CN102295685B - 18F-labeled PRGD2 compound, kit thereof, preparation method of kit thereof, and application thereof - Google Patents
18F-labeled PRGD2 compound, kit thereof, preparation method of kit thereof, and application thereof Download PDFInfo
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- CN102295685B CN102295685B CN 201110184202 CN201110184202A CN102295685B CN 102295685 B CN102295685 B CN 102295685B CN 201110184202 CN201110184202 CN 201110184202 CN 201110184202 A CN201110184202 A CN 201110184202A CN 102295685 B CN102295685 B CN 102295685B
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Abstract
The invention relates to an 18F labeled PRGD2 compound, a kit thereof, a preparation method of the kit, and an application thereof. The invention relates to a PET imaging agent, a preparation method thereof, and an application thereof. The invention belongs to the technical field of radiopharmaceuticals and nuclear medicines. The kit comprises NOTA-PRGD2 and aluminum chloride, wherein a molar ratio of NOTA-PRGD2 to aluminum chloride is (1-10):1. NOTA-PRGD2 and aluminum chloride exist in states of lyophilized powders. As results of preliminary studies, the kit has advantages of simple labeling, convenient operation, high labeling rate, low cost, and low time consumption. With the kit, a prepared complex 18F-FAl-NOTA-PRGD2 has same biological properties with those of 18F-FPPRGD2. Therefore, the compound and the kit have potentials to be popularized for clinical application.
Description
Technical field
The present invention relates to a kind of PET developer and preparation method and application, belong to radiopharmaceuticals and nuclear medicine technology field.
Background technology
Positron emission computerized tomography (PET) is as the sophisticated technology of 21 century biomedical research and clinical diagnosis, be called as " the biochemical video picture of live body " technology, can create, quantitatively, dynamically observe the physiology in the human body, the biochemical variation from external nothing, see clearly the activity of labeled drug in normal people or patient body.Compare with SPECT, PET resolving power height, but quantitative analysis has clear superiority.
18F has the positron efficient near 100%, and low positron energy (0.64 million electron volts) and relative short characteristics such as (t1/2=109.7 minutes) physical half life are desirable PET video picture nucleic.Polypeptide have tissue infiltration rapidly, remove fast in the blood, advantage such as immunogenicity is low, be the suitable carrier of preparation PET developer.At present, peptide is carried out
18The process of F mark comprises: the QMA column purification
18F, prothetic group (
18F-SFB or
18F-NFP) preparation and purifying, peptide and prothetic group be coupled HPLC purified product etc.Do not see solid preparation medicine box report is arranged both at home and abroad.
New vessel is most important to growth of tumor and transfer, and the integrin alpha v beta 3 acceptor is kept and regulated and bringing into play keying action in the vasculogenesis promoting.Arginine-glycine-aspartic acid (RGD) peptide dimer PRGD2 and integrin alpha v beta 3 acceptor height are affine, its
18The F marked product is suitable for tumor imaging, can be used for early diagnosis and the curative effect monitoring of tumour.Chen, preparation such as X
18F-FPPRGD2 has good tumor neogenetic blood vessels PET video picture characteristic, is used for clinical trial by the FDA approval.(Chen X, et al, J Nucl Med, 2007,48,1162-1171; Chen, X., et al Mol Imaging Biol 2010,12,530-538; Mittra ES, et al, Radiology, 2011,260 (1): 182-91.) but
18The preparation of F-FPPRGD2 is loaded down with trivial details, needs preparation prothetic group 18F-NFP earlier, be coupled with PRGD2 again, and two subgradient HPLC purifying, about 3h consuming time is difficult to clinical expansion at home, and its application is restricted.
