CN101723848B - Novel 18F labeled m-nitro benzoyl amino acids, preparation method and application thereof in tumor imaging - Google Patents

Novel 18F labeled m-nitro benzoyl amino acids, preparation method and application thereof in tumor imaging Download PDF

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CN101723848B
CN101723848B CN200810167557.9A CN200810167557A CN101723848B CN 101723848 B CN101723848 B CN 101723848B CN 200810167557 A CN200810167557 A CN 200810167557A CN 101723848 B CN101723848 B CN 101723848B
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齐传民
乔雅丽
张淑婷
贺勇
刘航
李桂霞
许荆立
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Beijing Normal University
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Abstract

The invention relates to novel 18F labeled m-nitro benzoyl amino acid compounds, which is characterized in that the compounds simultaneously have a 3-fluorine 18-5-nitro benzoyl structure and an alpha-amino acid structure, and have substituent R1 which is positioned on an alpha site of carboxyl 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 compounds is shown in a formula A. The compounds are simple to synthesize, high in uptake and slow to clear in tumor tissue, low in uptake or fast to clear in normal tissue and blood, high in the ratio of tumor to blood and the ratio of tumor to normal tissue and particularly high in the ratio of tumor to brain, so the compounds are high in degree of distinguishing tumor from brain background and long in stable time. The invention also relates to the application of the compounds serving as a PET tumor imaging agent.

