CN105884868A - 18F marked affinity compound and preparation method and application thereof - Google Patents

18F marked affinity compound and preparation method and application thereof Download PDF

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CN105884868A
CN105884868A CN201610144196.0A CN201610144196A CN105884868A CN 105884868 A CN105884868 A CN 105884868A CN 201610144196 A CN201610144196 A CN 201610144196A CN 105884868 A CN105884868 A CN 105884868A
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asn
ala
formula
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CN105884868B (en
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杨敏
徐宇平
潘栋辉
赵富宽
严骏杰
王立振
杨润琳
张波
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Jiangsu Institute of Nuclear Medicine
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Abstract

The invention belongs to the field of radiopharmaceuticals and nuclear medicine, and particularly relates to an 18F marked affinity compound and a preparation method and application thereof. On the one hand, the uptake value of tumors on the 18F marked affinity compound is high, and tumor development sensitivity is high; on the other hand, the uptake value of the liver on the 18F marked affinity compound is low, and toxic and side effects on the liver are small. Animal experiments indicate that the uptake value of tumors on the 18F marked affinity compound is high, the residence time is short, the target/target-to-nontarget ratio is high, good pharmacokinetics characteristics are achieved, the biological properties are good, and the compound can be directly used as a tumor PET photographic developer targeted to an HER2 receptor. The preparation method of the 18F marked affinity compound is low in cost, easy and fast to operate, high in labeling rate and high in radiochemical purity of labeled products, and the prepared 18F marked affinity compound can be clinically applied and popularized as the tumor PET photographic developer targeted to the HER2 receptor.

Description

A kind of18Affinity body compounds of F labelling and preparation method and application
Technical field
The invention belongs to radiopharmaceutical and the field of nuclear medicine, be specifically related to one18The affinity body of F labelling Compounds and preparation method and application.
Background technology
Positron emission computerized tomography (PET) is as 21 century biomedical research and the point of clinical diagnosis End technology, is referred to as " imaging of live body biochemistry " technology, can from external noinvasive, quantitatively, dynamically see Examine the physiology in human body, Biochemical changes, see clearly labeled drug activity in normal person or patient body.With SPECT compares, and it is high and can the clear superiority such as quantitative analysis that PET has resolution.
18F has the positron efficiency close to 100%, low positron energy (0.64 million electro-volt) and phase To shorter (t physical half time1/2=109.7min) etc. feature, be preferable PET image nucleic.
Polypeptide have tissue infiltration rapidly, blood is quickly removed, the advantage such as immunogenicity is low, be to prepare18The suitable carrier of F labelling developer.ErbB-2 (human epithelial Growth factor receptor-2, HER2) it is incorporated in the transmembrane receptor sample albumen of surface of cell membrane, tool There is tyrosine kinase activity, participate in the growth of cell by activating downstream signaling pathway, activate and bred Journey.HER2 expresses not notable in the normal tissue, but in breast carcinoma, ovarian cancer, cervical cancer and pulmonary carcinoma Express etc. malignant tumor camber.Therefore, HER2 is the important target spot of tumor diagnosis and therapy.Affine Body (Affibody), also known as " artificial antibody ", is that a class is based on nonimmune albumen affinity ligand novel many Peptide.Affinity body ZHER2:342 is made up of 58 amino acid residues, has specific knot with HER2 Conjunction ability, its18F marked product is suitable to tumor imaging, can be used for early diagnosis and the curative effect prison of tumor Survey.
At present, affinity body is carried out18The method of F labelling, comprises the following steps: QMA column purification18F, multistep reaction prepare prothetic group (18F-SFB or18And purification, couple peptide, HPLC F-FBEM) Purification etc.；The method not only time-consuming (about 1～2h), operation is more complicated, and in product18F's is overall Mark rate is relatively low.18F ion easily combines with metal (such as: aluminum), generation18F-aluminum complex (18F- Al) can by NOTA chela and.Utilizing this principle, McBride etc. passes through18F-Al's and connection NOTA Peptide carries out direct reaction, prepares18F labelling peptide.This preparation method, without the preparation and purification of prothetic group Deng, preparation time shortens, and label has high specific activity.