18Easy and metal (as the aluminium) combination of F ion, generation
18The F-aluminum complex (
18F-Al) group (as the NOTA) chelating that can be chelated.Laverman etc. pass through
18F-Al carries out direct reaction with the haptens peptide that is connected NOTA, makes
18F labeling moiety antigen peptide.This process need not prothetic group preparation and purifying (Laverman et al, J Nucl Med, 2009,50:991-998).On this basis, the inventor provides a kind of single stage method preparation
18The medicine box of F mark PRGD2.Preliminary study shows that this medicine box mark is simple, easy to operate, the mark rate height, and cost is low, and can make the title complex of preparation
18F-FAl-NOTA-PRGD2, have with
18The biological property that F-FPPRGD2 is identical is expected to be applied clinically.
Summary of the invention
The technical problem to be solved in the present invention is to overcome the existing preparation defective workmanship, and a kind of medicine box is provided, and simple, easy to operate, the consuming time weak point of its mark, mark rate height, cost are low, and can make the title complex of preparation
18F-FAl-NOTA-PRGD2 have with
18The biological property that F-FPPRGD2 is identical is expected to be applied clinically.
In order to solve the problems of the technologies described above, the invention provides following technical scheme:
A kind of
18The PRGD2 compound of F mark, structural formula is suc as formula shown in the I:
Above-mentioned
18The application of the PRGD2 compound of F mark in the preparation of PET developer.
A kind of for
18The medicine box of F mark PRGD2 comprises NOTA-PRGD2 and aluminum chloride, and the mol ratio of NOTA-PRGD2 and aluminum chloride is (1～10): 1, and preferred mol ratio is (1～5): 1.Can also comprise acetic acid-sodium-acetate buffer in the described medicine box.Further, be used for
18The application of the medicine box of F mark PRGD2 in the preparation of PET developer.In the raw material that above-mentioned medicine box preparation method uses, NOTA-PRGD2 can be synthetic according to the method for prior art, and other reagent in the raw material all can be buied from market.
Preferably, NOTA-PRGD2 and aluminum chloride exist with the lyophilized powder form in the medicine box.
The preparation method of above-mentioned medicine box, step is as follows: NOTA-PRGD2 is dissolved in acetic acid-sodium-acetate buffer or the deionized water; 2) aluminum chloride is dissolved in acetic acid-sodium-acetate buffer or the deionized water; 3) both mix; 4) with after the sterile filtration of step 3) gained solution, be sub-packed in the container, lyophilize namely gets described medicine box.The preferred control antibiotic bottle of described container or plastics centrifugal bottle.
A kind ofly utilize the preparation of above-mentioned medicine box
18The method of F-FAl-NOTA-PRGD2 is: add an amount of acetic acid solution or acetic acid-sodium-acetate buffer dissolving in the described medicine box, add acetonitrile or ethanol and fresh making
18The F aqueous solution, airtight 80-120 ℃ was reacted 5～20 minutes cooling down; Inject Sep-Pak C18 behind the thin up and separate pillar, with PBS or water flushing pillar; With ethanol solution hydrochloride or ethanol elution marked product, physiological saline dilution back sterile filtration namely
18F-FAl-NOTA-PRGD2.
Preparation provided by the present invention
18The medicine box of F-FAl-NOTA-PRGD2 has following beneficial effect:
1. using method is easy, is fit to clinical application more
Adopt homemade multifunctional fluoric mark module preparation
18The F-FPRGD2 complex steps, preparation condition requires harsh, needs 3h consuming time, and the about 10%-20% of productive rate need carry out the HPLC purifying twice, and to the requirement height of preparation personnel specialty state of the art, corresponding equipment cost is also higher.Adopt medicine box preparation of the present invention
18F-FAl-PRGD2, simple to operate, cost is extremely low, only needs 20min, and the about 20-40% of productive rate need not the HPLC purifying, is fit to clinical application more.
2. mark rate height, marked product purity height
Medicine box of the present invention is adding
18 F afterreaction 10 minutes, HPLC are identified and are shown that mark rate can reach 20-40 %.Thick product is after the separation and purification of C18 pillar, and it is pure greater than 97% that HPLC measures putting of marked product.