Description

Novel 18f mark m-nitro benzoyl amino acids, preparation method and the application in tumor imaging
Technical field:
The present invention relates to a kind of novel 18f mark m-nitro benzoyl amino acids compounds and 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 transmitting positron is 18f-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, while causing FDG for brain tumor video picture, may cause because there is inflammation the false positive results of diagnosing tumor.And amino acid in the absorption of normal cerebral tissue seldom, therefore cause broad interest.It as tumor developer according to being that tumor proliferation may cause that amino acid accumulating level increases, 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 in biological assessment, demonstrates good result, 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 that a kind of tumor uptake is high, the good radioactivity of specificity 18f mark m-nitro benzoyl amino acids compounds.
This kind 18f for the structure of compound suc as formula A:
Formula A
It is characterized in that: one end has 3-fluorine 18-5-oil of mirbane formyl structure; The other end has a-amino acid structure, there is substituent R to be positioned in alpha site of carboxyl group, the other end has a-amino acid methyl esters structure, substituent R is positioned on 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 is directly connected by amido linkage.
Its preparation is mainly 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)
Figure G2008101675579D00021
Formula B
Synthetic route is suc as formula shown in C:
Formula C
1) esterification of amino acid carboxyl protection (formula D)
Amino acid 0.02mol joins in anhydrous methanol 20mL, after ice bath is cooling, slowly drips SOCl 22.1mL, keeps the temperature of reaction system to be no more than 10 ℃ in dropping process, after being added dropwise to complete rear low temperature and keeping being warmed up to room temperature reaction after reaction 30min and spend the night, revolve excessive SOCl 2and methyl alcohol, obtain white solid, after fully washing with ether, dry, 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 D
2) 3, synthetic (the formula E) of 5-dinitrobenzene formyl amino acid formyl amino acid methyl esters
After amino acid methyl ester hydrochloride 3mmol is dissolved in 20mL methylene dichloride, heavily steam the rear stirring reaction 5min of triethylamine 0.42mL (3mmol) disposable adding, add 3, 5-dinitrobenzoic acid 0.424 gram of (2mmol) and HOBt (1-hydroxy benzo triazole) 0.298 gram (2.2mmol), reaction mixture is cooled to after 0 ℃, drip the dichloromethane solution 5mL of DCC0.46 gram (2.2mmol), dropwise and be warming up to room temperature reaction after rear continuation low-temp reaction 0.5h and spend the night, after TLC shows that reaction finishes, suction filtration is removed a large amount of white precipitate shape by product DCU of generation, organic phase is with water, saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying after saturated sodium-chloride water solution washing, after revolving desolventizing, obtain oily matter, silicagel column column chromatography, eluent (ethyl acetate: obtain light yellow or white solid sherwood oil=1:3), productive rate approximately 60%.
Figure G2008101675579D00032
Formula E
Two. the radio-labeling of precursor compound and aftertreatment:
1) radio-labeling of precursor compound (formula F)
18after F is caught by anion column QMA, with containing 10mg K2.2.2 and 3mg K 2cO 31mL acetonitrile and the mixed solution of 0.5mL water be 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, precursor compound shown in 5mg formula B is dissolved in to anhydrous N, dinethylformamide solution is poured in reaction flask, be warming up to rapidly 125 ℃, 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 18the thorough drip washing of F-is clean), with nitrogen, Sep-Pak C18 post is dried up, with 2mL acetonitrile washing C18 post, by filtrate collection to 3 bottle, obtain 18f marked product 3, whole reaction process approximately needs 30min.
Figure G2008101675579D00041
Formula F
2) hydrolysis of mark intermediate product (formula G)
Marker 3, through HPLC (band radio-metric probe) separation and purification, after the acetonitrile in solution being dried up with nitrogen, is hydrolyzed with a certain amount of lithium hydroxide, then uses the hcl acidifying of a certain amount of 1mol/L in the mixing solutions of water and methyl alcohol, obtains 18f is for product 4, and this process approximately needs 30min, adds the preparation time of marker 3, needs altogether about 60min.
Figure G2008101675579D00042
Formula G
The second, the present invention is above-mentioned 18the amino acid derivative of F mark 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 radioactivity loss is few.
2) of the present invention 18the compound of F mark has the particularly good biological property of cerebral tumor video picture of suitable tumor imaging.Mainly contain following some:
2.1 compounds of the present invention clearance rate in blood, muscle tissue and brain is very fast, in tumour, there is higher initial picked-up and remove relatively slow, in other internal organs initial picked-up low or remove very fast, thereby can be after injection the short period reach period of the high ratio of tumour/background.There is experiment for card:
By embodiment 1, make 18the acetonitrile solution of F tagged compound, dries up acetonitrile with nitrogen, then using product dilution, is that 8-10 μ Ci/0.1mL is as injection liquid with physiological saline.The injection liquid that takes out three parts of 0.1mL, adds respectively 9.9mL physiological saline, after mixing, from every part, take out again respectively 0.1mL, as standardized solution, in the time of the radiocounting of each tissue of mouse to be determined and internal organs, measure its radiocounting, averaging is that 1%ID is used.
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 injection, 30min, 60min, 120min, each is organized to mouse sacrificed by decapitation, it is dissected rapidly, 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.
The compound experimental result that in formula A, R is sec.-propyl 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 that in formula A, R is sec.-propyl)
Figure G2008101675579D00051
Table 1 data are through arranging, obtain this compound each time item tumour/healthy tissues unit mass radioactive activity ratio, as shown in table 2:
Table 2 18the T/B ratio of F marked product (compound that in formula A, R is sec.-propyl) in S-180-bearing mice body
Figure G2008101675579D00052
As can be seen from Table 2, the T/B ratio 5-30 of this compound divides rapid rising, all reaches peak value more stable within 30-60 divides after 30 minutes, slow decreasing afterwards, and therefore, this compound divides the most applicable video picture during this period of time at 30-60.
2.2 compare with current technology, of the present invention 18f tagged compound has novelty, is embodied in the obvious advantage of some aspects of biological property, is exemplified below:
With the PET tumor developer at present with very large application potential 18f-FET compares, of the present invention 18f tagged compound, in the differentiation of tumour and healthy tissues, has a clear superiority in.There is experiment for card:
