is previously added CuI (15mg, 78 μm of ol) and stirrer, then will dissolve [18F]KF/K222MeCN solution
It is added in bottle, in N2Heating removes solvent under gas shielded, super dry MeCN is added, in N2Heating removes solvent under gas shielded,
So in triplicate, by the H in system2O is all removed, and then the solution in B bottles is added in A bottles, and 150 DEG C are reacted 20 points
Clock.
Reaction system is cooled to room temperature, and adds a small amount of water quenching reaction.Mixture is through HPLC (Agilent, 1260Infinit)
Separate (mobile phase H2O:MeCN=65:35,0.1%TFA), precursor is adjacent with product when HPLC is separated, but precursor first elutes
Out.Product radiochemicsl purity is greater than 97%.Since first step reaction, reaction time 40min, total putting yield is about
5% (decay correction).
Embodiment 318The vitro stability of F-PTTP is tested
It is resulting with embodiment 2 respectively18About 10 μ Ci of F-PTTP is respectively placed in 100 μ L, 0.9% physiological saline and 0.1%
In BSA, stored at 37 DEG C after mixing well.It is sampled respectively in 1h, 2h, 4h and 6h, its purity is examined to become on analytic type HPLC
Change.It the results are shown in Table 1.
Table 1, compound18HPLC testing result of the F-PTTP in physiological saline and BSA
The result shows that compound18F-PTTP is highly stable, only a small amount of in 6h to decompose.
Embodiment 418The pharmacokinetic studies of F-PTTP
It is resulting with embodiment 2 respectively18About 200 μ Ci tail vein injection of F-PTTP is into 58 weeks male nude mouse bodies, respectively
Dock when 1,3,5,10,20,30,45,60,90 and 120min after injection, takes about 5 μ L sample of blood with capillary, be placed in meter
Number bottom of the tube, surveys its counting, draws its blood concentration-time curve.As a result as shown in Figure 1.
Embodiment 518F-PTTP and P2X7 receptor binding assays
Embodiment 2 is resulting18The RAW264.7 macrophage in 24 orifice plates is added in F-PTTP (the every hole 37kBq/0.5ml)
(every hole about 1 × 106It is a) in, after cell is incubated for 15,30,60 and 120 minutes respectively at 37 DEG C, respectively collect supernatant and
Cell suspending liquid carries out gamma counter counting, obtains time gradient saturation curve.By concentration range 25n M-300nM's18F-
PTTP is added by concentration gradient containing in macrophage orifice plate same as described above, collects supernatant respectively after being incubated for 2h and cell is outstanding
Liquid carries out gamma counter counting, using the cold compound group of PTTP for being added 100 μM as non-specific binding, obtains combining saturation bent
Line.As a result as shown in Figure 2.By curve it is found that Kd=12.37 ± 2.204nM, Bmax=13.54 × 10-15Mol/cell, table
It is bright18The combination stability of F-PTTP and P2X7 receptor is stronger.
Embodiment 618The biodistribution experiments of F-PTTP
It is resulting with embodiment 2 respectively18About 100 μ Ci tail vein injection of F-PTTP into 8 weeks male nude mouse 30, anaesthetize shape
Under state, takes and win eyeball and take blood mode, respectively put to death 5 nude mices in 5,10,15,30,60 and 90min respectively, collection includes
Blood, brain, the heart, lung, liver,spleen,kidney, stomach, small intestine, large intestine, bone, muscle and parathyroid tissue carry out weighing and radiocounting.Into
After row decay correction, compared with the counting of each tissue sample is counted with standard, it is as a result expressed as %ID/g (every gram of sample tissue
Radioactivity account for the percentage composition of injection dosage), as each internal organs pair18The relative absorption value of F-PTTP.It the results are shown in Table 2.
Table 1, compound18The bio distribution testing result of F-PTTP
Embodiment 718The dynamic animal scanning of F-PTTP is tested
It is resulting with embodiment 2 respectively18About 100 μ Ci/ of F-PTTP only passes through tail vein injection and enters 3 groups of 8 weeks male model mouses
(right hind of nude mice shifts to an earlier date five Nikkei turpentine oil processings, is in inflammatory conditions), it is dynamic to carry out PET/CT under continuous narcosis state
State images 1 hour.As a result as shown in figure 3, research discovery is in PET/CT image, imaging agent18F-PTTP can be concentrated on right hind
Inflammation musculature in.Image is shown, works as injection18After F-PTTP, the inflammation part of mouse can be obvious at 5 minutes (min)
It detects18The presence of F-PTTP.