The HPLC analytical system is as follows: anti-phase C18 post Φ 4.6 * 250mm, gradient elution: gradient was from 2 minutes 5%A(0.1%TFA acetonitrile solution) and the 95%B(0.1%TFA aqueous solution) being increased to 32 minutes 65%A, flow velocity is 1ml/min, retention time is 17min.
3. medicine box of the present invention makes
18The F-FAl-NOTA-PRGD2 biological property is good
Through experimental verification, make with the preparation method of prior art
18F-FPPRGD2 compares, and medicine box of the present invention prepares
18F-FAl-NOTA-PRGD2 has very high picked-up too and well is detained in the model mouse tumour, and have higher target/non-target ratio and better pharmacokinetic characteristics, biological property is good, can satisfy the requirement of tumour integrin alpha v beta 3 acceptor PET developer fully.
Description of drawings
Accompanying drawing is used to provide further understanding of the present invention, and constitutes the part of specification sheets, is used from explanation the present invention with embodiments of the invention one, is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is that the contrast experiment injects 3.7 MBq (100 μ Ci)
18The crown microPET video picture of BxPc-3 tumor model mouse whole body decay correction figure after 30,60,120 minutes behind the F-FPPRGD2, knub position is as shown by arrows;
Fig. 2 is that contrast experiment BxPc-3 tumour, liver, kidney and muscle are right
18The quantitative picked-up value figure of F-FPPRGD2;
Fig. 3 is that the present invention injects 3.7 MBq (100 μ Ci)
18The crown microPET video picture of BxPc-3 tumor model mouse whole body decay correction figure after 30,60,120 minutes behind the F-FAl-NOTA-PRGD2, knub position is as shown by arrows;
Fig. 4 is that BxPc-3 tumour, liver, kidney and muscle prepare the present invention
18The quantitative picked-up value figure of F-FAl-NOTA-PRGD2.
Embodiment
Below in conjunction with accompanying drawing the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for description and interpretation the present invention, and be not used in restriction the present invention.
One, 100 NOTA-RGD froze-dried kits of preparation
Method 1:
1) 1.6mgNOTA-RGD (R=OH) is dissolved in sodium-acetate-acetate buffer solution that 10mL concentration is 0.5M (pH4.0); Again with 0.08mg AlCl
3Be dissolved in sodium-acetate-acetate buffer solution that 10mL concentration is 0.5M (pH4.0); The two is mixed;
2) after the solution sterile filtration with the step 1) preparation, be sub-packed in 100 control antibiotic bottles; The antibiotic bottle that branch is installed imports on the Freeze Drying Equipment cold house shelf by pass-through, closes to the doorstep, and lyophilize is 24 hours by setup program, and gland seal namely gets the used medicine box of the present invention.
Method 2:
1) with 8.0mgNOTA-RGD (R=OH) and 0.08mg AlCl
3Be dissolved in respectively in the 10mL deionized water, again the two mixed;
2) after the solution sterile filtration with the step 1) preparation, be sub-packed in 100 control antibiotic bottles; The antibiotic bottle that branch is installed imports on the Freeze Drying Equipment cold house shelf by pass-through, closes to the doorstep, and lyophilize is 24 hours by setup program, and gland seal namely gets the used medicine box of the present invention.
Method 3:
1) with 4.0mgNOTA-RGD ((R=H)) and 0.08mg AlCl
3Be dissolved in respectively in the 10mL deionized water, again the two mixed;
2) after the solution sterile filtration with the step 1) preparation, be sub-packed in 100 control antibiotic bottles; The antibiotic bottle that branch is installed imports on the Freeze Drying Equipment cold house shelf by pass-through, closes to the doorstep, and lyophilize is 24 hours by setup program, and gland seal namely gets the used medicine box of the present invention.
