PSMA inhibitor, compound as well as preparation method and application of compound

A compound and inhibitor technology, applied in the field of compounds and their preparation, PSMA inhibitors, can solve the problems of low sensitivity, slow clearance in vivo, affecting the diagnosis of liver metastases, etc.

Active Publication Date: 2021-05-28
北京瑞达福明科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the above PSMA imaging agents all have the problems of low sensitivity, low detection rate when PSA<1 μg / L, and slow clearance in the body; some have high radioactive uptake in the liver, which may affect the diagnosis of liver metastases

Method used

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  • PSMA inhibitor, compound as well as preparation method and application of compound
  • PSMA inhibitor, compound as well as preparation method and application of compound
  • PSMA inhibitor, compound as well as preparation method and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: the synthesis of I-112 (2-pyridine-cyclohexylmethylamine-DOTA-PSMA)

[0062] Take 100 mg of Fmoc-Glu-urea-Lys-resin (tert-butyl protected glutamic acid urea-lysine resin) (0.22 mmol / g) in a solid-phase synthesis tube. DCM washed (3×5min×2mL), DMF washed (3×5min×2mL). De-Fmoc using 20% ​​piperidine in DMF (1 x 2 min x 2 mL, 2 x 10 min x 2 mL), followed by washing with DMF (6 x 1 min x 2 mL).

[0063] Take Fmoc-3-(2-pyridine)-D-alanine (3M, 0.06mmol, 26.2mg), HBTU (0.072mmol, 27mg), HOBt (0.072mmol, 10mg), DIPEA (0.15mmol, 25μL) in 3 mL DMF, room temperature for 15 minutes. The above activated 2-pyridine-alanine was added to the washed resin and reacted for 1 hour under nitrogen. Wash with DMF (6×1 min×2 mL). De-Fmoc using 20% ​​piperidine in DMF (1 x 2 min x 2 mL, 2 x 10 min x 2 mL), followed by washing with DMF (6 x 1 min x 2 mL).

[0064] Take trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (3M, 0.06mmol, 23mg), HBTU (0.072mmol, 27mg), HOBt (0.0...

Embodiment 2

[0067] Embodiment 2: the synthesis of I-113 (3 pyridine-cyclohexylamine-DOTA-PSMA)

[0068] The Fmoc-3-(2-pyridine)-D-alanine in Example 1 is replaced by Fmoc-3-(3-pyridine)-D-alanine, and the rest remain unchanged, and the final synthesis product is passed through HPLC Purified to obtain a white final product: 3-pyridine-cyclohexylmethylamine-DOTA-PSMA, mass spectrogram see figure 2 . MS: [M+H] (m / z=993.6)

Embodiment 3

[0069] Embodiment 3: the synthesis of I-114 (4-pyridine-cyclohexylamine-DOTA-PSMA)

[0070] The Fmoc-3-(2-pyridine)-D-alanine in Example 1 is replaced by Fmoc-3-(4-pyridine)-D-alanine, and the rest remain unchanged, and the final synthesis product is passed through HPLC Purified to obtain a white final product: 4-pyridine-cyclohexylmethylamine-DOTA-PSMA, mass spectrogram see image 3 . MS: [M+H] (m / z=991.99)

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Abstract

The invention discloses a PSMA inhibitor, a compound as well as a preparation method and application of the compound. The structure of the compound is shown as a formula A defined in the description, wherein R1 is cyclohexane methylamine or benzylamine, R2 is DOTA(I) or NODA(II) used for complexing (radioactive) metal ions, radioactive metal nuclides are used for diagnosis or treatment, and non-radioactive metal nuclides are used for being combined with radioactive nuclides. The invention also provides a preparation method and application of the compound. The compound has high affinity with prostate specific membrane antigen (PSMA), has the characteristic of rapid removal, and is especially suitable for tumor radionuclide target diagnosis, staging, treatment and the like.

Description

technical field [0001] The invention belongs to the technical field of radiopharmaceuticals and its preparation, and specifically relates to a PSMA inhibitor, a compound, its preparation method and application. Background technique [0002] Prostate cancer is a common malignant tumor of the male reproductive system. According to reports, in 2018, there were about 1.3 million new prostate cancer patients and 360,000 deaths from prostate cancer each year in the world, accounting for the second highest incidence of male tumors; Endocrine therapy is the main method, but it will eventually develop into castration-resistant prostate cancer (CRPC). CRPC has poor overall efficacy and high mortality, which has always been a difficult point in clinical treatment. Due to the extremely complex mechanism of occurrence and development of CRPC, no consensus treatment plan has been formed so far. In my country, the incidence of prostate cancer is lower than that of European and American co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07F5/06C07B59/00A61K51/04A61P35/00A61K103/30A61K103/40A61K103/32A61K103/00A61K101/02
CPCC07D401/12C07F5/069C07B59/00A61K51/0482A61P35/00C07B2200/05
Inventor 周彤张晓军崔孟超唐阿娟
Owner 北京瑞达福明科技有限公司
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