Above-mentioned experiment shows the compound that the present invention synthesizes18F-PTTP stability is strong, can specifically combine P2X7 by
Body, and combination stability is stronger can be used as and detect the radiological imaging agent of internal P2X7 receptor and non-invasively distinguish for PET/CT
Other inflammation and tumour are18The scientific research and clinical application of F-PTTP lays the foundation.
Claims (10)
1. a kind of P2X7 receptor developer of F-18 label, is compound shown in Formulas I18F- { (the chloro- 3- trifluorophenyl of 2-) (1-
(pyrimidine -2-base) -6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) ketone }, i.e.,18F-PTTP:
2. a kind of prepare compound described in claim 118The method of F-PTTP, comprising the following steps:
Make compound shown in Formula II (the chloro- 3- iodophenyl of 2-) (1- (pyrimidine -2-base) -6,7- dihydro -1H- [1,2,3] triazol
[4,5-c] pyridine -5 (4H)-yl) ketone and chlorine methyl difluoroacetate ClCF2CO2Me, tetramethylethylenediamine TMEDA, CuI,
[18F]KF/K222Reaction, obtains compound shown in Formulas I18F-PTTP:
3. according to the method described in claim 2, it is characterized in that, compound shown in Formulas I18F-PTTP is closed by following step
At:
Make chlorine methyl difluoroacetate ClCF2CO2Me, tetramethylethylenediamine TMEDA, compound is dissolved in anhydrous DMF shown in Formula II,
Form B liquid；
Make CuI and dissolved [18F]KF/K222Acetonitrile MeCN solution mixing, in N2Heating removes solvent acetonitrile under gas shielded,
And by the H in system2O is all removed, and forms A liquid；
React B liquid 20 minutes in 150 DEG C with A liquid, reaction system is cooled to room temperature, and adds a small amount of water quenching reaction；Mixture warp
HPLC separation, obtains compound shown in Formulas I.
4. according to the method described in claim 3, it is characterized in that, for dissolve [18F]KF/K222Solvent acetonitrile and for molten
The solvent DMF for solving compound shown in Formula II is handled using preceding by absolute.
5. according to the method described in claim 3, it is characterized in that, the HPLC separation condition are as follows: mobile phase H2O:MeCN=
65:35,0.1% trifluoroacetic acid TFA.
6. according to the method described in claim 2, it is characterized in that, compound shown in Formula II is synthesized by following step:
Make the iodo- chlorobenzoyl chloride of the chloro- 3- of compound 2- shown in compound, formula IV shown in formula III and triethylamine TEA in solvent tetrahydro furan
It mutters and reacts in THF, obtain compound shown in Formula II:
7. according to the method described in claim 6, H is added it is characterized in that, reaction solution stirs 30 minutes at 20 DEG C2O quenches
Reaction of going out is concentrated, crude product is chromatographed through column, obtains compound shown in Formula II with methylene chloride DCM extraction after organic phase is dry.
8. the method according to the description of claim 7 is characterized in that column chromatography condition is leacheate DCM:MeOH=1:0~10:
1。
9. a kind of drug as PET imaging agent, it includes the compounds described in claim 118F-PTTP is as active drug
Object ingredient.
10. drug according to claim 6, which is characterized in that for identifying lung inflammation and tumour.
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Cited By (7)
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| CN113861190A (en) * | 2021-09-08 | 2021-12-31 | 复旦大学附属中山医院 | PET (polyethylene terephthalate) imaging agent targeting P2X7 receptor, and preparation method, composition and application thereof |
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| CN114685389B (en) * | 2022-03-04 | 2023-10-27 | 复旦大学附属中山医院 | PET imaging agent based on Michael addition, preparation method and application |
| CN114671817A (en) * | 2022-04-20 | 2022-06-28 | 四川大学华西医院 | 5-CF3-1,2, 3-triazole compound and preparation method and application thereof |
| CN114671862A (en) * | 2022-04-20 | 2022-06-28 | 四川大学华西医院 | A kind of18F-labeled radioactive tracer and preparation method thereof |
| CN114671817B (en) * | 2022-04-20 | 2022-11-18 | 四川大学华西医院 | 5-CF 3 -1,2, 3-triazole compound and preparation method and application thereof |
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