Two, preparation
18F-FAl-NOTA-PRGD2
Method 1:
In the method 1 gained medicine box of step 1, add 5% acetic acid solution, 20 μ L, add the fresh 50mCi that makes of 100 μ L again
18F and 200 μ L acetonitriles, airtight 100 ℃ were reacted 10 minutes cooling down; Inject Sep-Pak C18 behind the thin up and separate pillar, water flushing pillar; Be the ethanol solution hydrochloride wash-out marked product of 7mM with 1.0mL concentration, physiological saline dilution back sterile filtration namely gets the formula II
18F-FAl-NOTA-PRGD2:
。
Method 2:
Adding concentration in the method 2 gained medicine boxs of step 1 is acetic acid-sodium-acetate buffer 20 μ L(pH4.0 of 0.5M), add the fresh 50mCi that makes of 100 μ L again
18F and 200 μ L ethanol, airtight 80 ℃ were reacted 20 minutes cooling down; Inject Sep-Pak C18 behind the thin up and separate pillar, wash pillar with PBS; With 1mL ethanol elution marked product, physiological saline dilution back sterile filtration namely gets the formula II
18F-FAl-NOTA-PRGD2.
Method 3:
Adding concentration in the method 3 gained medicine boxs of step 1 is acetic acid-sodium-acetate buffer 20 μ L(pH4.0 of 0.5M), add the fresh 50mCi that makes of 100 μ L again
18F and 200 μ L acetonitriles, airtight 120 ℃ were reacted 5 minutes cooling down; Inject Sep-Pak C18 behind the thin up and separate pillar, water flushing pillar; Be the ethanol solution hydrochloride wash-out marked product of 15mM with 0.5mL concentration, physiological saline dilution back sterile filtration namely gets the formula III
18F-FAl-NOTA-PRGD2:
Three, method 1 gained of step 2
18The F-FAl-NOTA-PRGD2 performance measurement
1) the HPLC method is identified to see before and is stated method;
2) vitro stability is measured:
Make above-mentioned respectively
18F-FAl-NOTA-PRGD2 solution is at room temperature placed different time (0.5,1,2,3,4 hours), carries out HPLC then and analyzes, and calculates radiochemical purity.Experimental result shows:
18F-FAl-NOTA-PRGD2 at room temperature can stablize and deposits more than 4 hours, and its outward appearance and radiochemical purity do not have considerable change.
3) model mouse MicroPET video picture and analysis:
Under isoflurane anesthesia, the lotus people BxPc-3 tumour about 3.7MBq of nude mice tail vein injection (100uCi)
18F-FAl-NOTA-PRGD2 or
18F-FPPRGD2.Adopt sequential 2 D subclass expectation maximization (two-dimentional OSEM) algorithm to carry out image reconstruction, the crown image of MicroPET scanning gained whole body decay correction is delineated region of interest (ROI).From a plurality of ROI average pixel values, obtain the radioactive activity in tumour, muscle, liver and the kidney and be converted into MBq/mL.It is 1g/ml that income value obtains %ID/g(supposition tissue density divided by injected dose).Result such as Fig. 1-shown in Figure 4, wherein, ROIs represents with average %ID/g ± SD.
Injected back 60 minutes, tumour is right
18The picked-up value of F-FPPRGD2 is 2.56 ± 0.48 % ID/g (n=5), and is consistent with bibliographical information.Under the identical time, tumour is right
18The picked-up value of F-FAl-NOTA-PRGD2 is 3.92 ± 0.48 % ID/g (n=5), is significantly higher than
18F-FPPRGD2 (p＜0.05).Except tumour, early stage (injecting back 30 minutes) all tracer agents are dense poly-at the kidney camber, after get rid of fast.The picked-up of all tracer agents in liver is lower.With
18F-FPPRGD2 compares,
18The removing of F-FAl-NOTA-PRGD2 in tumour is slower.