Kramer-Marek G etc. is prepared for18F-FBEM-(ZHER2:342), it can be as targeting Developer (Kramer-Marek G et al, the Eur J Nucl Med Mol of the tumor of HER2 receptor Imaging, 2008,35,1008-1018).But, on the one hand, tumor is to above-mentioned18F-FBEM- (ZHER2:342) uptake values is relatively low, and this causes tumor imaging sensitivity relatively low；On the other hand, liver Dirty to above-mentioned18The uptake values of F-FBEM-(ZHER2:342) is higher, and this causes, and the poison to liver is secondary to be made With bigger；Additionally, it is above-mentioned18The preparation method of F-FBEM-(ZHER2:342) is more complicated, thus Limit its clinical practice to a certain extent.
Therefore, research tumor imaging sensitivity is higher, less to the toxic and side effects of liver, preparation method relatively Easy18The PET tumor imaging agent targeting HER2 receptor of F labelling is significant.
Summary of the invention
To this end, the present invention proposes one18The affinity body compounds of F labelling, and and then provide preparation side Method and application.
For solving above-mentioned technical problem, the present invention is achieved through the following technical solutions:
The present invention provides the compound shown in formula I,
Val-Asp-Asn-Lys-Phe-Asn-Lys-Glu-Met-Arg-Asn-Ala-Tyr-Trp-Glu-Ile-Ala- Leu-Leu-Pro-Asn-Leu-Asn-Asn-Gln-Asp-Lys-Arg-Ala-Phe-Ile-Arg-Ser-Leu-Tyr- Asp-Asp-Pro-Ser-Gln-Ser-Ala-Asn-Leu-Leu-Ala-Glu-Ala-Lys-Lys-Leu-Asn-Asp- Ala-Gln-Ala-Pro-Lys-Asn-Asp-Arg-Gly-Gly-Gly-R1
Wherein, R1Represent be
The present invention also provides for a kind of medicine box for preparing the compound shown in formula I, described medicine box Reagent includes: the compound shown in 1～10 molar part formula II and 1 molar part formula aluminum chloride,
Val-Asp-Asn-Lys-Phe-Asn-Lys-Glu-Met-Arg-Asn-Ala-Tyr-Trp-Glu-Ile-Ala- Leu-Leu-Pro-Asn-Leu-Asn-Asn-Gln-Asp-Lys-Arg-Ala-Phe-Ile-Arg-Ser-Leu-Tyr- Asp-Asp-Pro-Ser-Gln-Ser-Ala-Asn-Leu-Leu-Ala-Glu-Ala-Lys-Lys-Leu-Asn-Asp- Ala-Gln-Ala-Pro-Lys-Asn-Asp-Arg-Gly-Gly-Gly-R2
Wherein, R2Represent be
Preferably, in the above-mentioned medicine box for preparing the compound shown in formula I of the present invention, described medicine The reagent of box includes: the compound shown in 1～5 molar part formula II and 1 molar part aluminum chloride.
It is further preferred that in the above-mentioned medicine box for preparing the compound shown in formula I of the present invention, The reagent of described medicine box includes: the compound shown in 3 molar part formula II and 1 molar part aluminum chloride.
It is further preferred that in the above-mentioned medicine box for preparing the compound shown in formula I of the present invention, The reagent of described medicine box also includes: Acetic acid-sodium acetate buffer.
It is further preferred that in the above-mentioned medicine box for preparing the compound shown in formula I of the present invention, Described Acetic acid-sodium acetate buffer is 0.4～0.6mol/L, and pH is 3.0～5.0.
It is further preferred that in the above-mentioned medicine box for preparing the compound shown in formula I of the present invention, Described Acetic acid-sodium acetate buffer be 0.5mol/L, pH be 4.0.
It is further preferred that in the above-mentioned medicine box for preparing the compound shown in formula I of the present invention, Compound shown in formula II and described aluminum chloride are lyophilized powder.
The present invention also provides for the preparation method of a kind of above-mentioned medicine box, comprises the following steps:
(1) compound shown in the formula II of selected molar part is dissolved in described Acetic acid-sodium acetate buffering In liquid, obtain solution A, standby；
(2) aluminum chloride of selected molar part is dissolved in described Acetic acid-sodium acetate buffer, obtains solution B, standby；
(3) by described solution A and described solution B mix homogeneously, solution C is obtained, standby；
(4) described solution C is carried out aseptic filtration, be sub-packed in container, lyophilization, to obtain final product.
It is further preferred that in the above-mentioned preparation method of the present invention, described container is control antibiotic bottle.
The present invention also provides for the medicine box that above-mentioned preparation method prepares.
