CN101723846B - Novel 18F labeled p-nitro benzoyl amino acid derivatives, preparation method and application thereof in tumor imaging - Google Patents
Novel 18F labeled p-nitro benzoyl amino acid derivatives, preparation method and application thereof in tumor imaging Download PDFInfo
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Abstract
The invention designs novel 18F labeled p-nitro benzoyl amino acid derivatives. The derivatives are characterized in that one end of the derivatives is provided with 2-fluorine 18-4-nitro benzoyl structure, and the other end of the derivatives is provided with alpha-amino acid derivative structure (derived group R2 is methoxyl group, methylamino group and N,N-dimethylamino group respectively); and substituent R1 is positioned on an alpha site of carbonyl group and is hydrogen, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, benzyl group, 2-methylthio-ethyl group, carboxyethyl group, carboxypropyl group, phenyl or imidazole methyl group. The structures at two ends are directly connected through amido bond. The structure of the derivatives is shown in a formula A. The compounds are simple to synthesize, fast to label, large in the amount of initial absorption and slow to clear in tumor tissue, low in uptake or fast to clear in other normal tissue and blood and high in degree of distinguishing tumor from background. The invention also relates to the application of the compounds serving as a PET brain tumor imaging agent. R2=OMe, HNCH3.
Description
Technical field:
The present invention relates to a kind of novel
18f mark p-nitrophenyl benzoyl amino acid derivatives and chemical preparation process thereof and as the application of the tumor developer of positron emission tomography (PET).
Background technology:
The early diagnosis of tumour is a large focus of current medical science, and positron emission tomography (PET) is subject to very big attention as a kind of more and more universal means, thereby the breakthrough of the early diagnosis of tumour depends on the exploitation of PET tumor developer.
Radionuclide
18f, because of its good nucleic character, is suitable as the video picture nucleic of PET very much.
The radiopharmaceuticals of at present most widely used emission positron is
18the F-deoxyglucose (
18f-FDG), research and the clinical diagnosis of tumour, coronary heart disease and neuropsychiatric disease have been widely used in.But because normal cerebral tissue is larger to the intake of FDG, in nonneoplastic tissue and inflammatory cell composition, also there is higher FDG to absorb, may cause because there being inflammation the false positive results of diagnosing tumor while causing FDG for the brain tumor video picture.And amino acid in the absorption of normal cerebral tissue seldom, therefore cause broad interest.It is that tumor proliferation may cause that the amino acid accumulating level increases as the foundation of tumor developer, to provide protein biosynthetic elementary cell.In addition, although the amino acid derivative of some mark does not participate in the synthetic of protein, as long as but can be transported by the system that transports of tumor tissues, also can be used as developer, therefore some amino acid derivative through radioisotope labeling also likely becomes tumor developer.
At present, have
18the amino acid of F mark is synthesized out, and demonstrates result preferably in biological assessment, as 0-(2-[
18f] fluoro ethyl)-TYR ([
18f] FET), O-(3-
18f-fluoro propyl group)-TYR ([
18f] FPT), shown
18f labeled amino acid derivative is as the potentiality of PET tumor developer.
Summary of the invention:
The first, the invention provides the radioactivity that tumor uptake is high, specificity is good novel
18f mark p-nitrophenyl benzoyl amino acid derivatives, this kind
18the amino acid derivative structure of F mark is suc as formula A:
Formula A
It is characterized in that: an end has 2-fluorine 18-4-oil of mirbane formyl structure; The other end has alpha-amino acid derivatives structure (R
2be respectively methoxyl group, methylamino, N, the N dimethylamine base), substituent R is arranged
1being positioned on carbonyl α position, is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, benzyl, 2-methylmercaptoethyl, propyloic, carboxylic propyl group, phenyl, imidazoles methyl.Two-end structure directly is connected by amido linkage.
Its preparation mainly is divided into the synthetic and precursor compound of labelled precursor compound
18two parts of F mark.
