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PSMA inhibitor, application thereof and PSMA-targeting nuclide imaging reagent

An inhibitor and imaging technology, applied in the field of biomedicine, can solve problems such as few clinical application prospects, and achieve good PSMA targeting and affinity, high cell uptake, and simple and fast labeling methods

Active Publication Date: 2020-06-05
PEKING UNIV FIRST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Since 2012, the pharmaceutical research on PSMA inhibitors has begun to deepen and focus on the core issues of clinical transformation such as metabolic kinetics, nuclide selection and optimization, and a number of improved molecules based on the Urea structure have been reported, but they really have clinical application prospects but very few

Method used

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  • PSMA inhibitor, application thereof and PSMA-targeting nuclide imaging reagent
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  • PSMA inhibitor, application thereof and PSMA-targeting nuclide imaging reagent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] This example is used to illustrate the synthesis and characterization of monomer ODAP-PSMA-HYNIC (DXJ63), the synthetic route is as follows Picture 1-1 Shown:

[0047] DXJ46 was prepared with reference to the patent CN201910108684X authorized by this laboratory. The process is as follows: Dissolve oxalyl chloride (1.0g, 7.88mmol) in 15mL of dichloromethane, and slowly add 15mL of dichloromethane dissolved in tert-butanol (584mg, 7.88mmol) in an ice bath. Dichloromethane was reacted at room temperature under nitrogen protection for 24 hours, and the solvent was removed under reduced pressure to obtain a colorless oil. Take (s)-3-amino-2-carbonylaminopropionic acid tert-butyl ester (1.0g, 3.40mmol) and dissolve it in 20mL of dichloromethane, add triethylamine (1.38g, 13.61mmol), and add the above A colorless product (1.29g, 7.88mmol) was reacted at room temperature for 6 hours, the solvent was removed under reduced pressure, and the residue was purified by a silica gel c...

Embodiment 2

[0066] This example is used to illustrate the synthesis and characterization of monomeric GLU-PSMA-HYNIC (DXJ102), the synthetic route is as follows Figure 3-1 Shown:

[0067] DXJ49 preparation and identification reference J.Am.Chem.Soc.2014,136:18034-18043, the process is as follows: take L-glutamic acid tert-butyl ester hydrochloride (1.0g, 3.38mmol) and triethylamine (1.6 mL, 11.09mmol) was added to 30mL of dichloromethane, then cooled to -78°C, and 10mL of dichloromethane dissolved with triphosgene (341mg, 1.15mmol) was added dropwise, after the dropwise addition was completed, it was raised to room temperature, and the reaction was continued for 30 minutes; benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (757mg, 2.03mmol) was added to the reaction solution, triethylamine (283μL, 2.03mmol) was added, and stirred overnight at room temperature; Diluted with 50mL of dichloromethane, washed twice with 100mL of water, the organic phase was dried over anhydrous sodiu...

Embodiment 3

[0083] This example is used to illustrate the ligand 99m Tc labeling and quality control.

[0084] 1. Optimization and determination of labeling conditions

[0085] The radiochemical purity of the complexes was determined using HPLC (High Performance Liquid Chromatography). There are two liquid phase conditions, System A uses water / acetonitrile / 0.1% trifluoroacetic acid as the mobile phase, System B uses ammonium phosphate buffer / acetonitrile as the mobile phase, and the gradients are shown in Table 1 and Table 2. Ammonium phosphate buffer preparation method: Take 13.61g of potassium dihydrogen phosphate, add 500mL of ultrapure water to dissolve, add 5mL of ammonia water, adjust the pH to 4.2 with phosphoric acid, add ultrapure water to dilute to 1000mL, shake well and set aside. The mobile phase needs to pass through a 0.22μm filter membrane before use, the reverse chromatographic column is Kromasil 100-5-C18, 4.6mm×250mm, and the flow rate of the mobile phase is 1.0mL / min....

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Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a PSMA inhibitor, an application thereof and a PSMA-targeting nuclide imaging reagent. The PSMA inhibitor has a structure as shown in a formula I. The PSMA-targeting nuclide imaging reagent prepared by adopting EDDA as a co-ligand has good PSMA targeting property and affinity; high stability is realized in normal saline and mouse serum; meanwhile, the cell uptake amount is relatively high, and the metabolic performance is good. Therefore, the inhibitor has a good clinical application prospect in tumor imaging of targeted PSMA.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and more specifically relates to a PSMA inhibitor and application thereof, and a nuclide imaging reagent targeting PSMA. Background technique [0002] Prostate cancer is one of the most common malignant tumors in men, and its incidence rate ranks first in European and American countries all the year round. Although the incidence of prostate cancer in China is lower than that in Europe and the United States, with the advent of China's aging society and the change of westernized living habits, the incidence of prostate cancer has increased rapidly in recent years. At the same time, there are more middle-, high-risk and advanced-stage prostate cancer patients in my country, and the proportion is significantly higher than that in Europe and the United States. The curative effect of tumor is closely related to the stage of the disease, so the mortality rate of prostate in my country is still at t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82C07F13/00A61K51/04A61K103/10
CPCA61K51/0455C07D213/82C07F13/005
Inventor 杨兴段小江范岩杨志张俊波
Owner PEKING UNIV FIRST HOSPITAL
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