The present invention also provides for the application in preparing the compound shown in formula I of the above-mentioned medicine box.
The present invention also provides for the preparation method of the compound shown in a kind of formula I, comprises the following steps:
A acetic acid solution is added in above-mentioned medicine box by (), dissolve, and is subsequently adding acetonitrile and i.e. joins18F Aqueous solution, confined reaction 5～20min at 80～110 DEG C, cooling, obtain reactant liquor；
B described reactant liquor is added water dilution by (), inject Sep-Pak C18 and separate pillar, with PBS and Water rinses described Sep-Pak C18 and separates pillar, obtains marked product；
C (), with marked product described in ethanol elution, with normal saline dilution, aseptic filtration, to obtain final product.
Preferably, the preparation method of the compound shown in the above-mentioned formula I of the present invention, including following step Rapid:
(a) by 10～50 μ L mass fractions be 2～8% acetic acid solution add in above-mentioned medicine box, molten Solve, be subsequently adding 100～400 μ L acetonitriles and 100～200 μ L i.e. join 20～150mCi18F aqueous solution, Confined reaction 5～20min at 80～110 DEG C, cooling, obtain reactant liquor；
B described reactant liquor is added water dilution by (), inject Sep-Pak C18 and separate pillar, with PBS and Water rinses described Sep-Pak C18 and separates pillar, obtains marked product；
(c) with marked product described in 0.2～1mL ethanol elution, with normal saline dilution, aseptic filtration, Obtain.
It is further preferred that the preparation method of the compound shown in the above-mentioned formula I of the present invention, including with Lower step:
A the acetic acid solution that 20 μ L mass fractions are 5% is added to above-mentioned medicine box by (), dissolve, then Add 200 μ L acetonitriles and 50mCi that 150 μ L i.e. join18F aqueous solution, confined reaction at 100 DEG C 10min, cooling, obtain reactant liquor；
B described reactant liquor is added water dilution by (), inject Sep-Pak C18 and separate pillar, with PBS and Water rinses described Sep-Pak C18 and separates pillar, obtains marked product；
(c) with marked product described in 0.5mL ethanol elution, with normal saline dilution, aseptic filtration, i.e. ?.
The present invention also provides for the compound shown in formula I or above-mentioned medicine box in preparation PET developer Application.
Compared with prior art, the technique scheme of the present invention has the advantage that
(1) of the present invention18The affinity body compounds of F labelling, on the one hand, tumor is to its uptake values Higher, tumor imaging sensitivity is higher, and on the other hand, liver is relatively low to its uptake values, the poison to liver Side effect is less；Zoopery shows, described18The affinity body compounds of F labelling, it is taken the photograph by tumor Holdup time, higher target/non-target ratio and the preferable pharmacokinetic property that value is higher, shorter, Biological property is excellent, can be as the PET tumor imaging agent targeting HER2 receptor；
(2) present invention is by making medicine box by reaction raw materials and reagent, can be made by easy operation Standby described18The affinity body compounds of F labelling, this preparation method not only cost is relatively low, easy and simple to handle, Fast, and mark rate is higher, the radiochemical purity of marked product is higher, is conducive to preparing Described18The affinity body compounds of F labelling exists as the PET tumor imaging agent targeting HER2 receptor Popularization and application clinically.
Accompanying drawing explanation
In order to make present disclosure be more likely to be clearly understood, being embodied as below according to the present invention Example also combines accompanying drawing, and the present invention is further detailed explanation, wherein:
Fig. 1 be injection the compound 30min shown in 3.7MBq (100 μ Ci) formula I, 60min, After 120min and 240min, the SKOV-3 Transplanted tumor model Mus crown microPET of whole body decay correction shows As figure, knub position is as shown by arrows；
Fig. 2 be injection the compound 30min shown in 3.7MBq (100 μ Ci) formula I, 60min, After 120min and 240min, in SKOV-3 Transplanted tumor model Mus body, tumor, liver, kidney and flesh The meat quantitative uptake values to the compound shown in formula I, ROIs represents with average %ID/g ± SD.
Detailed description of the invention
Below in conjunction with accompanying drawing, technical scheme is clearly and completely described, it is clear that institute The embodiment described is a part of embodiment of the present invention rather than whole embodiments.Based in the present invention Embodiment, it is all that those of ordinary skill in the art are obtained under not making creative work premise Other embodiments, broadly fall into the scope of protection of the invention.