Concrete steps are as follows:
One. synthesizing of labelled precursor compound (formula B)
Formula B
Synthetic route is suc as formula shown in C:
Formula C
1) 2, synthetic (the formula D) of 4-dinitrobenzoic acid
In three-necked flask, by 2, 4-dinitrotoluene (DNT) 5.5 grams (0.03mol) are added in pyridine 30mL and water 50mL, heating, temperature is maintained to 78-83 ℃, add potassium permanganate 32 grams (0.202mol) in batches, at 6-8h, add, the potassium permanganate that water 10mL will be bonded at the prolong inner wall at end again pours in bottle, continue reaction 3h, till treating that potassium permanganate all fades, suction filtration while hot, use a small amount of water washing, be chilled to room temperature, underpressure distillation, remove pyridine, to the not aobvious alkalescence of solution, cooling, suction filtration, salt acid for adjusting pH value to 5 with 35%, separating out the brown color solid is impurity, suction filtration is removed, regulate again pH value to 2, separate out faint yellow solid, water and ethanol obtain the mixed solvent recrystallization, obtain faint yellow needle-like crystal, productive rate 31%.
Formula D
2) esterification of amino acid carboxyl protection (formula E)
Amino acid 0.02mol joins in anhydrous methanol 20mL, after ice bath is cooling, slowly drips SOCl
22.1mL, in the dropping process, keep the temperature of reaction system to be no more than 10 ℃, after being added dropwise to complete rear low temperature and keeping after reaction 30min being warmed up to room temperature reaction and spend the night, revolve excessive SOCl
2and methyl alcohol, obtain white solid, dry after fully washing with ether, and, with the mixed solvent recrystallization of dehydrated alcohol or dehydrated alcohol and anhydrous diethyl ether, obtain white solid and be amino acid methyl ester hydrochloride.Productive rate 70-80%.
Formula E
3) 2, synthetic (the formula F) of 4-dinitrobenzene formyl amino acid formyl amino acid methyl esters
After amino acid methyl ester hydrochloride 3mmol is dissolved in the 20mL methylene dichloride, heavily steam the rear stirring reaction 5min of triethylamine 0.42mL (3mmol) disposable adding, add 2, 4-dinitrobenzoic acid 2mmol and HOBt (1-hydroxy benzo triazole) 0.298 gram (2.2mmol), after reaction mixture is cooled to 0 ℃, drip the dichloromethane solution 5mL of DCC0.46 gram (2.2mmol), dropwise after rear continuation low-temp reaction 0.5h and be warming up to room temperature reaction and spend the night, after TLC shows that reaction finishes, suction filtration is removed the by product DCU of a large amount of white precipitate states of generation, organic phase is with water, saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying after the saturated sodium-chloride water solution washing, obtain oily matter after revolving desolventizing, the silicagel column column chromatography, eluent is (with acetoacetic ester: obtain yellow solid sherwood oil=1:3), obtain faint yellow solid with the mixed solvent recrystallization of ethyl acetate and sherwood oil, productive rate approximately 40%.
Formula F
4) 2, the hydrolysis (formula G) of 4-dinitrobenzoyl amino acid methyl ester
2,4-dinitrobenzoyl amino acid methyl ester 3mmol is dissolved in 20mLTHF, adds the LiOH aqueous solution 6mL of 1M, after TLC shows and to react completely, with 1M hydrochloric acid, adjusts pH to 2 left and right, revolves THF/ water, and dries remaining moisture under infrared etc., obtains faint yellow oily matter.
Formula G
5) 2, synthetic (the formula H) of 4-dinitrobenzoyl amino amides
2, after 4-dinitrobenzene formamido group base acid 3mmol is dissolved in the 20mL methylene dichloride, heavily steam the rear stirring reaction 5min of triethylamine 0.42mL (3mmol) disposable adding, add methylamine hydrochloride/dimethylamine hydrochloride 2mmol and HOBt (1-hydroxy benzo triazole) 0.298 gram (2.2mmol), after reaction mixture is cooled to 0 ℃, drip the dichloromethane solution 5mL of DCC0.46 gram (2.2mmol), dropwise after rear continuation low-temp reaction 0.5h and be warming up to room temperature reaction and spend the night, after TLC shows that reaction finishes, suction filtration is removed the by product DCU of a large amount of white precipitate states of generation, organic phase is with water, saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying after the saturated sodium-chloride water solution washing, obtain oily matter after revolving desolventizing, the silicagel column column chromatography, eluent is (with acetoacetic ester: obtain yellow solid sherwood oil=1:2.5), obtain faint yellow solid with ethyl alcohol recrystallization, productive rate approximately 50%.
