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Probe capable of reducing radioactive kidney concentration based on enzyme digestion principle and preparation method thereof

A radioactive and radioactive labeling technology, applied in the field of medicine, can solve the problems of difficult prevention, restricting the dose of treatment, the number of courses of treatment and the final curative effect, and difficult to monitor sensitively, and achieves reduction of radioactive concentration and retention and excellent imaging. or therapeutic effect, the effect of high clinical promotion value

Pending Publication Date: 2021-01-22
西安华牧生物科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 2. The incidence of radiation kidney injury is high and the consequences are serious
[0006] 3. Radiation-induced kidney injury is delayed and insidious, making it difficult to monitor sensitively
[0007] 4. The dose threshold of radiation kidney injury is uncertain, and it is difficult to prevent it
[0008] In summary, in receptor-mediated radionuclide therapy, there are prominent problems of high incidence of radiation-induced kidney injury, serious consequences, uncertain threshold, and difficulty in monitoring and predicting. The main dose of radionuclide therapy is limited to the organ, which greatly restricts the dosage, number of courses of treatment and the final curative effect of the treatment, which has become a key problem to be solved urgently in receptor-mediated radionuclide therapy

Method used

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  • Probe capable of reducing radioactive kidney concentration based on enzyme digestion principle and preparation method thereof
  • Probe capable of reducing radioactive kidney concentration based on enzyme digestion principle and preparation method thereof
  • Probe capable of reducing radioactive kidney concentration based on enzyme digestion principle and preparation method thereof

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preparation example Construction

[0074] As shown in the above synthetic route, the preparation method specifically includes the following steps:

[0075] 1) Mix the protected lysine with 2-chlorotriphenyl chloride resin at a molar ratio of 1.2:1, and connect the protected lysine under the action of N,N-diisopropylethylamine (DIPEA) onto the resin;

[0076] 2) On the basis of the product obtained in step 1), continue to connect amino acid X and Boc-Met to obtain the second-step product;

[0077] 3) The second-step product obtained in step 2) is deprotected by the protecting agent Dde under the action of 2% hydrazine hydrate to obtain the third-step product;

[0078] 4) The third step product obtained in step 3) is cut off from the resin under the action of 20% 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) to obtain the fourth step product;

[0079] 5) The fourth-step product obtained in step 4) is reacted with 3-(maleimido) propionic acid N-hydroxysuccinimide ester under the action of triethylamine to obtain the...

Embodiment 1

[0100] Prepare a class of exendin 4 compounds containing enzyme-cleaved sequences, and its synthetic route is as follows:

[0101]

[0102]

[0103] Concrete preparation process comprises the following steps:

[0104] 1. Synthesis of Compound 2:

[0105] Add 0.5g Fmoc-Lys(Dde)-Resin (the amount of substance of Fmoc-Lys(Dde)-OH is 0.4mmol, 1 equivalent) in solid-phase synthesizer, take DMF as reaction solvent, with 0.8M DIPEA / DMF and 0.4M HBTU / DMF were used as activators, and 20% piperidine in DMF was used as the eluent of Fmoc. According to the sequence of the polypeptide, the second amino acid (Fmoc-Gly-OH, Fmoc-Val-OH , Fmoc-Phe-OH or Fmoc-Trp-OH, 4 equivalents) and Boc-Met-OH (0.399 g, 4 equivalents) to grow the peptide chain. After the solid-phase synthesis, the crude polypeptide product attached to the resin was placed in 3 mL of 2% hydrazine hydrate in DMF, stirred at room temperature for 1.5 h, filtered with suction, and the resin was washed with dichloromethan...

Embodiment 2

[0112] Preparation of a class of Z containing enzyme cleavage sequences HER2:2891 The compound, its synthetic route is as follows:

[0113]

[0114] Concrete preparation process comprises the following steps:

[0115] 1. The synthesis of compounds 1-2, 1-3, 2-2, 2-3, 3-2 and 3-3 is the same as in Example 1;

[0116] 2. Synthesis of Compound 5:

[0117] Compound 3 (0.66 μmol, 1.5 equiv) was added to Z HER2:2891 (commercially available, 3 mg, 0.44 μmol, 1 equiv.) in PBS solution, reacted at room temperature for two hours, and separated and purified by HPLC to obtain compound 5 with a yield of about 54-62%. After identification by LC-MS, the molecular weights of compounds 5-2 and 5-3 are [M+H] + =7794.00 and [M+7H] 7+ =1121.50, the calculated value (m / z) is 7793.90 (C 343 h 543 N 93 o 106 S 4 ) and 7841.90 (C 347 h 543 N 93 o 106 S 4 ). The HPLC analysis diagrams and LC-MS diagrams of compounds 5-2 and 5-3 are shown in figure 2 shown.

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Abstract

The invention relates to a probe capable of reducing radioactive kidney concentration based on an enzyme digestion principle and a preparation method of the probe. The general formula of the probe isas follows: R1 refers to a bifunctional chelating agent group, R2 refers to a side chain residue of hydrophobic amino acid, and R3 refers to a targeting ligand. A radioactive complex of the probe canbe used as a nuclide imaging probe or a radionuclide treatment probe, not only has an excellent imaging or treatment effect when applied to human or animals, but also can remarkably reduce radioactiveconcentration and retention of kidneys, has a very high target / non-target ratio, greatly reduces the radiation dose when being applied to human or animals, is safer and more effective and has extremely high clinical popularization value.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a probe capable of reducing radioactive kidney concentration based on the principle of enzymatic cleavage and a preparation method thereof. Background technique [0002] With the wide application of molecular biology technology and the rapid development of radionuclide tracer technology, molecular nuclear medicine has made great progress in the field of molecular functional imaging and molecular targeted therapy, making it an important place in the field of precision medicine . However, since many tumor-targeting ligands, such as polypeptides, folic acid, and nucleic acid aptamers, are mainly metabolized by the kidney in vivo, and the metabolites will continue to remain in the kidney due to renal reabsorption, resulting in the The associated radionuclides are highly concentrated in the kidneys for a prolonged period of time. [0003] Compared with nuclide imaging, the radionuc...

Claims

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Application Information

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IPC IPC(8): C07K5/02C07K19/00C07K1/04C07K1/06C07K1/13A61K51/08A61K103/00A61K103/30
CPCC07K5/0215C07K14/605C07K14/57563C07K7/06C07K14/001A61K51/08C07K2319/00Y02P20/55
Inventor 张明如陈小元
Owner 西安华牧生物科技有限责任公司
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