Above-mentionedly experiment showed, what gained medicine box of the present invention prepared
18F-FAl-NOTA-PRGD2 has
18The biological property that F-FPPRGD2 is good can satisfy the condition as tumour α v beta 3 receptor developer fully, and then illustrates that medicine box of the present invention can apply clinically.
It should be noted that at last: the above only is the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment the present invention is had been described in detail, for a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment puts down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (7)
1. one kind
18The PRGD2 compound of F mark, structural formula is suc as formula shown in the I:
2. claim 1 is described
18The application of the PRGD2 compound of F mark in the preparation of PET developer.
One kind described for the preparation of claim 1
18The medicine box of F-FAl-NOTA-PRGD2 is characterized in that: comprise in the described medicine box
NOTA-PRGD2 and aluminum chloride, the mol ratio of NOTA-PRGD2 and aluminum chloride are (1～10): 1; Also comprise acetic acid-sodium-acetate buffer in the described medicine box; Described NOTA-PRGD2 and aluminum chloride exist with the lyophilized powder form.
According to claim 3 described for the preparation of
18The medicine box of F-FAl-NOTA-PRGD2 is characterized in that: the mol ratio of described NOTA-PRGD2 and aluminum chloride is (1～5): 1.
Claim 3 or 4 described for the preparation of
18The application of the medicine box of F-FAl-NOTA-PRGD2 in the preparation of PET developer.
Claim 3 described for the preparation of
18The preparation method of the medicine box of F-FAl-NOTA-PRGD2 is characterized in that: step is as follows, and 1) NOTA-PRGD2 is dissolved in acetic acid-sodium-acetate buffer or the deionized water; 2) aluminum chloride is dissolved in acetic acid-sodium-acetate buffer or the deionized water; 3) both mix; 4) with after the sterile filtration of step 3) gained solution, be sub-packed in the container, lyophilize namely gets described medicine box.
One kind to utilize the described medicine box of claim 3 to prepare claim 1 described
18The method of F-FAl-NOTA-PRGD2 is characterized in that: add an amount of acetic acid solution or acetic acid-sodium-acetate buffer dissolving in the described medicine box, add acetonitrile or ethanol and fresh making
18The F aqueous solution, airtight 80-120 ℃ was reacted 5～20 minutes cooling down; Inject Sep-Pak C18 behind the thin up and separate pillar, with PBS or water flushing pillar; With ethanol solution hydrochloride or ethanol elution marked product, physiological saline dilution back sterile filtration namely
18F-FAl-NOTA-PRGD2.
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| CN108478817B (en) * | 2018-03-16 | 2020-10-27 | 北京大学 | Atherosclerosis detection reagent and preparation method thereof |
| CN111110873A (en) * | 2020-02-24 | 2020-05-08 | 苏州欣影生物医药技术有限公司 | Preparation method of magnetic resonance/nuclear medicine bimodal molecular imaging probe |
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| US7993626B2 (en) * | 2007-01-11 | 2011-08-09 | Immunomedics, Inc. | Methods and compositions for F-18 labeling of proteins, peptides and other molecules |
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Effective date of registration: 20190703 Address after: 214100 No. 20 Qian Rong Road, Binhu District, Wuxi City, Jiangsu Province Patentee after: Wuxi Jiangyuan Industry Company Jiangsu Institute of Nuclear Medicine Address before: 214063 No. 20 Qian Rong Road, Binhu District, Wuxi City, Jiangsu Province Patentee before: Jiangsu Prov. Inst. of Atomic Medicine |
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Address after: 214063 Jiangsu province Binhu District of Wuxi City Qian Rong Lu No. 20 Patentee after: Wuxi Jiangyuan industrial technology and Trade Co.,Ltd. Address before: 214100 No. 20 Qian Rong Road, Binhu District, Wuxi City, Jiangsu Province Patentee before: WUXI JIANGYUAN INDUSTRIAL TECHNOLOGY AND TRADE Corp. |