Formula H
Two. the radio-labeling of precursor compound (formula H)
18f
-after being caught by anion column QMA, with containing 10mg K2.2.2 and 3mg K
2cO
3the 1mL acetonitrile and the mixed solution of 0.5mL water it is flushed in reaction flask, to the anhydrous acetonitrile that adds 0.5mL in reaction flask, be heated to 100 ℃, constantly pass into nitrogen, utilize acetonitrile and water azeotropic water removing, after solvent is dried up, add respectively again the anhydrous acetonitrile of 0.5mL, repeat twice of this operation, 5mg precursor compound claimed in claim 2 is dissolved in to anhydrous DMSO, solution is poured in reaction flask, be warming up to rapidly 120 ℃, maintain this thermotonus 30min left and right, stopped reaction, add about 10mL water that reaction system is diluted, again by Sep-Pak C18 post, by filtrate collection, in headpin, (be mainly not participate in reaction
18f), and then with 10mL water washing pillar, will in filtrate collection to 2 bottle, (guarantee not participate in reaction
18f
-thoroughly drip washing is clean), with nitrogen, Sep-Pak C18 post is dried up, with 2mL acetonitrile washing C18 post, by filtrate collection to 3 bottle, obtain
18the F marked product, whole reaction process approximately needs 60min.Stand-by after the HPLC purifying.
Formula I
The second, the present invention is above-mentioned
18f mark p-nitrophenyl benzoyl amino acid derivative thing is as the application of PET tumor developer.
The present invention has following good characteristic:
1) in the present invention for carrying out
18f labelled precursor compou nd synthesis is easy, and raw material is cheap and easy to get.Mark total time is short, and effectively the radioactivity loss is few.
2) of the present invention
18the compound of F mark has suitable tumor imaging, particularly the good biological property of cerebral tumor video picture.Mainly contain following some:
2.1 compound of the present invention clearance rate in blood, muscle tissue and brain is very fast, higher initial picked-up is arranged in tumour and remove relatively slow, initially absorb low in other internal organs or remove very fast, thereby can be after injection the short period reach period of the high ratio of tumour/background, especially between half an hour and one hour, the ratio of tumour and related tissue is larger, and imaging results belongs to optimum range.Experiment is arranged for card:
By embodiment, make
18the acetonitrile solution of F tagged compound, dry up acetonitrile with nitrogen, then using the product dilution, be that 8-10 μ Ci/0.1mL is as injection liquid with physiological saline.Take out the injection liquid of three parts of 0.1mL, add respectively 9.9mL physiological saline, after mixing, take out again respectively 0.1mL from every part, as standardized solution, measure its radiocounting in the time of the radiocounting of each tissue of mouse to be determined and internal organs, averaging is that 1%ID is used.
Kunming mouse is divided into to five groups at random, 3 every group.From tail vein injection
18the injection liquid 0.1mL of F marked product (8-10 μ Ci), respectively at 5min, 15min after injection, 30min, 60min, 120min, each is organized to the mouse sacrificed by decapitation, by its rapid dissection, get tissue and the internal organs such as brain, the heart, liver, lung, kidney, back bone, muscle, small intestine, large intestine, spleen, blood, tumour, after drying, weigh, and measure its radiocounting separately, and calculating the radioactive uptake %ID/g of its each tissue and internal organs, three groups of panel datas are got in each experiment.
