CN101723850A - Novel 18F labeled aromatic amino acids, preparation method and application thereof in tumor imaging - Google Patents
Novel 18F labeled aromatic amino acids, preparation method and application thereof in tumor imaging Download PDFInfo
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Abstract
The invention discloses novel radioactive 18F labeled aromatic amino acids, which is characterized in that one end of the acids is provided with F substituted alkoxy benzoyl structure, and the other end of the derivatives is provided with alpha-amino acid structure; substituent R1 is positioned on an alpha site of carboxyl group and is phenyl group, benzyl group or 3-indole methyl group; R2 is methoxyl group; and n is a number between 1 and 5. The substituent R1 is positioned on an alpha site of carboxyl group and is phenyl group, benzyl group or 3-indole methyl group; the R2 is methoxyl group; and the n is a number between 1 and 5. Compounds improve fat solubility. Different amino acid structures are introduced into the structure, and F in the structure is 19F and 18F. The substituent R1 is positioned on an alpha site of carboxyl group and is phenyl group, benzyl group or 3-indole methyl group; the R2 is methoxyl group; and the n is a number between 1 and 5. The substituent R1 is positioned on an alpha site of carboxyl group and is phenyl group, benzyl group or 3-indole methyl group; the R2 is methoxyl group; and the n is a number between 1 and 5. Compared with the prior art, the 18F labeled amino acid derivatives provided by the invention have better discrimination degree of biological distribution, the potential of being used as a tumor imaging agent (particularly a brain tumor imaging agent), as well as the characteristics of simple preparation and high labeling rate.
Description
Technical field
It is novel to the present invention relates to a class
18F mark aromatic amino acid and preparation method thereof and as the application of positron emission tomography (PET) molecular probe of tumour (particularly cerebral tumor).
Background technology
Positron emission fault (Positron emission tomography) PET video picture is present unique technology of carrying out function, metabolism and rii receptor with the anatomic form mode, have very high sensitivity and specificity, can dynamically change at the intravital Physiology and biochemistry of people quantitatively with no damage from external, become diagnosis and instructed the optimum means for the treatment of tumour cardiovascular diseases and neuropsychiatric disease from molecular level observation medicine or metabolite.
18The F transformation period is grown (t
1/2=109.8min), pass through β
+With EC decay, β
+Energy 649kev has lower radiation dose and shorter range to tissue, is positron radionuclide the most commonly used, is suitable for complicated organic synthesis positron radiation medicine and PET clinical application.
In recent years because
18Obtaining comparatively easily and the continuous maturation of marking method and might realize automatic production of F nucleic had a large amount of compounds to be synthesized out and to study their conduct at present
18The imaging results of the tracer agent of F mark makes various
18The research of F radioactively labelled substance becomes a focus of PET drug research.
Natural amino acid Tyrosine is delivered to brain and participates in the synthetic of brain internal protein thereby can be used as photographic developer through behind the radio-labeling, as
18F-Tyrosine.But people find simultaneously, though the amino acid derivative of some mark does not participate in the synthetic of brain internal protein, as long as but can be transported by the system that transports of tumor tissues, can pass the brain barrier, also can be used as developer, therefore some amino acid derivative through radioisotope labeling also can be used as brain tumor imaging agent. and recent Tomio etc. pass through the electrophilic substitution method, with [
18F] AcOF is that electrophilic reagent has synthesized FMT, and studied in the body of FMT and distribute and a series of experiment, the conclusion that obtains is that FMT is a kind of IMT of being similar to (3-[
123I]-brain tumor imaging agent that application prospect is arranged of Iodo-α-Methyltyrosine).Wester etc. have explored a kind of easy nucleophilic substitution method, have successfully synthesized another kind
18The tyrosine derivative of F mark---O-(2-[
18F] fluoro ethyl)-L-tyrosine (FET), obtained higher productive rate and the satisfied interior distribution results of body.HideoTsukada etc. (Hideo Tsukada, Kengo Sato, Dai Fukumoto, Takeharu Kakiuchi, Eur J Nucl Med Mol Imaging, 2006,33,1017-1024) to the O-of D-or L-configuration
18F-fluoromethyl tyrosine (FMT), O-
18F-fluoroethyltyrosine (FET), O-
18F-fluoropropyl tyrosine (FPT) has carried out biological assessment.(Byung SeokMoon, Tae Sup Lee, Kyo Chul Lee, et al, Bioorganic﹠amp such as Byung Seok Moon; Medicinal Chemistry Letters, 2007,17,200-204) on the phenyl ring of FET, introduce methoxyl group or hydrogen and
18The F propyl group or
18The F ethyl changes the fat-soluble of FET, and the amino acid whose derivative that obtains has been obtained certain drug effect.
