CN101723849B - Novel 18F labeled amino acid derivatives, preparation method and application thereof in tumor imaging - Google Patents
Novel 18F labeled amino acid derivatives, preparation method and application thereof in tumor imaging Download PDFInfo
- Publication number
- CN101723849B CN101723849B CN2008101675564A CN200810167556A CN101723849B CN 101723849 B CN101723849 B CN 101723849B CN 2008101675564 A CN2008101675564 A CN 2008101675564A CN 200810167556 A CN200810167556 A CN 200810167556A CN 101723849 B CN101723849 B CN 101723849B
- Authority
- CN
- China
- Prior art keywords
- group
- hydrogen
- amino acid
- methyl
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 COC(CNC(c(cc1)ccc1OCC*)=O)=O Chemical compound COC(CNC(c(cc1)ccc1OCC*)=O)=O 0.000 description 1
- FUIOWANLBSKIQW-UHFFFAOYSA-N COC(CNC(c(cc1)ccc1OCCO)=O)=O Chemical compound COC(CNC(c(cc1)ccc1OCCO)=O)=O FUIOWANLBSKIQW-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention discloses novel radioactive 18F labeled amino acid derivatives, which are used in research on tumor positron emission tomography (PET) imaging. The derivatives are characterized in that one end of the derivatives 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 hydrogen, methyl group, ethyl group, propyl group, isopropyl group, butyl group, methylthio-ethyl group, methyl acetate group or propionate carbomethoxy group; R2 is methoxy group; and n is a number between 1 and 5. The R1 is hydrogen, methyl group, ethyl group, propyl group, isopropyl group, butyl group, methylthio-ethyl group, methyl acetate group or propionate carbomethoxy group; the R2 is hydrogen; 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. 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. The R1 is hydrogen, methyl group, ethyl group, propyl group, isopropyl group, butyl group, methylthio-ethyl group, methyl acetate group or propionate carbomethoxy group; the R2 is methoxy group; and the n is a number between 1 and 5. The R1 is hydrogen, methyl group, ethyl group, propyl group, isopropyl group, butyl group, methylthio-ethyl group, methyl acetate group or propionate carbomethoxy group; the R2 is hydrogen; and the n is a number between 1 and 5.
Description
Technical field
The present invention relates to one type novel
18F labeled amino acid analog derivative 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 the optimum means of diagnosis and guiding treatment tumour cardiovascular diseases and neuropsychiatric disease from molecular level observation medicine or metabolite.
18The F transformation period is grown (t
1/2=109.8min), 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 is not participated 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 distributed and a series of experiment, the conclusion that obtains be FMT be 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---0-(2-[
18F] fluoro ethyl)-L-tyrosine (FET), obtained higher productive rate and the satisfied interior distribution results of body.Hideo Tsukada 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-fluoroethyl tyrosine (FET), O-
18F-fluoropropyl tyrosine (FPT) has carried out biological assessment.Byung Seok Moon etc. (Byung Seok Moon, Tae Sup Lee, Kyo Chul Lee, et al, Bioorganic&Medicinal Chemistry Letters, 2007,17,200-204) on the phenyl ring of FET, introduce methoxyl group or hydrogen with
18The F propyl group perhaps
18The F ethyl changes the fat-soluble of FET, and the amino acid whose verivate that obtains has been obtained certain drug effect.
Of positron emission tomography (PET) imaging studies relatively late, the domestic Shanghai Applied Physics has been engaged in PET studies (Wang Mingwei, Yin Duanzhi, Zhengming Jiang et al., Nuclear and Radiochemistry ,2005,27,248-252), with the Synthesis of different methods [
18 F] 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 (fluoroalkyl) benzamido-acid compounds does not appear in the newspapers so far.
Based on above consideration; The contriver passes through complex sign F for the benzoyl-amido acid compounds; Preliminary study shows that this compounds mark is simple, working method is easy, and mark rate is high, cost is low; And the amino acids of affinity tag has good biological property, is expected to become clinical potential positron emission fault PET developer.
