Nuclear medicine of structure modified RGD polypeptide

A drug and peptide technology, applied in the field of nuclear medicine drugs, can solve the problems of complex synthesis, high cost, and low tumor uptake

Active Publication Date: 2019-09-13
PEKING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, many cyclic RGD monomeric peptide radiolabels have low tumor uptake, fast blood clearance, and high uptake in kidneys, liver and other organs, which limit the application of cyclic monomeric peptides as imaging agents; As the degree of multimerization increases, the uptake of radioactive RGD polypeptides in kidneys, liver, lungs and other organs also increases significantly. Moreover, the higher the degree of multimerization, the more complex the synthesis and the higher the cost. These are also the restrictive factors for the development of multimerization of RGD probes; The advantages of multimerization or modification of RGD probes with large molecular weight pharmacokinetic linkers are no longer apparent

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 168G

[0081] Example 1 68 Preparation of Ga-DOTA-A-c(RGDfk)

[0082] The synthetic route of DOTA-A-c (RGDfk) is as follows:

[0083]

[0084] (1) Synthesis of compound 1

[0085] Weigh 4-(4-iodophenyl)butanoic acid (9.8 mg, 33.8 mmol) into a one-necked bottle, dissolve it in 400 μL DMF, and add NHS (3.9 mg, 33.9 mmol). Then add 5.3 μL of DIC. The reaction was stirred at 30°C for 2 hours, and monitored by TLC (ethyl acetate:petroleum ether:acetic acid=100:200:2) until the raw materials disappeared. After the reaction was completed, the reaction solution was dissolved in ethyl acetate, washed with water three times, the ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (ethyl acetate:petroleum ether:acetic acid=100:200:2) , collected fractions for detection, and spin-dried the collected product to obtain 10.2 mg of a white solid, with a yield of 78%. The expected product was confirmed by MALDI-TOF mass spectrometry...

Embodiment 2

[0107] Example 2: In vivo biodistribution experiment of the molecular probe of Example 1

[0108] Thirty-six tumor-bearing C57BL / 6J mice were randomly divided into 9 groups with 4 mice in each group. The four groups were each injected with 0.1 mL of tail vein 68 Ga-DOTA-A-c (RGDfk) (about 1.85MBq), four groups of tail vein injection 68 Ga-DOTA-c (RGDfk) (about 1.85MBq) was sacrificed after blood was drawn at 0.5h, 1h, 2h, and 4h, and the heart, liver, spleen, lung, kidney, intestine, stomach, bone, meat, and tumor were dissected. . Measure mass and count radioactivity, weigh and measure radioactive cpm counts, and calculate percent injected dose per gram of tissue (%ID / g) after decay correction. Simultaneously inject 0.1 mL into the remaining group of tail veins 68 Ga-DOTA-A-c(RGDfk) and 0.05mL c(RGDfk) solution (0.5mg) were sacrificed one hour later, the organs were weighed and radioactive cpm counts were measured, and the percent injected dose per gram of tissue was calc...

Embodiment 3

[0110] Example 3: 99m Tc-HYNIC-A-3PRGD 2 preparation of

[0111] HYNIC-A-3PRGD 2 The schematic diagram of the synthetic route is as follows:

[0112]

[0113] R=3PRGD 2

[0114] (1) Synthesis of Compounds 1, 2, and 3

[0115] The synthesis method of the compound refers to Example 1.

[0116] (2) Synthesis of compound 7

[0117] Weigh compound 3 (5.64mg, 7.65mmol) in 1mL EP tube, dissolve in 500μL DMF, add 3PRGD 2 (15.75mg, 7.8mmol), then add DIEA to adjust pH=8.5, and react overnight at room temperature. The reaction was monitored using HPLC. Using HPLC (High Performance Liquid Chromatography) Method 1, the product peaked at 13.17 min. Collected by HPLC and identified by mass spectrometry, it was determined to be the expected product.

[0118] MALDI-TOF-MS: m / z=2680.89 (chemical formula: C 123 h 181 IN 24 o 35 , Calculated molecular weight: 2681.22Da.).

[0119] (3) Synthesis of Compound 8

[0120] Add 125 μL of piperidine to the EP tube of the previous rea...

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PUM

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Abstract

The invention provides a structure modified RGD polypeptide, a complex formed by the polypeptide and radionuclides and a medicinal composition containing the complex. The medicinal composition is usedfor diagnosing or treating integrin alpha v beta 3 positive tumors. The complex has the following definitions: A in the A-(L)n-RGD polypeptide has a structure as shown in the specification, L represents a linker arm molecule and has a structure as shown in the specification, and m is an integer of 1-8.

Description

technical field [0001] The present invention relates to a nuclear medicine drug modified for tumor-targeting RGD polypeptide, in particular to a radiopharmaceutical for diagnosis or treatment of structurally modified RGD polypeptide. Background technique [0002] Molecular imaging refers to the qualitative and quantitative research on cellular and molecular levels of biological processes in vivo using imaging. Molecular probes are the key to the development of molecular imaging. They have specific targeting of a specific biological molecule (such as protein, RNA, DNA) and can be traced in vivo or in vitro. These labeled compound molecules It can reflect the quantitative function of its target biomolecules. Molecular probes can be divided into nuclear medicine probes, optical probes, and MRI probes according to the different imaging methods used, among which nuclear medicine molecular probes have unique advantages. Molecular probes are classified according to molecular weig...

Claims

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Application Information

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IPC IPC(8): A61K51/08A61P35/00C07K7/64
CPCA61K51/082A61P35/00C07K7/64
Inventor 王凡史继云贾兵高瀚男
Owner PEKING UNIV
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