CN101723847A - Novel 18F labeled p-nitro benzoyl amino acid compound and preparation method and application thereof - Google Patents
Novel 18F labeled p-nitro benzoyl amino acid compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention designs a novel 18F labeled p-nitro benzoyl amino acid compound, which is characterized by simultaneously having 2-18F-4-nitro-benzoyl structure and an alpha-amino acid structure, and a substituent R positioned on a carboxyl alpha position, wherein the substituent R comprises hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, 2-methylthio-ethyl, carboxyethyl, carboxy-propyl, phenyl and imidazole methyl. Two end structures are directly connected with each other through an amido bond. The compound has a structure formula A. The compound can be synthesized simply and has a high labeling rate. The compound is absorbed for a large amount in tumor tissues and is eliminated slowly, but in normal tissues and blood, the compound is absorbed for a small amount or is eliminated quickly. The compound has a very high tumor/blood specific value and a very high tumor/normal tissue specific value, in particular a very high brain normal tissue specific value, and has a high discrimination degree of tumor and brain background. The invention also relates to the application of the compound as a PET brain tumor imaging agent.
Description
Technical field:
It is novel to the present invention relates to a class
18F mark p-nitrophenyl benzoyl amino acid compound and chemical preparation process thereof and as the application of tumour (especially cerebral tumor) developer of positron emission tomography (PET).
Background technology:
The early diagnosis of tumour is a big focus of current medical science, and positron emission tomography (PET) is subjected to very big attention as a kind of means of more and more popularizing, thereby the breakthrough of the early diagnosis of tumour depends on the exploitation of PET tumor developer.
Radionuclide
18F is suitable as the video picture nucleic of PET because of its good nucleic character very much.
The radiopharmaceuticals of at present most widely used emission positron is
18The F-deoxyglucose (
18F-FDG), the research and the clinical diagnosis of tumour, coronary heart disease and neuropsychiatric disease have been widely used in.But because normal cerebral tissue is bigger to the intake of FDG, also there is higher FDG to absorb in nonneoplastic tissue and the inflammatory cell composition, may causes the false positive results of diagnosing tumor when causing FDG to be used for the brain tumor video picture because there being inflammation.And amino acid in the absorption of normal cerebral tissue seldom, therefore causes extensive 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, though the amino acid derivative of some mark does not participate in proteinic synthetic, 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 might become 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)-L-tyrosine ([
18F] FET), 0-(3-
18F-fluoro propyl group)-L-tyrosine ([
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 tumor uptake height, radioactivity that specificity is good
8F mark p-nitrophenyl benzoyl amino acid compound.
It is characterized in that: an end has 2-fluorine 18-4-oil of mirbane formyl structure; The other end has the a-amino acid structure, has substituent R to be positioned on the alpha site of carboxyl group, is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, benzyl, 2-methylmercaptoethyl, propyloic, carboxylic propyl group, phenyl, imidazoles methyl.Two-end structure directly links to each other by amido linkage.Its structure is suc as formula A:
Formula A
Its preparation mainly is divided into the synthetic and precursor compound of labelled precursor compound
18Two parts of F mark and aftertreatment.Concrete steps are as follows:
One. synthesizing of labelled precursor compound (formula B)
Formula B
Synthetic route is suc as formula shown in the C:
Formula C
1) 2, synthetic (the formula D) of 4-dinitrobenzoic acid
In three-necked flask, with 2,4-dinitrotoluene (DNT) 5.5 grams (0.03mol) are added among pyridine 30ml and the water 50mL, heating at 78-83 ℃, adds potassium permanganate 32 grams (0.202mol) with temperature maintenance in batches, add at 6-8h, the water 10ml potassium permanganate that will be bonded at the prolong inner wall at end pours in the bottle again, continues reaction 3h, treat that potassium permanganate all fades till, suction filtration while hot, with the less water washing, be chilled to room temperature, underpressure distillation, remove pyridine, do not show alkaline to solution, cooling, suction filtration, salt acid for adjusting pH value to 5 with 35%, separating out pale brown look solid is impurity, and suction filtration is removed, re-adjustment pH value to 2, separate out faint yellow solid, water and ethanol get the mixed solvent recrystallization, get faint yellow needle-like crystal, productive rate 31%.