The positron emission fault of China (PET) video picture research is later relatively, domestic Shanghai Applied Physics be engaged in always PET research (Wang Mingwei, Yin Duan Isle, Zheng Mingqiang etc., nuclear chemistry and radiological chemistry, 2005,27,248-252), with diverse ways synthetic [
18F] FET.Various big hospital is in the majority to clinical PET video picture research, as: Nanfang Medical Univ Tang Gang China etc. (Tang Ganghua, 5 light are far away etc., and isotropic substance 2007,20 is 114-119) more to all kinds of clinical studyes such as tumours.
As formula (A) compound of on-radiation reference compound, and the preparation purification more complicated of the formula of the precursor that serves as a mark (B) compound.The 4-O-of F18 mark (2-fluoroalkyl) benzamide compound does not appear in the newspapers so far.
Based on above consideration, the contriver passes through complex sign F for aromatic amino acid, preliminary study shows, this compounds mark is simple, working method is easy, mark rate height, cost are low, and the aromatic amino acid of marker has good biological property, is expected to become clinical potential positron tomography PET developer.
Summary of the invention
The first, primary and foremost purpose of the present invention is: provide a class to can be used as novel positron emission fault (PET) developer
18The aromatic amino acid of F mark.
Of the present invention [
18F] fluorine mark aromatic amino acid, its structural formula is as shown in the formula shown in (A).
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
It is characterized in that: an end has alkoxy benzene formyl radical structure; The other end has the a-amino acid structure, has substituent R 1 to be positioned on the alpha site of carboxyl group, and R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.Two-end structure directly links to each other by amido linkage.
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, labelled precursor compound (formula B's is synthetic)
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
Synthetic route is shown below:
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
1) hydroxy alkoxy base benzoyl aromatic amino acid is synthetic
Amino acid methyl ester hydrochloride 1.5mmol is dissolved in the 20mL anhydrous methylene chloride, adds triethylamine 3mmol, hydroxy alkoxy yl benzoic acid 1mmol, and HOBT 1mmol, DCC 1.5mmol, under the condition of ice bath after reaction half an hour, stirring at room reaction 12 hours.After reaction finished, column chromatography for separation was purified.Obtain white solid, output is 40%-60%.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
2) the aromatic amino acid p-toluenesulfonic esters is synthetic.
Hydroxy alkoxy base benzoyl-amido acid 1mmol, Tosyl chloride 1.5mmol, triethylamine 1.5mmol, lutidine amine 0.2mmol is dissolved in the anhydrous methylene chloride, after ice bath reacts half an hour, stirring at room reaction two hours.After being spin-dried for solvent, column chromatography for separation is purified and is obtained white solid.Reaction yield is 70-90%.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
Two, the mark of precursor compound and aftertreatment.
80 ℃--in the time of 140 ℃, by the 2-5mg precursor at K
222Catalytic condition under
18Behind the F labeled reactant 20min, reaction solution is through Silica Sep-Pak (Plus) post, C18 Sep-Pak (Plus), Al
2O
3Sep-Pak (Plus) or HPLC purifying obtain
18F marked product ester.
18F marked product ester is under alkaline condition, and hydrolysis obtains
18The acid of F marked product.After the solution sterile filtration of preparation, make the target aromatic amino acid
18The F marked product.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
The second, the present invention is above-mentioned
18F mark aromatic amino acid is as the application of positron emission fault (PET) developer.
1) is used among the present invention carry out
18The precursor compound mark of F mark is simple, working method is easy, and mark rate height, cost are low.
2) the present invention
18The compound of F mark has good biological activity.Huge potentiality to be exploited is particularly arranged aspect cerebral tumor.
Preparation provided by the present invention
18The preparation of F mark aromatic amino acid is simple, is fit to the radiopharmaceuticals clinical application more.Prepare
18F tagged compound radiochemical purity is greater than 99%.