In following example of the present invention and experimental example, the compound shown in formula I,
Val-Asp-Asn-Lys-Phe-Asn-Lys-Glu-Met-Arg-Asn-Ala-Tyr-Trp-Glu-Ile-Ala- Leu-Leu-Pro-Asn-Leu-Asn-Asn-Gln-Asp-Lys-Arg-Ala-Phe-Ile-Arg-Ser-Leu-Tyr- Asp-Asp-Pro-Ser-Gln-Ser-Ala-Asn-Leu-Leu-Ala-Glu-Ala-Lys-Lys-Leu-Asn-Asp- Ala-Gln-Ala-Pro-Lys-Asn-Asp-Arg-Gly-Gly-Gly-R1
Wherein, R1Represent be
Compound shown in formula II, can synthesize (Mol Imaging Biol. by the method for prior art 2014,16 (4), 578-85),
Val-Asp-Asn-Lys-Phe-Asn-Lys-Glu-Met-Arg-Asn-Ala-Tyr-Trp-Glu-Ile-Ala- Leu-Leu-Pro-Asn-Leu-Asn-Asn-Gln-Asp-Lys-Arg-Ala-Phe-Ile-Arg-Ser-Leu-Tyr- Asp-Asp-Pro-Ser-Gln-Ser-Ala-Asn-Leu-Leu-Ala-Glu-Ala-Lys-Lys-Leu-Asn-Asp- Ala-Gln-Ala-Pro-Lys-Asn-Asp-Arg-Gly-Gly-Gly-R2
Wherein, R2Represent be
The concrete structure sequence of affinity body ZHER2:342 sees such as Publication about Document: Structural basis for high-affinity HER2 receptor binding by an engineered protein.Proceedings of the National Academy of Sciences of the United States of America, 2010,107 (34), 15,039 15044.
Remaining reagent and solvent are commercially available product, and the concentration of concrete reagent can be entered according to the method for prior art Row configuration.
Embodiment 1
The present embodiment is in the medicine box preparing the compound shown in formula (I), and its reagent includes: Compound shown in 25nmol formula II, 12nmol aluminum chloride, 0.5mol/L, pH are the acetic acid of 4.0 -sodium-acetate buffer；
The preparation method of this medicine box, comprises the following steps:
(1) compound shown in the formula II of selected mole is dissolved in the vinegar that 0.5mol/L, pH are 4.0 In acid-sodium-acetate buffer, obtain solution A, standby；
(2) aluminum chloride of selected mole is dissolved in the Acetic acid-sodium acetate buffer that 0.5mol/L, pH are 4.0 In, obtain solution B, standby；
(3) by described solution A and described solution B mix homogeneously, solution C is obtained, standby；
(4) described solution C is carried out aseptic filtration, be sub-packed in control antibiotic bottle, lyophilization 24 Hour, sealing of jumping a queue, to obtain final product.
The preparation method of the compound shown in the present embodiment formula I, comprises the following steps:
A the acetic acid solution that 20 μ L mass fractions are 5% is added to above-mentioned medicine box by (), dissolve, then Add 200 μ L acetonitriles and 50mCi that 150 μ L i.e. join18F aqueous solution, confined reaction at 100 DEG C 10min, cooling, obtain reactant liquor；
B described reactant liquor is added water dilution by (), inject Sep-Pak C18 and separate pillar, with PBS and Water rinses described Sep-Pak C18 and separates pillar, obtains marked product；
(c) with marked product described in 0.5mL ethanol elution, with normal saline dilution, aseptic filtration, i.e. ?.
Embodiment 2
The present embodiment is in the medicine box preparing the compound shown in formula I, and its reagent includes: Compound shown in 1nmol formula II, 1nmol aluminum chloride, 0.4mol/L, pH be 5.0 acetic acid- Sodium-acetate buffer；
The preparation method of this medicine box, comprises the following steps:
(1) compound shown in the formula II of selected mole is dissolved in the vinegar that 0.4mol/L, pH are 5.0 In acid-sodium-acetate buffer, obtain solution A, standby；
(2) aluminum chloride of selected mole is dissolved in the Acetic acid-sodium acetate buffer that 0.4mol/L, pH are 5.0 In, obtain solution B, standby；
(3) by described solution A and described solution B mix homogeneously, solution C is obtained, standby；
(4) described solution C is carried out aseptic filtration, be sub-packed in control antibiotic bottle, lyophilization 24 Hour, sealing of jumping a queue, to obtain final product.