Formula D
2) esterification of amino acid carboxyl protection (formula E)
Amino acid 0.02mol joins among the anhydrous methanol 20mL, after the ice bath cooling, slowly drips SOCl
22.1mL, keep the temperature of reaction system to be no more than 10 ℃ in the dropping process, after being added dropwise to complete back low temperature and keeping being warmed up to room temperature reaction behind the reaction 30min and spend the night, revolve excessive SOCl
2And methyl alcohol, obtain white solid, drying behind the ether thorough washing, and, obtain white solid and be the amino acid methyl ester hydrochloride with the mixed solvent recrystallization of dehydrated alcohol or dehydrated alcohol and anhydrous diethyl ether.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, triethylamine 0.42mL (3mmol) back stirring reaction 5min is heavily steamed in 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 DCC 0.46 gram (2.2mmol), being warming up to room temperature reaction behind the continuation low-temp reaction 0.5h after dropwising spends 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, saturated sodium-chloride water solution washing back anhydrous sodium sulfate drying, revolve and obtain oily matter after desolvating, the silicagel column column chromatography, eluent is (with acetoacetic ester: obtain yellow solid sherwood oil=1: 3), mixed solvent recrystallization with ethyl acetate and sherwood oil gets faint yellow solid, productive rate about 40%.
Formula F
Two. radio-labeling of precursor compound (formula G) and hydrolysis (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 the reaction flask, the anhydrous acetonitrile that in reaction flask, adds 0.5mL, be heated to 100 ℃, constantly feed nitrogen, utilize acetonitrile and water azeotropic water removing, after treating solvent dried up, add the anhydrous acetonitrile of 0.5mL more respectively, repeat twice of this operation, the described precursor compound of 5mg claim 2 is dissolved in anhydrous N, dinethylformamide solution is poured in the reaction flask, is warming up to 125 ℃ rapidly, keeps about this thermotonus 30min, stopped reaction, add about 10mL water reaction system is diluted, by Sep-Pak C18 post, filtrate collection (is not mainly participated in reacting in headpin again
18F
-), and then with 10ml water washing pillar, will (guarantee and will not participate in reaction in filtrate collection to 2 bottle
18F
-Thoroughly drip washing is clean), with nitrogen Sep-Pak C18 post is dried up, with 2ml acetonitrile washing C18 post, in filtrate collection to 3 bottle, obtain
18F mark intermediate product through HPLC (band radioactivity probe) separation and purification, after with nitrogen the acetonitrile in the solution being dried up, with a certain amount of lithium hydroxide hydrolysis, is used the hcl acidifying of a certain amount of 1mol/L again in the mixing solutions of water and methyl alcohol, obtain
18F mark end product, entire reaction course needs 60min approximately.
Formula G
Formula H
The second, the present invention is above-mentioned
18F mark p-nitrophenyl benzoyl amino acid compound is as the application of PET tumor developer.
The present invention has following good characteristic:
1) is used among the present invention carry out
18F labelled precursor compound is synthetic 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, initial picked-up is low or remove very fast in other internal organs, 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 bigger, and imaging results belongs to optimum range.Have experiment to be card:
Make by embodiment
18The acetonitrile solution of F tagged compound dries up acetonitrile with nitrogen, is that 8-10 μ Ci/0.1ml is as injection liquid with physiological saline with the product dilution again.Take out the injection liquid of three parts of 0.1ml, add 9.9ml physiological saline respectively, behind the mixing, from every part, take out 0.1ml respectively again, 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 uses.
Kunming mouse is divided into 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 the injection, 30min, 60min, 120min each is organized the mouse sacrificed by decapitation, with its rapid dissection, get tissue and internal organs such as brain, the heart, liver, lung, kidney, back bone, muscle, small intestine, large intestine, spleen, blood, tumour, weigh after drying, 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.