R1 is a benzyl, the tagged compound test-results when R2 is methoxyl group:
Table 1:
18The bio distribution data of the S180 mice with tumor model of F mark aromatic amino acid (%ID/g ± SD, n=5)
From table 1 column data as can be known,, compare with domestic existing method through verification experimental verification, the present invention have than [
18F] the better cellular uptake of FET, delay and metabolism.R1 is a benzyl, when R2 is methoxyl group,
18F tagged compound A is expelled in the tumor mouse model 120 minutes, and tumour/non-tumour ratio is up to 2.95.The clearance rate of marker in blood is also very fast, and the marker blood clearance is more than 65% behind the 120min.
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 normal cerebral tissue.Have test to be card:
Identical implementation method is carried out
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 2:
Table 2
18F-FDG is at the intravital tumour of S180 tumor-bearing mice/brain ratio
Contrast table 1 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.
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 test to be card:
Undertaken by identical implementation method
18The tumor-bearing mice bio distribution experiment of F-FET obtains behind the disposal data
18The tumour of F-FDG/healthy tissues ratio is as shown in table 3:
Table 3
18F-FET is at the intravital tumour/healthy tissues of S180 tumor-bearing mice (T/N) ratio
Contrast table 1 as can be seen, and is of the present invention
18The F tagged compound is similar at each time section tumour/brain ratio
18Phase when F-FET is corresponding.
18F-FET is at 60-120min, tumour/brain ratio is stabilized in the 30-60min level even also increases to some extent, 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
18F mark fragrant amido acid compound T/N ratio has similar effects, and this makes of the present invention
18The F tagged compound carries out the image that tumor imaging particularly may obtain equal in quality during the cerebral tumor video picture.
According to the research to the experiment that distributes in the S180 tumor-bearing mice body, we have further carried out the interior distribution research of neurospongioma tumor-bearing mice body, result and S180 tumor-bearing mice bio distribution similar trend, and it the results are shown in Table 4.
Table 4:
18Neurospongioma (glioma) tumor-bearing mice tumour/brain capture ratio of F mark aromatic amino acid
Contrast table 1 as can be seen, the radiation of neurospongioma animal model and S180 mice with tumor picked-up trend is identical.The ratio of tumour/healthy tissues organ presents the trend that increases progressively.The ratio of tumour/brain reaches 3.34, than
18The tumour of F-FET/brain capture ratio is big slightly.In subsequent P ET video picture, the imaging results of tumour may be more clear.Labeled drug clearance rate in the blood promptly reached more than 60% at 120 minutes.
In sum, provided by the present invention
18F mark aromatic amino acid compared with prior art, existing good bio distribution difference degree has as the tumor developer potentiality of brain tumor imaging agent particularly, has the characteristics that preparation is simple, mark rate is high again.
Therefore, formula of the present invention (A) aromatic amino acid can be used as the application of positron tomography (PET) the video picture molecular probe of report diagnosing tumour, and it is highly sensitive, selectivity good.
Description of drawings
Fig. 1 is that formula A of the present invention is at the intravital bio distribution figure of mice with tumor model.
Fig. 2 for formula A of the present invention with [
18F]-FET in the mice with tumor model tumour/the brain odds ratio.Formula A of the present invention with [
18F]-FET, [
18F] FDG in the mice with tumor model tumour/the brain odds ratio.
Embodiment
Below by concrete preparation example and embodiment the present invention is illustrated more clearly in:
After amino acid methyl ester hydrochloride (3mmol) is dissolved in the 20mL methylene dichloride, triethylamine (3mmol) back stirring reaction 5min is heavily steamed in disposable adding, add 4-(2-hydroxy alkoxy base) phenylformic acid (2mmol) and HOBt (1-hydroxy benzo triazole) (2.2mmol), reaction mixture is cooled to drip after 0 ℃ the dichloromethane solution 5mL of DCC (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. column chromatography, eluent (ethyl acetate: obtain light yellow oil methyl alcohol 10: 1), add the mixed solvent of amount of ethyl acetate and sherwood oil and fully obtain white solid, the solid ethyl acetate behind the suction filtration after the grinding, obtain white solid behind the mixed solvent recrystallization of sherwood oil and anhydrous methanol.