In embodiment, compound 6a experimental result is as shown in table 1:
Table 1
18bio distribution data (%ID/g ± SD, n=3) in the body of the S-180-bearing mice of F marked product (compound 6a in embodiment)
From table 1 column data, can find out, the initial intake in tumour is very high is 2.78%ID/g,, retained the radioactive activity more than 60% when 30min, when 60min, there is the radioactive activity more than 30% residual.Simultaneously, the initial intake in brain is 0.99%ID/g, removes comparatively fast, only has respectively 27%, 17% radioactive activity when 30min, 60min.The radioactive activity intake ratio of tumour/brain when 30min, 60min is all over 5.The peak value of tumour/blood ratio, tumour/meat ratio also appears at the 30min-60min interval, is respectively 2.91 and 2.41 (table 2) during 30min.To sum up, this compound has higher tumour/background area calibration, is applicable to tumor imaging.
In addition, the ratio of tumour/brain, tumour/blood, tumour/meat, until 60min can also maintain higher level is respectively, therefore can provide sufficient time of developing.As shown in table 2:
Table 2
18the T/B ratio of F marked product (compound 6a in embodiment) in the S-180-bearing mice body
2.2 with current technology, compare, of the present invention
18the F tagged compound has novelty, is embodied in the obvious advantage of some aspects of biological property, is exemplified below:
With the PET tumor developer that there is at present very large application potential
18f-FET compares, of the present invention
18the F tagged compound, in the differentiation of tumour and healthy tissues, has a clear superiority in.Experiment is arranged for card:
By 2.1 identical implementation methods, undertaken
18distribute and test in the tumor-bearing mice body of F-FET, experimental result is as shown in table 3:
Table 3
18bio distribution data (%ID/g ± SD, n=3) in the body of the S-180-bearing mice of F-FET
Contrast table 1 and table 3 can be found out, of the present invention
18f is for compound (compound 6a in embodiment) ratio
18the initial brain capture of F-FET is suitable, but tumor uptake compound of the present invention is obviously higher, is about 1.5 times of the latter, and compound of the present invention has the clearance rate of healthy tissues faster, of the present invention
18f can obtain higher tumour/background radiation ratio for compound (compound 6a in embodiment) through the short period.
After sorting table 3 data, obtain
18the tumour of F-FET/healthy tissues ratio is as shown in table 4:
Table 4
18the T/B ratio of F-FET in the S-180-bearing mice body
Contrast table 2 and table 4 can be found out, of the present invention
18f tagged compound (compound 6a in embodiment) the every T/B ratio of 30-60min section all higher than
18f-FET corresponding T/B value, particularly tumour/brain peak value is 2 times of the latter especially.Although at 60-120min,
18f-FETT/B ratio is stabilized in the 30-60min level even also to be increased to some extent, but consider the size of whole body distribution speed, normal injection dosage and the characteristic that radiopharmaceuticals is lost by the radioactive index Decay Law, the best visualization time should be after injection 30-60min, and in this interval, of the present invention
18the every T/B ratio pair of F tagged compound
18f-FET has clear superiority, and this makes of the present invention
18the F tagged compound carries out tumor imaging particularly may be compared during the cerebral tumor video picture
18the higher-quality image of F-FET.
2.3 because the experiment that distributes in the S-180-bearing mice body demonstrates of the present invention
18f mark m-nitro benzoyl amino acids derivative is the bio distribution performance preferably; we have tentatively carried out the interior distribution research to lotus lotus neurospongioma Mice Body; be distributed with many approximation in result and S-180-bearing mice body; its tumour/background ratio variation tendency and S180 knurl are similar; although the corresponding ratio of 5-15min is less; increase comparatively fast, very approaching at 30-60min, tumour/brain, tumour/blood, tumour/meat reach peak value 6.70,3.62 and 2.34 separately at 30-60min respectively.As shown in table 5:
Table 5
18the T/B ratio of F marked product (compound 6a in embodiment) in lotus neurospongioma Mice Body
Further performance test is carried out.
In sum, provided by the present invention
18f mark m-nitro benzoyl amino acids derivative compared with prior art, had both had more excellent bio distribution difference degree, had again the characteristics that preparation is simple, mark rate is high, had as the tumor developer potentiality of brain tumor imaging agent particularly.