It is as shown in table 1 that the R base is got the compound experimental result of sec.-propyl:
Table 1
18Bio distribution data in the body of the lotus S180 knurl mouse of F marked product (R is a sec.-propyl) (%ID/g ± SD, n=3)
From table 1 column data as can be seen, the initial intake in the tumour is 1.37%ID/g,, when 30min, kept 41% radioactive activity, when 60min, there is 20% radioactive activity residual.Simultaneously, the initial intake in the brain only is 0.15%ID/g, has 27%, 20% radioactive activity residual when 30min, 60min respectively.The radioactive activity intake ratio of the tumour/brain when 30min, 60min is respectively 10.40,13.30.The peak value of tumour/blood ratio, tumour/meat ratio also appears at 30min, is respectively 2.32 and 2.62.To sum up, this compound has tumors of higher/background area calibration, is fit to tumor imaging.
In addition, the ratio of tumour/brain, tumour/blood, tumour/meat can also maintain higher level up to 60min and be respectively 9.99,1.83 and 1.74, therefore can provide competent time of developing.As shown in table 2:
Table 2
18F marked product (R is a sec.-propyl) is at the intravital T/B ratio of lotus S180 knurl mouse
2.2 compare with present technology, of the present invention
18The F tagged compound has novelty, is embodied in the remarkable advantages of some aspects of biological property, is exemplified below:
2.2.1 with the PET tumor imaging is most widely used clinically at present
18F-FDG compares, and is of the present invention
18The F tagged compound has the advantage of some aspects in the differentiation of tumour and brain healthy tissues.Have experiment to be card:
Undertaken by 2.1 identical implementation methods
18Distribute in the tumor-bearing mice body of F-FDG and test, obtain behind the disposal data
18The tumour of F-FDG/brain ratio is as shown in table 3:
Table 3
18F-FDG is at the intravital tumour of lotus S180 knurl mouse/brain ratio
Contrast table 2 as can be seen, and is of the present invention
18F tagged compound ratio
18The tumour of F-FDG/normal cerebral tissue's discrimination is good.This makes of the present invention
18When carrying out the cerebral tumor video picture, the F tagged compound may obtain ratio
18The higher-quality image of F-FDG.
2.2.2 with the PET tumor developer that has very big application potential at present
18F-FET compares, and is of the present invention
18The F tagged compound also has a clear superiority in the differentiation of tumour and healthy tissues.Have experiment to be card:
Undertaken by 2.1 identical implementation methods
18Distribute in the tumor-bearing mice body of F-FET and test, obtain behind the disposal data
18The tumour of F-FDG/healthy tissues ratio is as shown in table 4:
Table 4
18F-FET is at the intravital T/B ratio of lotus S180 knurl mouse
Contrast table 2 as can be seen, and is of the present invention
18The F tagged compound all is higher than at the every T/B ratio of 30-60min section
18F-FET analog value, particularly tumour/brain ratio is more than 3 times of the latter especially.Though at 60-120min,
18F-FETT/B ratio is stabilized in the 30-60min level even also increases to some extent, but consider the size of whole body distribution speed, normal injection dosage and the characteristic that radiopharmaceuticals is lost by radioactive index decay rule, the best visualization time should be after injection 30-60min, and in this interval, of the present invention
18The every T/B ratio of F tagged compound is right
18F-FET has clear superiority, and this makes of the present invention
18The F tagged compound carries out tumor imaging particularly may obtain ratio during the cerebral tumor video picture
18The higher-quality image of F-FDG.
According to the research to the experiment that distributes in the lotus S180 knurl mouse body, we have further carried out the interior distribution research to lotus lotus neurospongioma mouse body, and result and lotus S180 knurl mouse be intravital to be distributed with many approximation, and it the results are shown in Table 5 and table 6.