Summary of the invention
The first, primary and foremost purpose of the present invention is: provide one type to can be used as novel positron emission fault (PET) developer
18F labeled amino acid verivate.
Of the present invention [
18F] fluorine labeled amino acid verivate, its structural formula is as shown in the formula shown in (A).
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a methoxyl group, and n is 1-5.
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a hydrogen, 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 hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a methoxyl group, and n is 1-5.R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a hydrogen, and n is 1-5.Two-end structure directly links to each other through 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 following:
One, labelled precursor compound (formula B's is synthetic)
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a methoxyl group, and n is 1-5.
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a hydrogen, and n is 1-5.
Synthetic route is shown below:
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a methoxyl group, and n is 1-5.
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a hydrogen, and n is 1-5.
1) hydroxy alkoxy base benzoyl-amido acid derivative 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 HOBT1mmol, DCC1.5mmol, under the condition of ice bath after reaction half a 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 hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a methoxyl group, and n is 1-5.
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a hydrogen, and n is 1-5.
2) synthesizing the acid of 4-[alkoxyl group (p-toluenesulfonyl)] benzoyl-amido.
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 a hour, stirring at room reaction two hours.After revolving dried solvent, column chromatography for separation is purified and is obtained white solid.Reaction yield is 70-90%.
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a methoxyl group, and n is 1-5.
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a hydrogen, and n is 1-5.
Two, the mark of precursor compound and aftertreatment.
80 ℃--in the time of 140 ℃, by 2-5mg precursor at K
222Catalytic condition under
18Behind the F labeled reactant 20min, reaction solution is through Silica Sep-Pak (Plus) post, C18Sep-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 target benzoyl-amido acids marked product.
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a methoxyl group, and n is 1-5.
R1 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, methylthio ethyl, methyl acetate base, methyl propionate base, and R2 is a hydrogen, and n is 1-5.
The second, the present invention is above-mentioned
18F labeled amino acid verivate 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 is high, cost is 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 labeled amino acid verivate is simple, is fit to the radiopharmaceuticals clinical application more.Prepare
18The F tagged compound, radiochemical purity is greater than 99%.
R1, the tagged compound experimental result when R2 is hydrogen:
Table 1:
18The bio distribution data of the S180 mice with tumor model of F labeled amino acid verivate (%ID/g ± SD, n=5)
Can know from table 1 column data,, compare with domestic existing method through verification experimental verification, the present invention have than [
18F] the better cellular uptake of FET, delay and metabolism.When R1 and R2 are hydrogen,
18F tagged compound A is expelled in the tumor mouse model 60 minutes, and tumour/non-tumour ratio is up to 5.1.The clearance rate of affinity tag in blood is also very fast, and the affinity tag blood clearance is more than 90% 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
18Distribution experiment in the tumor-bearing mice body of F-FDG obtains 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 can be found out, 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 possibly 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 can be found out, and is of the present invention
18The F tagged compound all is higher than the 18F-FET analog value at each time section tumour/brain ratio.Though
18F-FET is at 60-120min; Tumour/brain 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
18F tagged compound T/N ratio is right
18F-FET has clear superiority, and this makes of the present invention
18The F tagged compound carries out tumor imaging particularly possibly obtain ratio during the cerebral tumor video picture
18The higher-quality image of F-FET.
According to the research to distribution experiment 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 its result sees table 4.