The Compound C (1mmol) of getting above-mentioned preparation is dissolved into 20mL and heavily steams in the methylene dichloride, add TEA (triethylamine) (1.5mmol), after ice bath is cooled to below 0 ℃, add DMAP (4-N, the N-lutidine) Tosyl chloride of purification process (1.5mmol) (0.2mmol) and again, after continuing to rise to room temperature reaction behind the low-temp reaction 30min and spending the night, the TLC demonstration reacts completely. after the adding saturated sodium bicarbonate aqueous solution fully stirs, organic layer with the saturated aqueous common salt thorough washing after anhydrous sodium sulfate drying, column chromatography.
Synthesizing of embodiment 3 formula A compound 2-(4-(2-fluorine oxyethyl group) benzoylamino) methyl phenylpropionate.
After 2mmol 4-butyl ammonium fluoride trihydrate 0.63 restrains in the dry acetonitrile of heavy evaporate to dryness that is dissolved into 1mL, heat in the nitrogen atmosphere, constantly feed nitrogen and make the acetonitrile evaporate to dryness, add the 2mL acetonitrile again and repeat twice of aforesaid operations, the 10mL that adds the 1mmol compd B heavily steams acetonitrile solution, reaction mixture under nitrogen atmosphere behind the back flow reaction 6h, TLC show react completely after, revolve acetonitrile, column chromatography can get
19F is for product, productive rate about 60%.
The radioactivity of embodiment 4 formulas (A) 4-(2-Fluoroalkyloxy) benzoylamino amino acid methyl ester is synthetic.
Get 100 μ L[
18F] F
-Solution join and include K
222(10-15mg) and in the reaction flask of salt of wormwood (3mg), this reaction flask is immersed 80 ℃--in 140 ℃ the oil bath, add acetonitrile 500 μ L azeotropic water removing under condition of nitrogen gas.Add the precursor solution that is dissolved in 0.5mLDMF, confined reaction 20min.Reaction finishes postcooling to room temperature.Putting productive rate 20%--40%, putting be pure＞and 99%.
Raw material among this preparation method: acetonitrile, N, N-dimethylformamide, Kriyptofix222 purchase the chemical reagents corporation in fluka.Triethylamine is purchased in the Beijing Chemical Plant.[
18F] F
-Provide by chain hospital unit.
The physico-chemical property and the spectroscopic data of final product of the present invention and main intermediate are as follows:
2-4-(2-hydroxyl-oxethyl) benzoylamino-3-phenylpropionic acid methyl esters
m.p：115-120℃；IR(KBr，cm
-1)：v?3451，3200，1734，1630，1610，1634，1497，1257；
1HNMR(CDCl
3，500MHz)：δ7.72(d，2H，J＝8.6Hz，Ar-H)，7.32(t，2H，J＝6.8Hz，Ar-H)，7.15(d，2H，J＝6.9Hz，Ar-H)，6.95(2H，J＝8.6Hz，Ar-H)，6.51(d，1H，J＝7.1Hz，NH)，5.10(q，1H，J＝5.6Hz，NHCHCH
2PhCOOCH
3)，4.15(t，2H，J＝4.1Hz，CH
2CH
2OH)，4.01(t，2H，J＝4.5Hz，CH
2CH
2OH)，3.78(s，3H，COOCH
3)，3.27(dq，2H，J＝5.7Hz，-CH
2Ph，)；
13CNMR(CDCl
3，125MHz)δ：172.18，161.49，135.92，129.36，128.93，128.62，127.18，69.36，61.33，53.48，52.41，37.99，23.46.