Table 5
18Bio distribution data in the body of the lotus neurospongioma mouse of F marked product (R is a sec.-propyl) (%ID/g ± SD, n=3)
Table 6
18F marked product (R is a sec.-propyl) is at the intravital T/B ratio of lotus neurospongioma mouse
Table 7
18Bio distribution data in the body of the lotus neurospongioma of F-FET [glioma (9L)] mouse (%ID/g ± SD, n=4)
Biodistribution?data?of[
18F]ortho-FET([
18F]1)in?rats?bearing?9L?tumor
(Number?of?rats/group；n＝4.Data?represent?as?means±SD).
Can find from the bio distribution of table 5, table 6 and table 7, of the present invention when the 30min left and right sides
18The every T/B ratio of F mark p-nitrophenyl benzoyl amino acid compound is right
18F-FET is with the obvious advantage, proves that further they will be very potential brain tumor imaging agent.
In sum, provided by the present invention
18F mark p-nitrophenyl benzoyl amino acid compound had compared with prior art both had more excellent bio distribution difference degree, had as the tumor developer potentiality of brain tumor imaging agent particularly, had the characteristics that preparation is simple, mark rate is high again.
Embodiment:
Below by embodiment the present invention is more clearly described, but the present invention is not limited to following examples.
Embodiment
According to following steps preparations be that the R base be the compound of sec.-propyl among the formula A, comprise the synthetic and precursor compound of labelled precursor (R gets the compound of sec.-propyl among the formula B)
18F mark, two parts of hydrolysis.
1) labelled precursor (R gets the compound of sec.-propyl among the formula B) is synthetic
1.12, synthetic (the formula H) of 4-dinitrobenzoic acid
In three-necked flask, with 2,4-dinitrotoluene (DNT) 5.5 grams (0.03mol) are added among pyridine 30mL and the water 50mL, heating at 78-83 ℃, adds potassium permanganate 32g (0.202mol) with temperature maintenance in batches, add at 6-8h, the water 10ml potassium permanganate that will be bonded at the prolong inner wall at end pours in the bottle again, continues reaction 3h, treat that potassium permanganate all fades till, suction filtration while hot, with the less water washing, be chilled to room temperature, underpressure distillation, remove pyridine, do not show alkaline to solution, cooling, suction filtration, hydrochloric acid with 35% is regulated pH value to 5, separating out pale brown look solid is impurity, and suction filtration is removed, re-adjustment pH value to 2, separate out faint yellow solid, water and ethanol get the mixed solvent recrystallization, get faint yellow needle-like crystal, productive rate 31%.m.p：177-179℃；IR(KBr，cm
-1)：v?3443，3096，1674，1614，1602，1537，1354。
Formula I
1.23-synthetic (the formula J) of methyl-2-aminobutyric acid methyl ester hydrochloride
3-methyl-2-aminobutyric acid (Xie Ansuan) 0.02mol joins among the anhydrous methanol 20mL, after the ice bath cooling, slowly drips SOCl
22.1mL, keep the temperature of reaction system to be no more than 10 ℃ in the dropping process, after being added dropwise to complete back low temperature and keeping being warmed up to room temperature reaction behind the reaction 30min and spend the night, revolve excessive SOCl
2And methyl alcohol, obtain white solid, drying behind the ether thorough washing, and, obtain white solid and be 3-methyl-2-aminobutyric acid methyl ester hydrochloride with the mixed solvent recrystallization of dehydrated alcohol or dehydrated alcohol and anhydrous diethyl ether.Productive rate 70-80%.m.p：156-158℃；IR(KBr，cm
-1)：v?3432，1740，1265。
Formula J
Synthetic (the formula K) of (1.32-2, the 4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters
After the 3-methyl-2-aminobutyric acid methyl ester hydrochloride 0.504 gram (3mmol) is dissolved in the 20mL methylene dichloride, triethylamine 0.42mL (3mmol) back stirring reaction 5min is heavily steamed in 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 DCC 0.46 gram (2.2mmol), being warming up to room temperature reaction behind the continuation low-temp reaction 0.5h after dropwising spends 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, saturated sodium-chloride water solution washing back anhydrous sodium sulfate drying, revolve and obtain oily matter after desolvating, the silicagel column column chromatography, eluent is (with acetoacetic ester: obtain yellow solid sherwood oil=1: 3), mixed solvent recrystallization with ethyl acetate and sherwood oil gets faint yellow solid 0.25 gram, productive rate 38%.m.p：127-128℃；IR(KBr，cm
-1)：v?3276，3108，2964，1747，1731，1679，1652，1605，1545，1348，1266；
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 K
2) mark of precursor
18F mark (formula L) and hydrolysis (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 the reaction flask, the anhydrous acetonitrile that in reaction flask, adds 0.5mL, be heated to 100 ℃, constantly feed nitrogen, utilize acetonitrile and water azeotropic water removing, after treating solvent dried up, the anhydrous acetonitrile that adds 0.5mL more respectively, repeat twice of this operation, 5mg2-(2, the 4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters is dissolved in anhydrous N, and dinethylformamide solution is poured in the reaction flask, be warming up to 125 ℃ rapidly, keep about this thermotonus 30min, stopped reaction adds about 10mL water reaction system is diluted, by Sep-Pak C18 post, filtrate collection (is not mainly participated in reacting in headpin again
18F
-), and then with 10mL water washing pillar, will (guarantee and will not participate in reaction in filtrate collection to 2 bottle
18F
-Thoroughly drip washing is clean), with nitrogen Sep-Pak C18 post is dried up, with 2mL acetonitrile washing C18 post, in filtrate collection to 3 bottle, obtain 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters, through HPLC (band radioactivity probe) separation and purification (HPLC condition: flow velocity 1mL/min, moving phase is acetonitrile: water=70%: 30%, retention time is 7.3min), after with nitrogen the acetonitrile in the solution being dried up, in the mixing solutions of water and methyl alcohol with a certain amount of lithium hydroxide hydrolysis, use the hcl acidifying of a certain amount of 1mol/L again, obtain 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid, entire reaction course needs 60-80min.HPLC (band radioactivity probe) shows, radiochemicsl purity) 99.5, can directly carry out bio distribution experiment (HPLC condition: flow velocity 1mL/min, moving phase is acetonitrile: water=70%: 30%, retention time are 3.0min).
Formula L
Formula M
Lipid is an important physical and chemical parameter of bioactive compounds, and it is as follows that 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid lipid is measured enforcement:
In centrifuge tube, add 2ml n-Octanol and 1.9mL pH successively and be 7.4 phosphate buffer soln, and radioactive activity is about the 0.1mL aqueous solution of 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid of 8-10 μ Ci, the centrifugal layering 5min in back fully vibrates, get each 0.1mL of organic phase and water respectively in clean tube, measure its radiocounting N respectively, 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 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid is-0.25.
Undue toxicity is checked:
Undertaken by Pharmacopoeia of People's Republic of China described method of version in 2005.10 normal kunming mices (18-20g) tail vein is injected 0.5mL (37MBq) 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid injection liquid (being equivalent to hundreds of times to adult's consumption), observed 48 hours.The mouse growth is normal, and no death and untoward reaction phenomenon take place.Dissect the back and observe, do not see any organ damage.The undue toxicity inspection meets requirements of radiopharmaceuticals..