Table 4:
18Neurospongioma (glioma) the tumor-bearing mice bio distribution data of F labeled amino acid verivate (%ID ± SD of unit, n=5)
15min 30min 60min
The heart 1.93 ± 0.55 0.95 ± 0.29 0.91 ± 0.27
Liver 4.11 ± 0.05 3.08 ± 0.06 2.63 ± 0.23
Lung 1.69 ± 0.56 1.32 ± 0.07 0.87 ± 0.21
Kidney 4.07 ± 1.04 1.77 ± 0.24 0.97 ± 0.14
Brain 1.26 ± 0.42 0.51 ± 0.25 0.55 ± 0.14
Bone 1.33 ± 0.07 3.53 ± 0.19 1.07 ± 0.29
Muscle 1.25 ± 0.23 0.94 ± 0.14 0.53 ± 0.16
Stomach 0.97 ± 0.30 0.78 ± 0.28 0.97 ± 0.31
Small intestine 1.45 ± 0.02 1.05 ± 0.55 0.92 ± 0.62
Large intestine 1.85 ± 0.48 1.06 ± 0.24 1.69 ± 0.56
Blood 2.17 ± 0.03 1.28 ± 0.21 0.98 ± 0.27
Spleen 1.19 ± 0.16 0.79 ± 0.02 0.64 ± 0.22
Tumour 3.30 ± 0.06 2.71 ± 0.15 2.48 ± 0.44
Tumour/brain 2.62 5.41 4.51
Tumour/muscle 2.64 2.88 4.67
Tumour/blood 1.52 2.11 2.53
Tumour/lung 1.95 2.05 2.53
Tumour/liver 0.81 0.87 0.94
Contrast table 1 can find out that the initial radiation intake of animal model is successively decreased from high to low successively.And the ratio of tumour/healthy tissues organ demonstrates the trend that increases progressively.The intake of tumour is reduced to 2.48 by 3.3, and from 30 minutes to 60 minutes, the ratio of tumour/brain reached 5.41 and 4.51.The ratio of tumour and other healthy tissues shows that 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 50% at 60 minutes.
In sum, provided by the present invention
18F labeled amino acid verivate compared with prior art, existing more excellent 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) amino acids 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 through concrete preparation example and embodiment the present invention is illustrated more clearly in:
Embodiment 1 formula C compound 4-(2-hydroxyl-oxethyl) BM methyl acetate
After amino acid methyl ester hydrochloride (3mmol) was dissolved in the 20mL methylene dichloride, triethylamine (3mmol) back stirring reaction 5min was heavily steamed in disposable adding, adds 4-(2-hydroxyl-oxethyl) 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); Dropwise and be warming up to room temperature reaction behind the continued low-temp reaction 0.5h and spend the night, after TLC showed that reaction finishes, suction filtration was 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 revolves and obtains oily matter after desolvating.Column chromatography; Eluent (ETHYLE 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 after the grinding, obtain white solid behind the mixed solvent recrystallization of the solid behind the suction filtration with ETHYLE ACETATE, sherwood oil and anhydrous methanol.
Synthesizing of embodiment 2 formula B compound 4-(2-p-toluenesulfonic esters base oxethyl) benzoylamino amino acid methyl esters.
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, N-lutidine) (0.2mmol) with the Tosyl chloride of purification process (1.5mmol) again; After continuing to rise to room temperature reaction behind the low-temp reaction 30min and spending the night, TLC shows and reacts completely.Add after saturated sodium bicarbonate aqueous solution fully stirs, organic layer with the saturated aqueous common salt thorough washing after anhydrous sodium sulfate drying, column chromatography for separation is purified.
Synthesizing of embodiment 3 formula A compound 4-(2-fluorine oxyethyl group) benzoylamino amino acid methyl esters.
2mmol 4-butyl ammonium fluoride trihydrate 0.63 heats in the nitrogen atmosphere after restraining in the dry acetonitrile of heavy evaporate to dryness that is dissolved into 1mL, constantly feeds nitrogen and makes 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, and reaction mixture is behind nitrogen atmosphere refluxed reaction 6h, after the TLC demonstration reacts completely; Revolve acetonitrile, column chromatography for separation is purified and can be got
19F is for product, productive rate about 60%.
The radioactivity of embodiment 4 formula A compound 4-(2-fluorine oxyethyl group) benzoylamino amino acid methyl esters is synthetic.