By 2.1 identical implementation methods, undertaken 18in the S-180-bearing mice body of F-FET, distribute and test, 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
Figure G2008101675579D00061
Contrast table 1 and table 3 can be found out, of the present invention 18f is for compound (compound 4a in embodiment) ratio 18f-FET has the clearance rate of obviously high healthy tissues, of the present invention 18f can obtain higher tumour/background radiation ratio for compound (compound 4a in embodiment) through the short period.
After sorting table 3 data, obtain 18tumour/healthy tissues ratio of F-FET is as shown in table 4:
Table 4 18the T/B ratio of F-FET in S-180-bearing mice body
Figure G2008101675579D00062
Contrast table 2 and table 4 can be found out, of the present invention 18f tagged compound (compound 4a in embodiment) the every T/B ratio of 30-60min section all higher than 18the corresponding T/B value of F-FET, particularly tumour/brain peak value be 4 times of the latter especially.Although at 60-120min, 18f-FETT/B ratio is stabilized in 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 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 18f tagged compound carries out tumor imaging particularly may be compared during cerebral tumor video picture 18the higher-quality image of F-FET.
2.3 because the experiment that distributes in S-180-bearing mice body demonstrates of the present invention 18the good bio distribution performance of F mark m-nitro benzoyl amino acids derivative; we have tentatively carried out the interior distribution research to lotus lotus neurospongioma Mice Body; result and S-180-bearing mice tumour/background ratio variation tendency are similar; although the corresponding ratio of 5-15min is less; but 30-60min is very approaching; tumour/brain, tumour/blood, tumour/meat reach peak value 8.77,1.43 and 2.60 separately at 30-60min respectively, and after comparatively stable.As shown in table 5:
Table 5 18the T/B ratio of F marked product (compound that in formula A, R is sec.-propyl) in lotus neurotic glioma Mice Body
To sum up, 18F tagged compound provided by the present invention compared with prior art, had both had good biological property, had again the simple feature of preparation.Have as the tumor developer potentiality of brain tumor imaging agent particularly.
Embodiment:
By embodiment, can make the present invention be more clearly described below, but the present invention is not limited to following examples.
Embodiment:
What according to following steps, prepare is the compound that in formula A, R base is sec.-propyl, comprises the synthetic and precursor compound of labelled precursor (in formula B, R gets the compound of sec.-propyl) 18f mark, two parts of hydrolysis.
1) labelled precursor (in formula B, R gets the compound of sec.-propyl) is synthetic
Synthetic (the formula H) of 1.13-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, keeps the temperature of reaction system to be no more than 10 ℃ in dropping process, after being added dropwise to complete rear low temperature and keeping being warmed up to room temperature reaction after reaction 30min and spend the night, revolve excessive SOCl 2and methyl alcohol, obtain white solid, after fully washing with ether, dry, 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。
Figure G2008101675579D00072
Formula H
Synthetic (the formula I) of 1.22-(3,5-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters
After 3-methyl-2-amino methyl-butyrate hydrochloride 0.504 gram (3mmol) is dissolved in 20mL methylene dichloride, heavily steam the rear stirring reaction 5min of triethylamine 0.42mL (3mmol) disposable adding, add 3, 5-dinitrobenzoic acid 0.424 gram of (2mmol) and HOBt (1-hydroxy benzo triazole) 0.298 gram (2.2mmol), reaction mixture is cooled to after 0 ℃, drip the dichloromethane solution 5mL of DCC0.46 gram (2.2mmol), dropwise and be warming up to room temperature reaction after rear continuation low-temp reaction 0.5h and spend the night, after TLC shows that reaction finishes, suction filtration is removed a large amount of white precipitate shape by product DCU of generation, organic phase is with water, saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying after saturated sodium-chloride water solution washing, after revolving desolventizing, obtain oily matter, silicagel column column chromatography, eluent is (with acetoacetic ester: obtain faint yellow solid sherwood oil=1:3), productive rate 62%.m.p：129-131℃；IR(KBr，cm -1)：v3491，3260，3114，2958，2874，1752，1664，1645，1541，1343，1215；? 1HNMR(400MHz，CDCl 3)：δ9.14(m，1H，Ar-H)，8.90(m，2H，Ar-H)，4.83(m，1H，CHCOOCH 3)，3.84(s，3H，OCH 3)，2.36(m，IH，CH(CH 3) 2)，1.04(d，6H，J＝3.6Hz，CH(CH 3) 2)； 13CNMR(100MHz，?CDCl 3)：δ172.66，162.67，148.69，137.28，127.26，121.32，58.19，52.73，31.53，19.04，18.03。
Figure G2008101675579D00081
Formula I
2) mark of precursor 18f mark (formula J) and hydrolysis (formula K)
18f -after being caught by anion column QMA, with containing 10mg K2.2.2 and 3mg K 2cO 31mL acetonitrile and the mixed solution of 0.5mL water be 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-(3, 5-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters is dissolved in anhydrous N, dinethylformamide solution is poured in reaction flask, be warming up to rapidly 125 ℃, 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 intermediate product 2-(3-fluorine 18-5-dinitrobenzene) benzoylamino-3 Methylbutanoic acid methyl esters (3a), through HPLC (band radio-metric probe) separation and purification (HPLC condition: flow velocity 1mL/min, moving phase is acetonitrile: water=70%:30%, retention time is 7.9min), after the acetonitrile in solution being dried up with nitrogen, in the mixing solutions of water and methyl alcohol, with a certain amount of lithium hydroxide, be hydrolyzed, use again the hcl acidifying of a certain amount of 1mol/L, obtain 18f marked product 2-(3-fluorine 18-5-dinitrobenzene) benzoylamino-3 Methylbutanoic acid (4a), whole reaction process needs 60-80min.Through HPLC (band radio-metric probe), measure (HPLC condition: flow velocity 1mL/min, moving phase is acetonitrile: water=70%:30%, retention time is 3.0min), hydrolysis reaction is very complete, and radiochemical purity reaches bio distribution requirement of experiment.
Figure G2008101675579D00082
Formula J
Figure G2008101675579D00091
Formula K
Lipid is an important physical and chemical parameter of bioactive compounds, and 2-(3-fluorine 18-5-dinitrobenzene) benzoylamino-3 Methylbutanoic acid lipid is measured and is implemented as follows:
In centrifuge tube, add successively the phosphate buffer soln that 2mL n-Octanol and 1.9mL pH are 7.4, and radioactive activity is about the 0.1mL aqueous solution of 2-(3-fluorine 18-5-dinitrobenzene) benzoylamino-3 Methylbutanoic acid 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-(3-fluorine 18-5-dinitrobenzene) benzoylamino-3 Methylbutanoic acid is-0.53.
Abnormal toxicity test:
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-(3-fluorine 18-5-dinitrobenzene) benzoylamino-3 Methylbutanoic acid 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.After dissecting, observe, have no any organ damage.Abnormal toxicity tests meets requirements of radiopharmaceuticals..