Claims (7)
- One kind novel 18F mark p-nitrophenyl formamido-acid compounds, it is characterized in that: an end has 2- 18F-4-oil of mirbane formyl structure; The other end has the a-amino acid structure, and substituent R is positioned on the alpha site of carboxyl group, is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, benzyl, 2-methylmercaptoethyl, propyloic, carboxylic propyl group, phenyl, imidazoles methyl.Two-end structure directly links to each other by amido linkage.Structure is suc as formula A:
Formula A - 2. claim 1 is described 18The precursor compound of F mark p-nitrophenyl formamido-acid compounds, it is characterized in that: an end has 2,4-oil of mirbane formyl structure; The other end has a-amino acid methyl esters structure, and substituent R is positioned on the ester group 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 links to each other by amido linkage.Structure is suc as formula B:
Formula B - 3. claim 1 is described 18The preparation method of F mark p-nitrophenyl formamido-acid compounds may further comprise the steps: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 the reaction flask, the anhydrous acetonitrile that in reaction flask, adds 0.5mL, be heated to 100 ℃, constantly feed nitrogen, utilize acetonitrile and water azeotropic water removing, after treating solvent dried up, add the anhydrous acetonitrile of 0.5mL more respectively, repeat this operation twice, the described precursorization of 5mg claim 2 is not participated in reacting 18F -), and then with 10ml water washing pillar, will (guarantee and will not participate in reaction in filtrate collection to 2 bottle 18F -Thoroughly drip washing is clean), with nitrogen Sep-Pak C18 post is dried up, with 2mL acetonitrile washing C18 post, in filtrate collection to 3 bottle, obtain 18The F intermediate product through the HPLC separation and purification, after with nitrogen the acetonitrile in the solution being dried up, with a certain amount of lithium hydroxide hydrolysis, is used the hcl acidifying of a certain amount of 1mol/L again in the mixing solutions of water and methyl alcohol, obtain 18F mark end product.
- 4. claim 3 is described 18The F marking method is characterized in that: 18F -Obtaining of source is with containing 10mg K2.2.2 and 3mg K 2CO 31mL acetonitrile and the flushing of the mixed solution of 0.5mL water medical 18F -The QMA anion column obtains, and uses the acetonitrile azeotropic water removing.
- 5. claim 3 is described 18The F marking method is characterized in that: use DMF as reaction solvent, K2.2.2 is a phase-transfer catalyst.
- 6. claim 3 is described 18The F marking method is characterized in that: the labeled reactant optimum temps is 115-120 ℃, and Best Times is 30 minutes.
- 7. claim 1 is described 18F mark p-nitrophenyl formamido-acid compounds is as the application of positron emission tomography (PET) tumor developer.
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| WO2014045306A2 (en) | 2012-09-21 | 2014-03-27 | Kasina Laila Innova Pharmaceuticals Private Limited | F-18 radiolabeled compounds for diagnosing and monitoring kidney function |
| CN106632439B (en) * | 2016-12-15 | 2018-06-08 | 中南大学湘雅医院 | A kind of Radiolabelling method of novel fluoboric acid class compound |
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| SU1051064A1 (en) * | 1981-09-02 | 1983-10-30 | Предприятие П/Я В-2343 | Sodium omega-(o-iodobenzoylamino) aliphatic carboxylates marked with iodine isotopes as radioactive materials for studying oxidation of fatty acids in the body |
| GB0206750D0 (en) * | 2002-03-22 | 2002-05-01 | Amersham Plc | Radiofluorination methods |
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|---|---|---|---|---|
| WO2014045306A2 (en) | 2012-09-21 | 2014-03-27 | Kasina Laila Innova Pharmaceuticals Private Limited | F-18 radiolabeled compounds for diagnosing and monitoring kidney function |
| JP2015535824A (en) * | 2012-09-21 | 2015-12-17 | カシナ ライラ イノバ ファーマシューティカルズ プライベート リミテッド | F-18 radiolabeled compound for diagnosing and monitoring renal function |
| EP2900629A4 (en) * | 2012-09-21 | 2016-05-18 | Kasina Laila Innova Pharmaceuticals Private Ltd | F-18 radiolabeled compounds for diagnosing and monitoring kidney function |
| AU2013319747B2 (en) * | 2012-09-21 | 2018-02-08 | Kasina Laila Innova Pharmaceuticals Private Limited | F-18 radiolabeled compounds for diagnosing and monitoring kidney function |
| CN106632439B (en) * | 2016-12-15 | 2018-06-08 | 中南大学湘雅医院 | A kind of Radiolabelling method of novel fluoboric acid class compound |
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