Get 100 μ L [
18F] solution of F-joins and includes K
222(10-15mg) and in the reaction flask of salt of wormwood (3mg), this reaction flask immersed in 90 ℃-150 ℃ 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-provides by chain hospital unit.
The physico-chemical property and the spectroscopic data of final product of the present invention and main intermediate are following:
4-(2-hydroxyl-oxethyl) m.p:85-90 ℃ of benzoyl-glycine methyl esters (dec); IR (KBr, cm
-1): v 3444,3400, and 2918,1722,1634,1634,1608,1545,1497,1272,1227;
1HNMR (CDCl
3, 500MHz): δ 7.80 (d, 2H, J=8.6Hz, Ar-H), 6.96 (d, 2H, J=8.6Hz, Ar-H), 6.65 (s, 1H, NH), 4.26 (d, 2H, J=4.9Hz, NHCH
2COOCH
3), 4.15 (t, 2H, J=4.1Hz, CH
2CH
2OH), 4.01 (t, 2H, J=4.5Hz, CH
2CH
2OH), 3.82 (s, 3H, COOCH
3);
13CNMR (CDCl
3, 125MHz): δ 170.75,167.04,161.55,129.02,126.26,114.35,69.39,61.20,52.45,41.17.
4-(2-p-toluenesulfonic esters base oxethyl) benzoyl-glycine methyl esters
IR(DCM，cm
-1)：ν3401?1750，1637，1602，1542，1501，14564，1352，1243，1157，902；
1HNMR(CDCl
3，500MHz)：δ7.82(d，2H，J＝8.2Hz，Ar-H)，7.76(d，2H，J＝8.7Hz，Ar-H)，7.36(d，2H，J＝8.1Hz，Ar-H)，6.81(d，2H，J＝8.7Hz，Ar-H)，6.75(s，1H，NH)，4.39(t，2H，J＝4.4Hz，CH
2CH
2OTs)，4.24(d，2H，J＝5.0Hz，NHCH
2COOCH
3)，4.20(t，2H，J＝4.7Hz，CH
2CH
2OTs)，3.80(s，3H，COOCH3)，3.04(s，3H，Ts-CH
3)；?
13CNMR(CDCl
3，125MHz)δ：170.67，166.61，160.77，145.12，132.80，129.92，128.97，127.99，125.68，114.31，67.87，65.51，52.44，41.17，33.88。
4-(2-fluorine oxyethyl group) benzoyl-glycine methyl esters
m.p：95-97℃；IR(KBr，cm
-1)：ν3313，2956，1749，1638，1601，1546，1504，1261，1209，1172，1046；
1HNMR(CDCl
3，500MHz)：δ7.81(d，2H，J＝8.7Hz，Ar-H)，6.98(d，2H，J＝8.7Hz，Ar-H)，6.65(s，1H，NH)，4.85-4.75(d×t，2H，2JHF＝47.3Hz，-CH
2CH
2F)，4.31-4.26(d×t，2H，3J
HF＝27.7Hz，-CH
2CH
2F)，4.00(d，2H，J＝4.8Hz，NHCH2COOCH3)，3.82(s，3H，COOCH3)；19FNMR(CDCl
3，400MHz)：-224.168(J
CH2CH2F＝27.3Hz)，-224.296(J
CH2CH2F＝47.8Hz)；
13CNMR(CDCl
3，125MHz)δ：170.69，166.84，161.24，129.01，126.59，114.42，82.37，81.01，52.45，41.72；MS-EI：m/z＝255.09(found：254.98)；Anal.calcd?forC
12H
14FNO
4：C?56.46，H?5.59，N?5.43；found：C56.47，H5.49，N5.53。
4-(2-fluorine oxyethyl group) benzoyl-glycine
IR(KBr，cm
-1)：ν3313，2956，1749，1638，1601，1546，1504，1261，1209，1172，1046；
1HNMR(CDCl
3，500MHz)：δ12.55(s，1H，δ7.85(d，2H，J＝8.7Hz，Ar-H)，7.05(d，2H，J＝8.6Hz，Ar-H)，6.65(s，1H，NH)，4.82-4.71(d×t，2H，
2J
HF＝47.8Hz，-CH
2CH
2F)，4.34-4.27(d×t，2H，
3J
HF＝27.7Hz，-CH
2CH
2F)，3.90(d，2H，J＝4.8Hz，NHCH
2COOH)；
13CNMR(CDCl
3，125MHz)δ：171.94，166.36，161.05，129.61，126.89，114.54，83.18，81.85，67.75，67.60；MS-EI：m/z＝241.08(found：241.13)；
The bio distribution test of test 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 saline water, and digestion adds in the culture medium solution its suspension-s 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, count, carry out after the decay correction, the counting of each tissue sample is all counted relatively with standard.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 are as shown in Figure 1 to the relative absorption value of formula (A) compound.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 5.1 at 60min.