2-4-(2-tolysulfonyl base oxethyl) benzoylamino-3-phenylpropionic acid methyl esters: m.p:118-119 ℃ of IR (KBr, cm
-1): v 3340,1741, and 1626,1605,1497,1357,1261,1172,1220,1017,936,765;
1HNMR (CDCl
3, 500MHz): δ 7.83 (d, 2H, J=8.1Hz, Ar-H), 7.67 (d, 2H, J=8.5Hz, Ar-H), 7.36 (d, 1H, J=7.9Hz, Ar-H), 7.31 (t, 2H, J=7.1Hz, Ar-H), 7.29 (d, 2H, J=5.7Hz, Ar-H), 7.14 (d, 2H, J=7.0Hz, Ar-H), 6.80 (d, 2H, J=8.6Hz, Ar-H), 6.48 (d, 1H, J=7.3Hz, NH), 5.09 (m, 1H, J=5.8Hz, CHCOOCH
3), 4.40 (t, 2H, J=4.5Hz, CH
2CH
2OTs), 4.20 (t, 2H, J=4.7Hz, CH
2CH
2OTs), 3.78 (s, 3H, COOCH
3), 3.27 (dq, 2H, J=5.7Hz, CH
2Ph), 3.01 (s, 3H, Ts-CH
3);
13CNMR (CDCl
3, 125MHz) δ: 172.17,166,11,150.77,145.08,135.92,129.91,129.35,128.88,128.63,128.01,127.19,126.89,114.34,67.83,65.52,53.49,52.42,37.96,21.67; Anal.calcd for C
26H
27NO
7S:C, 62.76; H, 5.47; N, 2.82; Found:C, 62.84; H, 5.78; N, 2.95.
2-4-(2-fluorine oxyethyl group) benzoylamino-3-phenylpropionic acid methyl esters:
m.p118-120℃；IR(KBr，cm
-1)：v?3333，1741，1626，1605，1538，1504，1257，1224，1176，1068，839；
1HNMR(CDCl
3，500MHz)：δ7.73(d，2H，J＝8.7Hz，Ar-H)，7.15(d，2H，J＝7.1Hz，Ar-H)，6.96(d，2H，J＝8.7Hz，Ar-H)，6.53(d，1H，J＝7.3Hz，NH)，5.10(q，1H，J＝5.6Hz，-CHCH
2Ph)，4.84-4.75(d×t，2H，
2J
HF＝47.3Hz，-CH
2CH
2F)，4.30-4.24(d×t，2H，
3J
HF＝27.7Hz，CH
2CH
2F)，3.79(s，3H，COOCH
3)，3.27(dq，2H，J＝5.8Hz，-CH
2Ph)；
19FNMR(CDCl
3，400MHz)：-224.167(
JCH2CH2F＝27.7Hz)，-224.292(J
CH2CH2F＝47.4Hz)；
13CNMR(CDCl
3，125MHz)δ：172.19，166.20，161.23，135.93，129.36，128.95，128.63，127.19，126.79，114.43，82.36，81.01，53.49，52.40，37.97；MS-EI：m/z＝345.14(found：345.13)；Anal.calcdfor?C
19H
20FNO
4：C?66.08，H?5.84，N?4.06；found：C?65.90，H?5.64，N?4.07.
2-(4-2-fluorine ethoxy benzamide base)-3-phenylpropionic acid
IR(KBr，cm
-1)：v?3344，1746，1626，1608，1532，1510，1255，1222，1176，1069，841；
1HNMR(CDCl
3，500MHz)：8.58(d，1H，J＝8.0Hz，NH)，δ7.79(d，2H，J＝8.7Hz，Ar-H)，7.31(d，2H，J＝8.7Hz，Ar-H)，7.26(d，2H，J＝7.4Hz，Ar-H)，7.17(d，2H，J＝7.2Hz，Ar-H)，7.02(d，2H，J＝8.7Hz，Ar-H)，4.81-4.70(d×t，2H，
2J
HF＝47.8Hz，-CH2CH2F)，4.58(q，1H，J＝4.2Hz，-CHCH2Ph)，4.33-4.25(d×t，2H，
3J
HF＝30.2Hz，CH
2CH
2F)，3.11(dq，2H，J＝4.3Hz，-CH
2Ph)；
13CNMR(CDCl
3，125MHz)δ：172.19，166.20，161.23，135.93，129.36，128.95，128.63，127.19，126.79，114.43，82.36，81.01，53.49，52.40，37.97；MS-EI：m/z＝331.12(found：331.06)
2-4-(2-tolysulfonyl base oxethyl) benzoylamino-3-(2-indyl)-methyl propionate:
IR(Film，cm
-1)：v?3416，1737，1642，1607，1499，1356，1254，1189，1175，930；
1HNMR(CDCl
3，500MHz)：δ8.36(s，1H，indole-NH)，7.82(d，2H，J＝8.2Hz，Ar-H)，7.62(d，2H，J＝8.8Hz，Ar-H)，7.55(d，1H，J＝7.9Hz，Ar-H)，7.37(d，1H，J＝8.2Hz，Ar-H)，7.35(d，2H，J＝8.0Hz，Ar-H)，7.19(t，1H，J＝7.2Hz，Ar-H)，7.09(s，1H，J＝7.2Hz，Ar-H)，7.01(d，1H，J＝7.0Hz，Ar-H)，6.74(d，2H，J＝8.7Hz，Ar-H)，6.62(d，1H，J＝7.5Hz，amide-NH)，5.14(m，1H，CHCOOCH
3)，4.38(t，2H，J＝4.5Hz，CH
2CH
2OTs)，4.16(t，2H，J＝4.6Hz，CH
2CH
2OTs)，3.73(s，3H，CHCOOCH
3)，3.45(q，2H，J＝2.5Hz，Indole-CH
2)，2.45(s，2H，Ts-CH3)；
13CNMR(CDCl
3，125MHz)δ：172.50，1δ6.20，160.68，145.11，136.18，132.79，129.91，128.96，127.99，127.68，126.85，122.89，122.27，119.70，118.65，114.24，111.37，110.02，67.87，65.47，53.46，52.43，27.69，21.65，14.21.