Claims (7)

1. one kind 18f mark m-nitro benzoyl amino acids analog derivative, is characterized in that: one end has 3- 18f-5-oil of mirbane formyl structure; The other end has a-amino acid structure, and two-end structure is directly connected by amido linkage, and structural formula is as schemed A:
Figure FSB0000117561560000011
Figure A.
2. one kind 18f mark m-nitro benzoyl amino acids analog derivative, is characterized in that: one end has 3- 18f-5-oil of mirbane formyl structure; The other end has a-amino acid structure, and two-end structure is directly connected by amido linkage, and structural formula is as schemed B:
Figure FSB0000117561560000012
Figure B.
3. claimed in claim 1 18the marking method of F mark m-nitro formamido group acid compounds, comprises the following steps:
18f -after being caught by anion column QMA, with containing 10mg K 2.2.2with 3mg K 2cO 31mL acetonitrile and the mixed solution of 0.5mL water rinsed to reaction flask, to the anhydrous acetonitrile that adds 0.5mL in reaction flask, be heated to 100C, 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 is schemed to precursor compound shown in C and be dissolved in anhydrous N, dinethylformamide solution is poured in reaction flask, be warming up to rapidly 125 ℃, 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 lotion C18 post, by in filtrate collection to 3 bottle, obtain 18f mark intermediate product through HPLC separation and purification, after the acetonitrile in solution being dried up with nitrogen, is hydrolyzed with a certain amount of lithium hydroxide, then uses the hcl acidifying of a certain amount of 1mol/L in the mixing solutions of water and methyl alcohol, obtains 18f mark end product, by 18f mark intermediate product arrives 18the process of F mark end product approximately needs 30 minutes
Figure C.
4. claimed in claim 2 18the marking method of F mark m-nitro formamido group acid compounds, comprises the following steps:
18f -after being caught by anion column QMA, with containing 10mg K 2.2.2with 3mg K 2cO 31mL acetonitrile and the mixed solution of 0.5mL water 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 is schemed to precursor compound shown in D and be dissolved in anhydrous N, dinethylformamide solution is poured in reaction flask, be warming up to rapidly 125 ℃, 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 lotion C18 post, by in filtrate collection to 3 bottle, obtain 18f mark intermediate product through HPLC separation and purification, after the acetonitrile in solution being dried up with nitrogen, is hydrolyzed with a certain amount of lithium hydroxide, then uses the hcl acidifying of a certain amount of 1mol/L in the mixing solutions of water and methyl alcohol, obtains 18f mark end product, by 18f mark intermediate product arrives 18the process of F mark end product approximately needs 30 minutes
Figure FSB0000117561560000022
Figure D.
5. described in claim 3 or 4 18f marking method, is characterized in that: 18f -obtaining of source is with containing 10mg K 2.2.2with 3mg K 2cO 31mL acetonitrile and the mixed solution of 0.5mL water rinse medical 18f-QMA anion column obtains, and uses acetonitrile azeotropic water removing.
6. described in claim 3 or 4 18f marking method, is characterized in that: use DMF as reaction solvent, K 2.2.2for phase-transfer catalyst.
7. described in claim 1 or 2 18f mark m-nitro benzoyl amino acids compounds is as the application for the preparation of positron emission fault tumor developer.
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