Embodiment:
Below by embodiment, can make the present invention be more clearly described, but the present invention is not limited to following examples.
Embodiment:
That according to following steps, prepare is R in formula A
1base is sec.-propyl, R
2the compound that base is methoxyl group, comprise labelled precursor (R in formula B
1base is sec.-propyl, R
2the compound that base is methoxyl group) synthetic and precursor compound
18two parts of F mark.
1) labelled precursor (R in formula B
1base is sec.-propyl, R
2the synthesizing compound that base is methoxyl group)
1.12, synthetic (the formula J) of 4-dinitrobenzoic acid
In three-necked flask, by 2, 4-dinitrotoluene (DNT) 5.5 grams (0.03mol) are added in pyridine 30mL and water 50mL, heating, temperature is maintained to 78-83 ℃, add potassium permanganate 32g (0.202mol) in batches, at 6-8h, add, the potassium permanganate that water 10mL will be bonded at the prolong inner wall at end again pours in bottle, continue reaction 3h, till treating that potassium permanganate all fades, suction filtration while hot, use a small amount of water washing, be chilled to room temperature, underpressure distillation, remove pyridine, to the not aobvious alkalescence of solution, cooling, suction filtration, salt acid for adjusting pH value to 5 with 35%, separating out the brown color solid is impurity, suction filtration is removed, regulate again pH value to 2, separate out faint yellow solid, water and ethanol obtain the mixed solvent recrystallization, obtain faint yellow needle-like crystal, productive rate 31%.m.p：177-179℃；IR(KBr，cm
-1)：v3443，3096，1674，1614，1602，1537，1354。
Formula J
1.2 synthetic (the formula K) of 3-methyl-2-amino methyl-butyrate hydrochloride
3-methyl-2-amino butyric acid (α-amino-isovaleric acid) 0.02mol joins in anhydrous methanol 20mL, after ice bath is cooling, slowly drips SOCl
22.1mL, in the dropping process, keep the temperature of reaction system to be no more than 10 ℃, after being added dropwise to complete rear low temperature and keeping after reaction 30min being warmed up to room temperature reaction and spend the night, revolve excessive SOCl
2and methyl alcohol, obtain white solid, dry after fully washing with ether, and, with the mixed solvent recrystallization of dehydrated alcohol or dehydrated alcohol and anhydrous diethyl ether, obtain white solid and be 3-methyl-2-amino methyl-butyrate hydrochloride.Productive rate 70-80%.m.p：156-158℃；IR(KBr，cm
-1)：v3432，1740，1265。
Formula K
Synthetic (the formula L) of (1.32-2,4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters
After 3-methyl-2-amino methyl-butyrate hydrochloride 0.504 gram (3mmol) is dissolved in the 20mL methylene dichloride, heavily steam the rear stirring reaction 5min of triethylamine 0.42mL (3mmol) disposable adding, add 2, 4-dinitrobenzoic acid 0.424 gram (2mmol) and HOBt (1-hydroxy benzo triazole) 0.298 gram (2.2mmol), after reaction mixture is cooled to 0 ℃, drip the dichloromethane solution 5mL of DCC0.46 gram (2.2mmol), dropwise after rear continuation low-temp reaction 0.5h and be warming up to room temperature reaction and spend the night, after TLC shows that reaction finishes, suction filtration is removed a large amount of white precipitate DCU of generation, organic phase is with water, saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying after the saturated sodium-chloride water solution washing, obtain oily matter after revolving desolventizing, the silicagel column column chromatography, eluent is (with acetoacetic ester: obtain yellow solid sherwood oil=1:3), obtain faint yellow solid 0.25 gram with the mixed solvent recrystallization of ethyl acetate and sherwood oil, productive rate 38%.m.p：127-128℃；IR(KBr，cm
-1)：v3276，3108，2964，1747，1731，1679，1652，1605，1545，1348，1266；
1HNMR(500MHz，CDCl