2-4-(2-fluorine oxyethyl group) benzoylamino-3-(2-indyl)-methyl propionate:
m.p：86-88℃；IR(KBr，cm
-1)：v?3416，1737，1642，1607，1499，1254，1189，1175，930；
1HNMR(CDCl
3，500MHz)：δ8.21(s，1H，Indole-NH)，7.69(d，2H，J＝8.7Hz，Ar-H)，7.56(d，1H，J＝7.9Hz，Ar-H)，7.39(d，1H，J＝8.1Hz，Ar-H)，7.28(s，1H，Ar-H)，7.21(t，1H，J＝7.2Hz，Ar-H)，7.10(t，1H，J＝7.3Hz，Ar-H)，7.03(d，1H，J＝1.5Hz，Ar-H)，6.92(d，2H，J＝8.7Hz，Ar-H)，6.62(d，1H，J＝7.3Hz，Amide-NH)，5.17(m，1H，CHCOOCH
3)，4.84-4.74(d×t，2H，
2J
HF＝47.3Hz，CH
2CH
2F)，4.29-4.23(d×t，2H，
3J
HF＝27.7Hz，CH
2CH
2F)，3.74(s，3H，COOCH
3)，3.47(d，2H，J＝5.3Hz，Indole-CH
2)；
13CNMR(CDCl
3，125MHz)δ：172.52，166.29，161.15，136.15，129.03，127.72，126.78，122.81，122.32，119.76，118.73，114.33，111.28，110.18，82.37，81.01，67.25，53.44，52.42，49.19，33.96，27.72，25.62，24.95；MS-EI：m/z＝384.15(found：385.38)；Anal.calcd?for?C
21H
21FN
2O
4：C，65.62；H，5.51；N，7.29；Found：C，65.16；H，5.24；N，7.37.
The bio distribution test of experimental example 1 formula A compound of the present invention
The establishment method of tumor mouse model: the S180 cell that is in logarithm production phase washs through physiological saline, and digestion adds in the culture medium solution its suspension of system.Subcutaneous injection at KM mouse left upper extremity.Use for (A) compound biological assessment and micro-PET video picture test after forming solid tumor in 7 days.
To having planted 25 of S180 tumor model KM mouse, formula (A) compound formulation of difference tail vein injection 10 μ Ci, 5min, 15min, 30min, 60min, 120min puts to death, dissect, gather interested organs and tissues: the heart, liver, spleen, lung, kidney, stomach, small intestine, large intestine, bone, muscle, brain, tumour, blood etc.Weigh respectively, technology, carry out after the decay correction, with the counting of each tissue sample all with the standard counting relatively.The result is expressed as %ID/g ± SD (radioactivity of every gram tissue accounts for the percentage composition of injection volume), is the relative absorption value of each internal organs to formula (A) compound.Each internal organs to the relative absorption value of formula (A) compound as shown in Figure 1.Visible among the figure (A) compound in liver, kidney, blood initial absorption than higher.Clearance rate is also very fast.Tumour and non-tumour ratio reach as high as 2.95 at 120min.
