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Radioisotope labeled polypeptide developer of targeted transferrin receptor and application of radioisotope labeled polypeptide developer

A technology of radioisotopes and transferrin, which is applied in the field of radioisotope-labeled polypeptide imaging agents, can solve the problems of long distribution time, short elimination half-life, and functional inactivation, achieving high accuracy and sensitivity, simple labeling methods, and labeling high rate effect

Pending Publication Date: 2020-12-08
SUN YAT SEN UNIV CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Existing studies are mostly based on the TFRC-Tf mechanism, using TF as a targeting ligand to design imaging agents. However, there are three shortcomings in this mechanism: ① Endogenous Tf in the body can compete with Tf ligand imaging agents for TFRC ②Tf protein has a large molecular weight (76-81kDa), and the distribution in the body takes a long time, requiring a radioactive isotope with a particularly long half-life (such as 89 Zr 1 / 2 =78.4h) labeling for PET imaging increases the extra radiation dose of the body; ③The change of the spatial conformation of the Tf protein easily leads to its functional inactivation and is not conducive to the targeting effect
However, peptide drugs also have disadvantages such as rapid metabolism of prototype drugs in vivo, short elimination half-life, and low bioavailability.

Method used

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  • Radioisotope labeled polypeptide developer of targeted transferrin receptor and application of radioisotope labeled polypeptide developer
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  • Radioisotope labeled polypeptide developer of targeted transferrin receptor and application of radioisotope labeled polypeptide developer

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Experimental program
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preparation example Construction

[0093] Preparation of polypeptide precursors

[0094] 1. Preparation of Fmoc-Pip-OH

[0095] Fmoc-Pip-OH can be obtained by protecting 4-amino-(1-carboxymethyl)piperidine with tert-butanol and Fmoc-Cl, of course, it can also be prepared by other methods familiar to those skilled in the art.

[0096] The structural formula of Fmoc-Pip-OH finally prepared in this embodiment is as follows:

[0097]

[0098] 2. Preparation of Fmoc-AEEP-OH

[0099] Fmoc-AEEP-OH can be obtained by sequential protection of 3-[2-(2-aminoethoxy)ethoxy]-propionic acid through tert-butanol and Fmoc-Cl. Of course, other methods familiar to those skilled in the art can also be used. method to prepare.

[0100] The structural formula of Fmoc-AEEP-OH finally prepared in this embodiment is as follows:

[0101]

[0102] 3. Preparation of NOTA-tBu(2)

[0103] NOTA-tBu (2) can be prepared by reacting NOTA and tert-butanol under the trifluoromethanesulfonic anhydride catalyzed system, and can also be p...

Embodiment 168

[0121] Example 1 68 Preparation of Ga-NOTA-Pip-HAIYPRH

[0122] 1. 68 Ga-labeled NOTA-Pip-HAIYPRH

[0123] Dissolve 20ug of the above-mentioned polypeptide precursor NOTA-Pip-HAIYPRH in 200ul 1M sodium acetate solution, put it into a reaction bottle, and draw 0.05mol / L HCl 5ml with a 5ml syringe to 68 Ge / 68 The Ga generator performs segmental leaching, the flow rate is 1ml / min, and the middle 1.5ml of high activity is collected 68 Add the Ga eluent into the reaction bottle, adjust the pH of the reaction solution to 3.8-4.2, seal it, and place it in a water bath with a multifunctional heater at 90°C for 10 minutes.

[0124] The radiochemical purity of the product was measured, and if the radiochemical purity of the product was ≥80%, it indicated that the labeling was successful.

[0125] 2. Product purification

[0126] Draw the above-mentioned labeled product solution after the reaction with a syringe, add it to the activated Sep-pak C-18 column, and then use 5ml physio...

Embodiment 268G

[0131] Example 2 68 Preparation of Ga-NOTA-AEEP-HAIYPRH

[0132] 1. 68 Ga-labeled NOTA-AEEP-HAIYPRH

[0133] Dissolve 20ug of the above-mentioned polypeptide precursor NOTA-AEEP-HAIYPRH in 200ul 1M sodium acetate solution, put it into a reaction bottle, and draw 0.05mol / L HCl 5ml with a 5ml syringe to 68 Ge / 68 The Ga generator performs segmental leaching, the flow rate is 1ml / min, and the middle 1.5ml of high activity is collected 68 Add the Ga eluent into the reaction bottle, adjust the pH of the reaction solution to 3.8-4.2, seal it, and place it in a water bath with a multifunctional heater at 90°C for 10 minutes.

[0134] The radiochemical purity of the product was measured, and if the radiochemical purity of the product was ≥80%, it indicated that the labeling was successful.

[0135] 2. Product purification

[0136] Draw the above-mentioned labeled product solution after the reaction with a syringe, add it to the activated Sep-pak C-18 column, and then use 5ml phy...

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Abstract

The invention discloses a radioisotope labeled polypeptide developer of a targeted transferrin receptor and application of the radioisotope labeled polypeptide developer. The invention particularly discloses a 68Ga chelation reaction labeling method of two polypeptide precursors and application of the two polypeptide precursors as an imaging agent in positron emission tomography (PET) of a transferrin receptor overexpressed tumor. The radioisotope labeled product has radiochemical purity of more than 95% and good in-vivo stability, can be rapidly aggregated within 5 minutes at a tumor site, has obvious tumor muscle contrast, can realize clear imaging of tumor tissues and margins, and has a certain difference between pharmacokinetics and biodistribution due to structural modification of different linking groups, so that the compound can be used as a tumor-specific imaging agent of a targeted transferrin receptor.

Description

technical field [0001] The invention belongs to the field of preparation and application of biomedical imaging agents, and in particular relates to radioisotope-labeled polypeptide imaging agents targeting transferrin receptors and applications thereof. Background technique [0002] Positron Emission Tomography (PET) is the most cutting-edge medical molecular imaging technology, widely used in the early diagnosis and curative effect evaluation of malignant tumors, cardiovascular, nervous system and other major diseases. PET has significant advantages: ① three-dimensional functional imaging of radioactive probes can be obtained, showing the spatial distribution of biomolecular activities in human models; ② non-invasive in vivo imaging can realize real-time visualization of cancer-related processes, and promote the understanding of tumor evolution; ③By combining with other imaging modalities such as magnetic resonance imaging (MRI) and computed tomography (CT) to form multimod...

Claims

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Application Information

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IPC IPC(8): A61K51/08C07K7/06A61K103/00
CPCA61K51/08C07K7/06
Inventor 樊卫王瑞敏张晓飞张旭
Owner SUN YAT SEN UNIV CANCER CENT
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