3)；δ8.95(s，1H，Ar-H)，8.56(d，2H，J＝8.3Hz，Ar-H)，7.80(d，2H，J＝8.3Hz，Ar-H)，6.54(m，1H，NH)，4.81(m，1H，NHCHCOOCH
3)，3.83(s，3H，OCH
3)，2.37(m，1H，CH(CH
3)
2)，1.05(m，6H，CH(CH
3)
2)；
13CNMR(125MHz，CDCl
3)：δ171.83，164.11，148.49，146.91，137.62，130.31，128.08，120.19，57.90，52.54，33.91，31.43，18.83，17.80。
Formula L
2) mark of precursor
18f mark (formula M)
18f
-after being caught by anion column QMA, with containing 10mg K2.2.2 and 3mg K
2cO
3the 1mL acetonitrile and the mixed solution of 0.5mL water it is flushed in reaction flask, to the anhydrous acetonitrile that adds 0.5mL in reaction flask, be heated to 100 ℃, constantly pass into nitrogen, utilize acetonitrile and water azeotropic water removing, after solvent is dried up, add respectively again the anhydrous acetonitrile of 0.5mL, repeat twice of this operation, by 5mg2-(2, the 4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters is dissolved in anhydrous DMSO, solution is poured in reaction flask, be warming up to rapidly 120 ℃, maintain this thermotonus 30min left and right, stopped reaction, add about 10mL water that reaction system is diluted, again by Sep-Pak C18 post, by filtrate collection, in headpin, (be mainly not participate in reaction
18f), and then with 10mL water washing pillar, will in filtrate collection to 2 bottle, (guarantee not participate in reaction
18f
-thoroughly drip washing is clean), with nitrogen, Sep-Pak C18 post is dried up, with 2mL acetonitrile washing C18 post, by in filtrate collection to 3 bottle, obtain 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters, carry out separation and purification (HPLC condition: flow velocity 1mL/min, moving phase is acetonitrile: water=70%:30%, retention time is 7.3min) with HPLC (band radio-metric probe).
Formula M
Lipid is an important physical and chemical parameter of bioactive compounds, and 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters lipid is measured and is implemented as follows:
Add successively the phosphate buffer soln that 2mL n-Octanol and 1.9mL pH are 7.4 in centrifuge tube, and radioactive activity is about the 0.1mL aqueous solution of 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters of 8-10 μ Ci, centrifugal layering 5min after fully vibrating, get respectively each 0.1mL of organic phase and water in clean tube, measure respectively its radiocounting N, calculation of distribution coefficient P=N
have/ N
water, repeat to average after this operation 3 times, P is taken the logarithm, logP is this
18the lipid of F marked product.
The lipid that records as stated above 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters is 0.58.
Abnormal toxicity tests:
By the Pharmacopoeia of People's Republic of China described method of version in 2005, undertaken.10 normal kunming mices (18-20g) tail vein is injected to 0.5mL (37MBq) 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters injection liquid (being equivalent to hundreds of times to adult's consumption), observe 48 hours.Mouse growth is normal, without death and untoward reaction phenomenon, occurs.Observe after dissecting, have no any organ damage.Abnormal toxicity tests meets requirements of radiopharmaceuticals..
Claims (8)
1. one kind
18f mark p-nitrophenyl benzoyl amino acid derivatives, it is characterized in that: an end has 2-
18f-4-oil of mirbane formyl structure; The other end has the alpha-amino acid derivatives structure, and two-end structure directly is connected by amido linkage, and structural formula is suc as formula A:
R
1＝H，Me，Pr
R
2＝OMe，HNCH
3，N(CH
3)
3
Formula A.
2. one kind
18f mark p-nitrophenyl benzoyl amino acid derivatives, it is characterized in that: an end has 2-
18f-4-oil of mirbane formyl structure; The other end has the alpha-amino acid derivatives structure, and two-end structure directly is connected by amido linkage, and structural formula is suc as formula B:
R
1＝i-Pr
R
2＝OMe，
Formula B.