The undue toxicity inspection of test example 2 formula A compounds of the present invention
Undertaken by Pharmacopoeia of People's Republic of China said 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 (4)
1. one type
18F labeled amino acid analog derivative is used for the research of tumour positron emission tomography, 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 a hydrogen; R2 is a hydrogen, and n is 1-5, and F does
18F,
2. claim 1 is described
18The preparation method of F labeled amino acid analog derivative is characterized in that it comprises the following steps: to use 15mg K
222And 3mgK
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
-Mixture and labelled precursor formula (B) compound at N, in the N-dimethylformamide solvent, reaction under heating condition, temperature of reaction is 80 ℃--140 ℃, the reaction times is 20 minutes, separates purification with performance liquid (HPLC), obtains
18F target-marking product, putting of affinity tag is pure greater than 99%,
R1 is a hydrogen, and R2 is a hydrogen, and n is 1-5.
3. the described preparation method of claim 2 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.
4. claim 1 is described
18The application of F labeled amino acid analog derivative in the positron emission tomography molecular probe of preparation report tumour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101675564A CN101723849B (en) | 2008-10-10 | 2008-10-10 | Novel 18F labeled amino acid derivatives, preparation method and application thereof in tumor imaging |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101675564A CN101723849B (en) | 2008-10-10 | 2008-10-10 | Novel 18F labeled amino acid derivatives, preparation method and application thereof in tumor imaging |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101723849A CN101723849A (en) | 2010-06-09 |
| CN101723849B true CN101723849B (en) | 2012-11-21 |
Family
ID=42445482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008101675564A Expired - Fee Related CN101723849B (en) | 2008-10-10 | 2008-10-10 | Novel 18F labeled amino acid derivatives, preparation method and application thereof in tumor imaging |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101723849B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012012612A2 (en) | 2010-07-23 | 2012-01-26 | University Of Delaware | Tetrazine-trans-cyclooctene ligation for the rapid construction of radionuclide labeled probes |
| CN103254140B (en) * | 2012-02-17 | 2016-02-17 | 北京师范大学 | Novel 18f marks substituted quinazoline compounds and preparation method thereof and applies with PET tumor imaging |
| CN102675329B (en) * | 2012-06-05 | 2014-12-24 | 浙江大学 | Positron emission tomography agent and preparation method thereof |
| CN106496062A (en) * | 2016-10-20 | 2017-03-15 | 复旦大学附属华山医院 | A kind of PET developers and preparation method thereof |
| CN109867591B (en) * | 2019-03-12 | 2020-11-06 | 浙江大学 | 18F-labelled AIEfluorescence/PET bimodal probe and preparation method and application thereof |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1674943A (en) * | 2002-08-02 | 2005-09-28 | 马林克罗特公司 | Radioactively labelled amino acid analogues, their preparation and use |
| CN1938244A (en) * | 2004-04-08 | 2007-03-28 | 通用电气健康护理有限公司 | Fluoridation method |
-
2008
- 2008-10-10 CN CN2008101675564A patent/CN101723849B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1674943A (en) * | 2002-08-02 | 2005-09-28 | 马林克罗特公司 | Radioactively labelled amino acid analogues, their preparation and use |
| CN1938244A (en) * | 2004-04-08 | 2007-03-28 | 通用电气健康护理有限公司 | Fluoridation method |
