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RGD-type polypeptide pet imaging agent targeting integrin αvβ3 and its preparation method and application

A PET imaging agent, integrin technology, applied in the direction of radioactive carriers, etc., to achieve the effects of stable reaction system, good in vivo and in vitro stability, and low production cost

Active Publication Date: 2015-10-28
SHANGHAI ATOM KEXING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on the above reasons, a large number of linear or cyclic polypeptides containing RGD sequences have been synthesized as αvβ3 antagonists, and some of them have been successfully made into PET probes (Beer AJ, Lorenzen S, et al, Integrin alpha v beta3antagonist Cilengitide enhances efficacy of radiotherapy in endothelial cell and non-small-cell lung cancer models, J.Nucl.Med., 2008, 49(1):22-29; Schnell O, Krebs B, et al, Imaging of 4integrinαvβ3expression in patients with malignant glioma by[18F]Galacto -RGD positron emission tomography, Neuro Oncol.2009.11(6):861-870; Kenny LM, Coombes RC, et al, Phase I trial of the positron-emitting Arg-Gly-Asp(RGD) peptide radioligand18F-AH111585in breast cancer patients , J.Nucl.Med., 2008, 49(6):879-886; Liu S, Liu Z, et al, Molecular imaging and biology MIB the official publication of the Academy of Molecular Imaging, Mol. Imaging Biol., 2010 , 12(5):530-538; Haubner R, Weber WA, et al, Noninvasive Visualization of the Activated αvβ3 Integrin in Cancer Patients by Positron Emission Tomography and [18F]Galacto-RGD, PLoS Med., 2005, 2:244- 252, but so far no 18 F mark clinical product

Method used

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  • RGD-type polypeptide pet imaging agent targeting integrin αvβ3 and its preparation method and application
  • RGD-type polypeptide pet imaging agent targeting integrin αvβ3 and its preparation method and application
  • RGD-type polypeptide pet imaging agent targeting integrin αvβ3 and its preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] 5-[ 18 Radiosynthesis of F]fluoropentyne

[0041]

[0042] 25mCi18F-quaternary ammonium type anion column QMA (product of Waters, USA, 18 f - After capture, take 1.0mL K222 (ie Kryptofix222) solution (17.5mgK222, 3.5mg K 2 CO 3 , 1155μL acetonitrile, 45μL water solution) will 18 f - Rinse into the reaction bottle, immerse the reaction bottle in a 95°C oil bath, dry it with nitrogen, then add 500 μL of anhydrous acetonitrile to dry it, repeat the above operation twice; then dissolve 5 mg of 5-p-toluenesulfonylpentyne in 400 μL of anhydrous The acetonitrile solution was quickly added to the reaction flask under the protection of nitrogen, and the reaction was sealed at 95°C for 5 minutes, the reaction was stopped, and cooled in an ice-water bath. The marking rate can reach more than 95%, such as figure 1 shown. 5-[ 18 F] The retention time of fluoropentyne is 13.2min.

[0043] Add 200 μL of acetonitrile to the reaction solution, nitrogen assisted carrier, dis...

Embodiment 2

[0047] 5-[ 18 F]Radiolabeling of RGD polypeptide B by fluoropentyne

[0048] Dissolve 2 mg RGD polypeptide B (1.3 μmol) in a mixed solution of 200 μL pH6.0 phosphate buffer and 200 uL tert-butanol, add 50 μL 0.4M copper sulfate and 100 μL 1.2M sodium ascorbate solution, and then add 5- [ 18 F] 200 μL of acetonitrile solution of fluoropentyne was reacted at 50° C. for 15 minutes. The product is detected by HPLC (U.S. Agilent1100HPLC system, and the analytical column is Agilent ZORBAX EclipseXDB C18column (4.6mm × 250mm). The mobile phase is water (A) and acetonitrile (B) that have added 0.1% trifluoroacetic acid, and the gradient separation condition is: 0 -25min, 5%→50% B. The flow rate is 1.0mL / min. After UV (220nm) detection and radioactivity detection.)

[0049] like figure 2 As shown, radioactive HPLC analysis showed that the labeling rate of this experiment was >95%, and the retention time of the labeled product was tR=15.9min.

[0050] The reaction mixture was adde...

Embodiment 3

[0052] An RGD-type polypeptide PET imaging agent targeting integrin αvβ3, the structure of the imaging agent is:

[0053]

[0054] The above-mentioned RGD peptide PET imaging agent targeting integrin αvβ3 was prepared by the following method: in solvent water, the pH was adjusted to 3 by phosphate buffer solution, and under the catalysis of Cu(I), compound B and C were stacked The 1,3-dipolar cycloaddition reaction between nitrogen and terminal alkynyl groups for 1 to 80 minutes to obtain the product compound A;

[0055] The reaction formula is:

[0056] in:

[0057]

[0058] n is 2.

[0059] Wherein Cu(I) as a catalyst is prepared by the following method: by carrying out a reduction reaction of copper sulfate and ascorbic acid in a molar ratio of 1: 1.1;

[0060] The molar volume of the compound C and solvent water is 5.0×10 -14mol / 0.2mL; the concentration of the compound B in the reaction solution is 0.1mmol / L; the amount of the Cu (I) is 1 times the molar amou...

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Abstract

The invention discloses an RGD (Arg-Gly-Asp)-like peptide PET (positron emission tomography) developing agent of targeting integrin alpha v beta 3 and a preparation method thereof. The preparation comprises the following steps of: performing 1, 3 dipolar cycloaddition reaction of nitrine and alkynyl in the terminal position on a compound B and a compound C under the catalysis of Cu (I) in a solvent to prepare a compound A. The compound A can be used for diagnosing tumors, cardiovascular diseases and other diseases, such as malignant glioma, melanoma, H22 liver cancer and the like. The invention finds that the RGD-like peptide PET developing agent can specifically target the tumors with high expression of alpha v beta 3 by studies. A marking method of the PET developing agent is simple and universal, a reaction system is stable, conditions are mild, and the radiochemical purity, the specific activity and the radiochemical yield are higher. RGD-like peptide monomers used in the preparation method are low in production cost and convenient to perform large-quantity synthesis and modification, and the used other chemical reagents are low in cost and easy to obtain.

Description

technical field [0001] The present invention relates to a PET imaging agent, in particular to an RGD polypeptide PET imaging agent targeting integrin αvβ3 and its preparation method and application. Background technique [0002] Integrin αvβ3 is a heterodimeric transmembrane glycoprotein adhesion molecule formed by non-covalent linkage of α subunit and β subunit, and plays an important role in many important pathophysiological processes, such as cell proliferation , differentiation, invasion and migration, apoptosis, tissue repair and tumor invasion and metastasis (Cox D, Aoki T, Seki J, et al. The Pharmacology of the integrins, J. Med Res Rev, 1994, 14 (2) : 195-228; Hood JD, Cheresh DA, Role of integrins in cell invasion and migration, Nature Reviews Cancer, 2002, 2: 91-100; Hynes RO, Integrins: bidirectional, allosteric signaling machines, Cell, 2002, 110: 637 -687). αvβ3 is hardly expressed in mature vasculature, but overexpressed in neovascularization and a variety of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K51/08A61K101/02
Inventor 贾丽娜曹本红
Owner SHANGHAI ATOM KEXING PHARMA
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