The preparation method of the compound shown in the present embodiment formula I, comprises the following steps:
A the acetic acid solution that 10 μ L mass fractions are 8% is added to above-mentioned medicine box by (), dissolve, then Add 100 μ L acetonitriles and 20mCi that 200 μ L i.e. join18F aqueous solution, confined reaction 5min at 110 DEG C, Cooling, obtains reactant liquor；
B described reactant liquor is added water dilution by (), inject Sep-Pak C18 and separate pillar, with PBS and Water rinses described Sep-Pak C18 and separates pillar, obtains marked product；
(c) with marked product described in 1mL ethanol elution, with normal saline dilution, aseptic filtration, i.e. ?.
Embodiment 3
The present embodiment is in the medicine box preparing the compound shown in formula I, and its reagent includes: Compound shown in 5nmol formula II, 1nmol aluminum chloride, 0.6mol/L, pH be 3.0 acetic acid- Sodium-acetate buffer；
The preparation method of this medicine box, comprises the following steps:
(1) compound shown in the formula II of selected mole is dissolved in the vinegar that 0.6mol/L, pH are 3.0 In acid-sodium-acetate buffer, obtain solution A, standby；
(2) aluminum chloride of selected mole is dissolved in the Acetic acid-sodium acetate buffer that 0.6mol/L, pH are 3.0 In, obtain solution B, standby；
(3) by described solution A and described solution B mix homogeneously, solution C is obtained, standby；
(4) described solution C is carried out aseptic filtration, be sub-packed in control antibiotic bottle, lyophilization 24 Hour, sealing of jumping a queue, to obtain final product.
The preparation method of the compound shown in the present embodiment formula I, comprises the following steps:
A the acetic acid solution that 50 μ L mass fractions are 2% is added to above-mentioned medicine box by (), dissolve, then Add 400 μ L acetonitriles and 150mCi that 100 μ L i.e. join18F aqueous solution, confined reaction at 80 DEG C 20min, cooling, obtain reactant liquor；
B described reactant liquor is added water dilution by (), inject Sep-Pak C18 and separate pillar, with PBS and Water rinses described Sep-Pak C18 and separates pillar, obtains marked product；
(c) with marked product described in 0.2mL ethanol elution, with normal saline dilution, aseptic filtration, Obtain.
Embodiment 4
The present embodiment is used for the district of the medicine box preparing the compound shown in formula I and the medicine box of embodiment 1 It is not only that: the compound shown in formula II is 6nmol, and remaining reagent is same as in Example 1；
Differing only in of the preparation method of the preparation method of the present embodiment medicine box and the medicine box of embodiment 1, Compound shown in formula II is 6nmol, the preparation method of the medicine box of remaining operating procedure and embodiment 1 Identical.
Shown in the preparation method of the compound shown in the present embodiment formula I and embodiment 1 formula I The preparation method of compound is identical.
Embodiment 5
The present embodiment is used for the district of the medicine box preparing the compound shown in formula I and the medicine box of embodiment 1 It is not only that: the compound shown in formula II is 9nmol, and remaining reagent is same as in Example 1；
Differing only in of the preparation method of the preparation method of the present embodiment medicine box and the medicine box of embodiment 1, Compound shown in formula II is 9nmol, the preparation method of the medicine box of remaining operating procedure and embodiment 1 Identical.
Shown in the preparation method of the compound shown in the present embodiment formula I and embodiment 1 formula I The preparation method of compound is identical.
Experimental example 1The identification experiment of the compound shown in formula I
1, experiment purpose
The retention time of detection compound shown in formula I and radiochemical purity.
2, experimental technique
2.1 experimental apparatus and reagent
Waters 515 pump, UV-detector, gamma-ray detector.
Chromatographic column: Phenomenex Luna C-18 (4.6 × 250mm) analytical column.
Flowing phase: mobile phase A is the acetonitrile solution containing 0.1% trifluoroacetic acid, and Mobile phase B is containing 0.1% The aqueous solution of trifluoroacetic acid.
2.2 experimental technique
Following program carries out gradient elution: 0-2min, A:B are 5%:95%；2-32min, A:B For 5%:95% → 65%:35%；Flow velocity 1.0mL/min, detects wavelength 218nm.
The each 20 μ L of PBS solution of the compound shown in formula I that respectively prepared by Example 1-5, Inject chromatograph of liquid, measure.
