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Prostate-specific membrane antigen inhibitor, radionuclide labeled substance thereof, preparation method and application

A prostate-specific, radionuclide technology, applied in the field of prostate-specific membrane antigen inhibitors, can solve problems such as insufficient cell internalization rate and cell uptake rate, and renal toxicity

Pending Publication Date: 2021-09-10
THE AFFILIATED HOSPITAL OF SOUTHWEST MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

177 Lu-labeled PSMA-617 and PSMA-I&T drugs still have the problem of insufficient cell internalization rate and cellular uptake rate (uptake rate is about 20%, internalization rate is less than 10%), and there is still a lot of room for improvement
On the other hand, the kidney is the dose-limiting organ for this class of radiopharmaceuticals, and higher renal uptake may also lead to nephrotoxicity when used therapeutically

Method used

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  • Prostate-specific membrane antigen inhibitor, radionuclide labeled substance thereof, preparation method and application
  • Prostate-specific membrane antigen inhibitor, radionuclide labeled substance thereof, preparation method and application
  • Prostate-specific membrane antigen inhibitor, radionuclide labeled substance thereof, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] This example discloses the synthesis of compound b3-3 (i.e. in compound b3, n=3), and its reaction formula is:

[0094]

[0095] Specifically, compound b1 (1.224 g, 2.513 mmol) and b2-3 (335 mg, 2.639 mmol) were dissolved in methanol (40 mL), and stirred at 0° C. for 30 minutes. Add CH to the above solution 3 BNNa (241 mg, 3.77 mmol) was stirred at room temperature for 4 hours. The above reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine three times, and dried over anhydrous sodium sulfate overnight. The organic phase was separated by filtration, and the organic solvent was removed by rotary evaporation. The product was purified by column chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain 1.15 g of yellow oily liquid b3-3, yield: 55.3%.

Embodiment 2

[0097] This example discloses the synthesis of compound b5-3 (i.e. in compound b5, n=3), and its reaction formula is:

[0098]

[0099] Dissolve b3-3 (403mg, 0.674mmol) and b4 (215mg, 0.809mmol) in dichloromethane (10mL), then add triethylamine (81mg, 0.809mmol), and stir at room temperature for 12 hours. The reaction solution was washed three times with saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was dried overnight with anhydrous sodium sulfate. The organic phase was rotary evaporated to remove the organic solvent. The product was purified by column chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain 383 mg of yellow oily liquid product b5-3, with a yield of 68.6%.

Embodiment 3

[0101] This example discloses the synthesis of compound b6-3 (i.e. in compound b6, n=3), and its reaction formula is:

[0102]

[0103] Reactant b5-3 (150 mg, 0.181 mmol) and triphenylphosphine (71 mg, 0.272 mmol) were dissolved in tetrahydrofuran (2.5 ml) and water (0.5 ml), and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into ice water, extracted with dichloromethane, washed with saturated brine three times, and the organic phase was dried overnight with anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporation. Column chromatography (DCM / MeOH=15 / 1) obtained white solid product b6-3, totaling 135 mg, yield: 93.1%.

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PUM

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Abstract

The invention discloses a prostate-specific membrane antigen inhibitor, a radionuclide labeled substance thereof, a preparation method and application, and belongs to the technical field of biological medicines. The chemical structure of the prostate-specific membrane antigen inhibitor is shown as a formula I, the chemical structure of the radionuclide labeled substance is shown as a formula II, and the prostate-specific membrane antigen inhibitor is used for preparing prostate cancer diagnostic reagents / drugs or / and therapeutic drugs. The compound is novel in structure and stable in physicochemical property, and can be used for preparing drugs for diagnosis and treatment of prostate cancer and be applied to the fields of diagnosis, staging, curative effect evaluation and treatment of prostate cancer.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a prostate-specific membrane antigen inhibitor, a radionuclide marker, a preparation method and an application thereof. Background technique [0002] Precisely targeted radiopharmaceuticals usually consist of radionuclides, targeting structures, and linking groups. With the wide application of positron emission tomography (PET) and single photon emission tomography (SPECT) in medicine, medical isotopes play an increasingly important role in medical diagnosis and treatment, especially in the diagnosis and localization of tumors. , staging, and efficacy evaluation play an irreplaceable role, and truly achieve what you see is what you get. When the radionuclide is β-electrons, α-ions or Auger electrons, radiopharmaceuticals can often be used as radioligand therapy (RLT) for therapeutic purposes. Up to now, dozens of radiopharmaceuticals have been approved for clinic...

Claims

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Application Information

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IPC IPC(8): C07D257/02C07D255/02C07C275/16C07C273/18C07B59/00A61K51/04A61P35/00A61K103/00A61K103/30A61K103/40A61K101/02
CPCC07D257/02C07D255/02C07C275/16C07C273/1854C07C273/189C07B59/00A61K51/044A61K51/0406A61K51/0482A61P35/00C07B2200/05Y02P20/55
Inventor 周志军刘洋陈跃刘楠陈环宇冯悦孙占良赵岩
Owner THE AFFILIATED HOSPITAL OF SOUTHWEST MEDICAL UNIV
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