The undue toxicity inspection of experimental example 2 formula A compounds of the present invention
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) 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)
1. a class
18F mark aromatic amino acid is used for PET video picture research, is used for tumour positron tomography (PET) video picture research, and it is characterized in that: an end has F substituted alkoxy benzoyl structure; The other end has the a-amino acid structure, and substituent R 1 is positioned on the alpha site of carboxyl group, and R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.Tagged compound has improved fat-soluble, and structure has been introduced different carbochain of length and different amino acid structures, and in the structure F is
19F and
18F.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
2. the preparation method of the described compound of claim 1, it comprises following formula (B) the compound tolysulfonyl ester precursor that serves as a mark, and carries out routine
18The F mark.It is characterized in that: an end is the alkoxy benzene formyl structure with p-toluenesulfonyl; the other end has a-amino acid or a-amino acid methyl esters structure, and substituent R 1 is positioned on the alpha site of carboxyl group, and R1 is phenyl, benzyl, 3-indole methyl; R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
R1 is phenyl, benzyl, 3-indole methyl, and R2 is a methoxyl group, and n is 1-5.
3. the described preparation method of claim 1 is characterized in that it comprises the following steps: to use 15mg K
222With 3mg K
2CO
3Acetonitrile solution drip washing
18F
-The QMA post of enrichment is behind the acetonitrile azeotropic water removing, with containing K
2CO
3, K
222, [
18F]-F
-Mixture and labelled precursor formula (B) compound at N, in the N-dimethylformamide solvent, under heating condition, react, temperature of reaction is about 80 ℃--140 ℃, the reaction times is about 20 minutes.Separate purification with high performance liquid phase (HPLC).Obtain
18F target-marking product.Putting of marker is pure greater than 99%.
4. claim 3 is described
18The F marking method is characterized in that: take 15mg K
222With 3mg K
2CO
3Acetonitrile 1mL and the mixed solution of water 0.5mL obtain radioactivity as elutriant
18The F ion, and use the anhydrous acetonitrile azeotropic water removing.
5. claim 3 is described
18The F marking method is characterized in that: use DMF or DMSO or acetonitrile to be reaction solvent, K
222Be phase-transfer catalyst.
6. claim 3 is described
18The F marking method is characterized in that: 80 ℃-140 ℃ of labeled reactant optimum tempss, Best Times is 20-30 minute.
Claim 1 described [
18F] application of F labeled amino acid analog derivative in the positron emission tomography molecular probe of preparation report tumour.
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| CN105963724A (en) * | 2016-05-11 | 2016-09-28 | 厦门大学 | {0><}0{>Radio-labeled tumor developing agent as well as preparation method and application thereof |
| 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 |
| CN109369433A (en) * | 2018-10-29 | 2019-02-22 | 庄晓青 | A kind of 5-ALA derivative, synthetic method and the application of F-18 label |
| CN113527162A (en) * | 2021-07-28 | 2021-10-22 | 西南医科大学附属医院 | Radioactive fluorine labeled phenylsulfone compound, preparation method and application thereof |
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|---|---|---|---|---|
| EP1539250A1 (en) * | 2002-08-02 | 2005-06-15 | Mallinckrodt Inc. | Radioactively labelled amino acid analogues, their preparation and use |
| GB0407952D0 (en) * | 2004-04-08 | 2004-05-12 | Amersham Plc | Fluoridation method |
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| CN105963724A (en) * | 2016-05-11 | 2016-09-28 | 厦门大学 | {0><}0{>Radio-labeled tumor developing agent as well as preparation method and application thereof |
| CN105963724B (en) * | 2016-05-11 | 2019-01-15 | 厦门大学 | A kind of radiolabeled tumor developer, preparation method and application |
| 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 |
| CN109369433A (en) * | 2018-10-29 | 2019-02-22 | 庄晓青 | A kind of 5-ALA derivative, synthetic method and the application of F-18 label |
| CN109369433B (en) * | 2018-10-29 | 2020-01-17 | 庄晓青 | F-18 labeled 5-aminolevulinic acid derivative, and synthesis method and application thereof |
| WO2020087794A1 (en) * | 2018-10-29 | 2020-05-07 | 庄晓青 | F-18 labeled 5-aminolevulinic acid derivative, synthesis method therefor, and application thereof |
| CN113527162A (en) * | 2021-07-28 | 2021-10-22 | 西南医科大学附属医院 | Radioactive fluorine labeled phenylsulfone compound, preparation method and application thereof |
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