3, experimental result
Understanding through experiment, the retention time of the compound shown in formula I is about 13min, activation Learn purity and be all higher than 95%.
Experimental example 2The vitro stability experiment of the compound shown in formula I
1, experiment purpose
The radiochemical purity of the compound shown in formula I after detection placement different time.
2, experimental technique
Under room temperature, the PBS solution of the compound shown in formula I embodiment 1-5 prepared respectively is put Put different time (0.5h, 1h and 2h), carry out HPLC analysis according to the experimental technique of experimental example 1, Calculate radiochemical purity.
3, experimental result
Through experiment understand, the compound shown in formula I at room temperature can more than stable existence 4h, Its outward appearance and radiochemical purity are without significant change.
Experimental example 3The MicroPET imaging experiment of the compound shown in formula I
1, experiment purpose
Verified and analyze the MicroPET imaging work of the compound shown in formula I by zoopery With.
2, experimental technique
Under isoflurane anesthesia, lotus human ovarian cancer SKOV-3 tumor nude mice tail vein injection about 3.7MBq The compound shown in formula I of (100 μ Ci) embodiment 1 preparation.
Sequential 2 D subset expectation maximization (two dimension OSEM) algorithm is used to carry out image reconstruction.Every time During MicroPET scanning, the software using supplier to provide on whole body decay correction coronal image is delineated Region of interest (ROI).Obtain in tumor, liver, kidney and muscle from multiple ROI average pixel values Radioactivity (adding up) and be converted into MBq/mL, income value divided by injection dosage obtain %ID/g (assuming that tissue density is 1g/mL).
3, experimental result
Experimental result is as depicted in figs. 1 and 2.
From Fig. 1 and Fig. 2, after injection 60min, tumor is taken the photograph the compound shown in formula I Value is 16.54 ± 2.69%ID/g, is all remarkably higher than document (Kramer-Marek G et al, Eur J Nucl Med Mol Imaging, 2008,35,1008-1018) tumor pair reported18F-FBEM- (ZHER2:342) uptake values 9.73 ± 1.91%ID/g.
From Fig. 1 and Fig. 2, after injection 30min, in addition to tumor, the compound shown in formula I Dense poly-at kidney camber, the most quickly get rid of.
From Fig. 1 and Fig. 2, the uptake values in liver of the compound shown in formula I is 3.02 ± 0.51%ID/g, substantially less than document (Kramer-Marek G et al, Eur J Nucl Med Mol Imaging, 2008,35,1008-1018) liver pair reported18F-FBEM-'s (ZHER2:342) Uptake values 5.04 ± 0.69%ID/g.
To sum up, of the present invention18The affinity body compounds of F labelling, on the one hand, it is absorbed by tumor Being worth higher, tumor imaging sensitivity is higher, and on the other hand, liver is relatively low to its uptake values, to liver Toxic and side effects is less；Zoopery shows, described18The affinity body compounds of F labelling, tumor is to it Holdup time, higher target/non-target ratio and the preferable pharmacokinetics that uptake values is higher, shorter Matter, biological property is excellent, can be as the PET tumor imaging agent targeting HER2 receptor；The present invention By reaction raw materials and reagent are made medicine box, can be prepared described by easy operation18F labelling Affinity body compounds, this preparation method not only cost is relatively low, easy and simple to handle, quick, and mark rate Radiochemical purity higher, marked product is higher, and be conducive to preparing is described18The parent of F labelling Fit compounds is as the PET tumor imaging agent popularization and application clinically targeting HER2 receptor.
Obviously, above-described embodiment is only for clearly demonstrating example, and not to embodiment Restriction.For those of ordinary skill in the field, can also do on the basis of the above description Go out change or the variation of other multi-form.Here without also all of embodiment being given thoroughly Lift.And the obvious change thus extended out or variation are still in the protection domain of the invention Among.