Non-Patent Citations (4)
| Title |
|---|
| 刘占峰等.同位素标记氨基酸的应用研究进展.《核技术》.2004,第27卷(第09期), * |
| 唐刚华等.O-(2-18F-氟代乙基)-L-酪氨酸的全自动合成.《核化学与放射化学》.2003,第25卷(第1期), * |
| 李俊玲等.18F标记氨基酸的研究进展.《同位素》.2002,第15卷(第1期), * |
| 李俊玲等.有潜力的PET脑肿瘤显像剂――18F标记的氨基酸药物.《核技术》.2002,第25卷(第6期), * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101723849A (en) | 2010-06-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101723849B (en) | Novel 18F labeled amino acid derivatives, preparation method and application thereof in tumor imaging | |
| CN101709060B (en) | F-triazole ring-polyethylene glycol-metronidazole compound and preparation method thereof | |
| CN107353323B (en) | Al18F-labeled PSMA (PSMA) targeted inhibitor and preparation method and application thereof | |
| EA017713B1 (en) | [f-18]-labeled l-glutamic acid, [f-18]-labeled l-glutamine, derivatives thereof and use thereof and processes for their preparation | |
| CN112175025B (en) | Glucose derivative containing benzene ring and application thereof | |
| CN111138504B (en) | A kind of99mTc-CNPEDG complex and preparation method and application thereof | |
| US20110263819A1 (en) | Simplified one-pot synthesis of [18f]sfb for radiolabeling | |
| CN101723850B (en) | Novel 18F labeled aromatic amino acids, preparation method and application thereof in tumor imaging | |
| CN113372285A (en) | Prostate specific membrane antigen inhibitor, radionuclide marker thereof, preparation method and application | |
| CN101768208B (en) | Novel 18F-labelled polypeptide, preparation method and application thereof in tumor imaging | |
| CN108299482A (en) | F-BPA and its intermediate synthetic method, intermediate and its application | |
| CN101723846B (en) | Novel 18F labeled p-nitro benzoyl amino acid derivatives, preparation method and application thereof in tumor imaging | |
| Mukai et al. | Design of Ga–DOTA-based bifunctional radiopharmaceuticals: Two functional moieties can be conjugated to radiogallium–DOTA without reducing the complex stability | |
| CN103254139A (en) | Novel <18>F marked 4-aminoquinazoline derivatives, and preparation methods and tumor PET development application thereof | |
| CN101891791B (en) | Derivate for labeling bile acid and reference compound, preparation method and application thereof | |
| CN101723847B (en) | Novel 18F labeled p-nitro benzoyl amino acid compound and preparation method and application thereof | |
| CN114031652B (en) | Glucose derivative containing cyclohexane and application thereof | |
| CN113583066B (en) | Mannose derivative and application thereof | |
| CN102603647B (en) | 18/19F-ester nitroimidazole compound, preparation method thereof and application as hypoxic tissue developing agent | |
| CN101723848B (en) | Novel 18F labeled m-nitro benzoyl amino acids, preparation method and application thereof in tumor imaging | |
| CN111362828A (en) | A kind of18F-labeled fluoropropionylated ornithine as well as preparation method and application thereof | |
| CN109438265B (en) | Compound with affinity with brown adipose tissue and preparation method and application thereof | |
| CN106631863B (en) | Radiosynthesis method of DTP (polyethylene terephthalate) developer | |
| CN110577478A (en) | Positron probe and preparation method and application thereof | |
| KR101389258B1 (en) | Nitroimidazole-amino acid compound type nuclide hypoxia imaging agent and intermediates for preparing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20121121 Termination date: 20141010 |
|
| EXPY | Termination of patent right or utility model |