3. claim 1 is described
18the precursor compound of F mark p-nitrophenyl benzoyl amino acid derivatives is characterized in that: an end has 2,4-dinitrobenzene formyl structure; The other end has the alpha-amino acid derivatives structure, and two-end structure directly is connected by amido linkage, and structural formula is suc as formula C:
R
1＝Me，Pr
R
2＝HNCH
3，N(CH
3)
3
Formula C.
4. claim 1,2 described
18the preparation method of F mark p-nitrophenyl formamido group acid derivative comprises the following steps:
18f
-after being caught by anion column QMA, with containing 10mg K
2.2.2with 3mg K
2cO
3the 1mL acetonitrile and the mixed solution of 0.5mL water it is rinsed to reaction flask, to the anhydrous acetonitrile that adds 0.5mL in reaction flask, be heated to 100 ℃, constantly pass into nitrogen, utilize acetonitrile and water azeotropic water removing, after solution is dried up, the anhydrous acetonitrile that adds again 0.5mL, repeat twice of this operation, 5mg labelled precursor compound is dissolved in to anhydrous DMSO, solution is poured in reaction flask, be warming up to rapidly 120 ℃, maintain this thermotonus 30min, stopped reaction, add about 10mL water that reaction system is diluted, again by Sep-Pak C18 post, by filtrate collection in headpin, and then with 10mL water washing pillar, by in filtrate collection to 2 bottle, with nitrogen, Sep-Pak C18 post is dried up, with 2mL acetonitrile washing C18 post, by in filtrate collection to 3 bottle, obtain
18the F marked product, the HPLC separation and purification, dry up the acetonitrile in solution with nitrogen, obtains
18f target-marking product.
5. claim 4 is described
18the marking method of F tagged compound is characterized in that:
18f
-to obtain be with containing 10mg K
2.2.2and 3mgK
2cO
31mL acetonitrile and the mixed solution of 0.5mL water rinse medical
18the F-QMA anion column obtains, and uses the acetonitrile azeotropic water removing.
6. claim 4 is described
18the marking method of F tagged compound is characterized in that: use DMSO as reaction solution, K
2.2.2for phase-transfer catalyst.
7. claim 4 is described
18the marking method of F tagged compound is characterized in that: the labeled reactant optimum temps is 120 ℃, and Best Times is 30 minutes.
8. claim 1,2 described
18f mark p-nitrophenyl benzoyl amino acid derivatives is as the application for the preparation of the positron emission fault tumor developer.
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| CN104326937B (en) * | 2014-09-03 | 2016-08-24 | 天津市肿瘤研究所 | Antitumoral compounds and medical usage thereof |
| CN107556236B (en) * | 2017-08-25 | 2020-01-21 | 华中科技大学同济医学院附属协和医院 | Isotope-substituted targeted melanoma positron imaging agent and preparation method and application thereof |
| CN107501283B (en) * | 2017-09-13 | 2020-06-02 | 北京师范大学 | Preparation of substituted arylmethyl hetero-substituted anilino ethylene glycol ether cycloquinazoline and application of tumor treatment drug |
| CN113501789B (en) * | 2021-06-16 | 2023-03-31 | 首都医科大学脑重大疾病研究中心(北京脑重大疾病研究院) | Nitroimidazole derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1410129A (en) * | 2002-11-20 | 2003-04-16 | 南方医院 | Tumour positive electron developer S-(18 fluro-n-alkyl)-L-methionine and its preparation method |
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| CN1410129A (en) * | 2002-11-20 | 2003-04-16 | 南方医院 | Tumour positive electron developer S-(18 fluro-n-alkyl)-L-methionine and its preparation method |
Non-Patent Citations (2)
| Title |
|---|
| EVGENY A. SEREBRYAKOV ET AL..SELECTIVE SYNTHESISI OF 1,2-BENZISOTHIAZOL-3-ONE-1-OXIDE NITRO DERIVTIVES.《SYNTHESIS》.2001,(第11期),1659-1664. * |
| EVGENYA.SEREBRYAKOVETAL..SELECTIVESYNTHESISIOF1 2-BENZISOTHIAZOL-3-ONE-1-OXIDE NITRO DERIVTIVES.《SYNTHESIS》.2001 |
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