Claims (10)

1. the compound shown in formula I:
Val-Asp-Asn-Lys-Phe-Asn-Lys-Glu-Met-Arg-Asn-Ala-Tyr-Trp-Glu-Ile-Ala- Leu-Leu-Pro-Asn-Leu-Asn-Asn-Gln-Asp-Lys-Arg-Ala-Phe-Ile-Arg-Ser-Leu-Tyr- Asp-Asp-Pro-Ser-Gln-Ser-Ala-Asn-Leu-Leu-Ala-Glu-Ala-Lys-Lys-Leu-Asn-Asp- Ala-Gln-Ala-Pro-Lys-Asn-Asp-Arg-Gly-Gly-Gly-R1
Wherein, R1Represent be
2. the medicine box being used for preparing the compound shown in formula I, it is characterised in that described medicine The reagent of box includes: the compound shown in 1～10 molar part formula II and 1 molar part aluminum chloride,
Val-Asp-Asn-Lys-Phe-Asn-Lys-Glu-Met-Arg-Asn-Ala-Tyr-Trp-Glu-Ile-Ala- Leu-Leu-Pro-Asn-Leu-Asn-Asn-Gln-Asp-Lys-Arg-Ala-Phe-Ile-Arg-Ser-Leu-Tyr- Asp-Asp-Pro-Ser-Gln-Ser-Ala-Asn-Leu-Leu-Ala-Glu-Ala-Lys-Lys-Leu-Asn-Asp- Ala-Gln-Ala-Pro-Lys-Asn-Asp-Arg-Gly-Gly-Gly-R2
Wherein, R2Represent be
Medicine box for preparing the compound shown in formula I the most according to claim 2, it is special Levying and be, the reagent of described medicine box includes: the compound shown in 1～5 molar part formula II and 1 molar part Aluminum chloride.
4. according to the medicine box for preparing the compound shown in formula I described in Claims 2 or 3, It is characterized in that, the reagent of described medicine box also includes: Acetic acid-sodium acetate buffer.
Medicine box for preparing the compound shown in formula I the most according to claim 4, it is special Levying and be, described Acetic acid-sodium acetate buffer is 0.4～0.6mol/L, and pH is 3.0～5.0.
6. the preparation method of the medicine box described in a claim 4, it is characterised in that include following step Rapid:
(1) compound shown in the formula II of selected molar part is dissolved in described Acetic acid-sodium acetate buffering In liquid, obtain solution A, standby；
(2) aluminum chloride of selected molar part is dissolved in described Acetic acid-sodium acetate buffer, obtains solution B, standby；
(3) by described solution A and described solution B mix homogeneously, solution C is obtained, standby；
(4) described solution C is carried out aseptic filtration, be sub-packed in container, lyophilization, to obtain final product.
7. the answering in preparing the compound shown in formula I of the medicine box described in any one of claim 3-5 With.
8. the preparation method of the compound shown in a formula I, it is characterised in that include following step Rapid:
A acetic acid solution is added to the medicine box described in any one of claim 3-5 by (), dissolve, then Add acetonitrile and i.e. join18F aqueous solution, confined reaction 5～20min at 80～110 DEG C, cooling, obtain instead Answer liquid；
B described reactant liquor is added water dilution by (), inject Sep-Pak C18 and separate pillar, with PBS and Water rinses described Sep-Pak C18 and separates pillar, obtains marked product；
C (), with marked product described in ethanol elution, with normal saline dilution, aseptic filtration, to obtain final product.
The preparation method of the compound shown in formula I the most according to claim 8, its feature exists In, comprise the following steps:
(a) by 10～50 μ L mass fractions be 2～8% acetic acid solution add to any one of claim 3-6 In described medicine box, dissolve, be subsequently adding 100～400 μ L acetonitriles and 100～200 μ L i.e. join 20～150mCi18F aqueous solution, confined reaction 5～20min at 80～110 DEG C, cooling, obtain reactant liquor；
B described reactant liquor is added water dilution by (), inject Sep-Pak C18 and separate pillar, with PBS and Water rinses described Sep-Pak C18 and separates pillar, obtains marked product；
(c) with marked product described in 0.2～1mL ethanol elution, with normal saline dilution, aseptic filtration, Obtain.
10. the compound shown in formula I or the medicine box described in any one of claim 3-6 are in preparation Application in PET developer.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008118601A2 (en) * 2007-02-27 2008-10-02 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Radiolabeled affibody molecules

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008118601A2 (en) * 2007-02-27 2008-10-02 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Radiolabeled affibody molecules

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* Cited by examiner, † Cited by third party
Title
CHARLES EIGENBROT等: "Structural basis for high-affinity HER2receptor binding by an engineered protein", 《PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA》 *
YUPING XU等: "pilot study of a novel 18F-labeled FSHR prove for tumor imaging", 《MOLECUL ARIMAGING AND BIOLOGY》 *

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