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Diagnosis and treatment integrated PSMA inhibitor, compound and preparation method and application thereof

A compound and inhibitor technology, applied in the field of radiopharmaceuticals and their preparation, can solve the problems of inability to treat the imaging agent, decreased sensitivity, low sensitivity, etc., and achieve the effects of reducing non-specific uptake and accelerating radioactive excretion

Active Publication Date: 2021-06-04
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

68Ga-PSMA-11 was approved by the US FDA in 2020, showing rapid in vivo clearance, but the sensitivity decreases when the PSA level is lower than 2ng / mL; 18F- PSMA1007 and 18F-DCFPyL also have low sensitivity when the PSA level is low, and due to structural limitations, this type of imaging agent cannot be used directly for treatment; while 177Lu - PSMA-617 was named the 2019 Image of the Year by the American Nuclear Medicine Annual Meeting due to its good therapeutic effect on CRPC, but its toxic side effects (Sjogren's syndrome) caused by high uptake in the glands still hinder clinical promotion and application The main reason; at the same time, 177Lu-PSMA-617 cannot be commercially supplied when it is directly marked with gallium-68Ga. At the same time, the beta energy of 68Ga is high, and the image is not as good as 18 F, leading to a decrease in diagnostic sensitivity

Method used

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  • Diagnosis and treatment integrated PSMA inhibitor, compound and preparation method and application thereof
  • Diagnosis and treatment integrated PSMA inhibitor, compound and preparation method and application thereof
  • Diagnosis and treatment integrated PSMA inhibitor, compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment 1: the synthesis of I-11 (3-quinoline-cyclohexylamine-DOTA-PSMA)

[0057] 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).

[0058] Take Fmoc-3-(3-quinoline)-D-alanine (3M, 0.06mmol, 26.2mg), HBTU (0.072mmol, 27mg), HOBt (0.072mmol, 10mg), DIPEA (0.15mmol, 25μL) in 3 mL of DMF at 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).

[0059] Take trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (3M, 0.06mmol, 23mg), HBTU (0.072mmol, 27mg), HOBt (0.0...

Embodiment 2

[0062] Embodiment 2: the synthesis of I-12 (3-quinoline-benzylamine-DOTA-PSMA)

[0063] The trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid in Example 1 was replaced by trans-4-(Fmoc-aminomethyl)benzoic acid, and finally synthesized and purified by HPLC to obtain a white final product: 4 Pyridine-Benzylamine-NODA-PSMA. MS: 1022.4[M+H]

Embodiment 3

[0064] Embodiment 3: the synthesis of I-13 (3-quinoline-butylamine-DOTA-PSMA)

[0065] The trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid in Example 1 was replaced by trans-4-(Fmoc-aminomethyl)butyric acid, and finally synthesized and purified by HPLC to obtain a white final product: 4 Pyridine-Benzylamine-NODA-PSMA. MS: 1003.4[M+H]

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Abstract

The invention discloses a diagnosis and treatment integrated PSMA inhibitor, a compound and a preparation method and application thereof. The structure of the compound is shown as a formula A in the specification, wherein the R1 is DOTA or NODA used for complexing (radioactive) metal ions, radioactive metal nuclide is used for diagnosis or treatment, non-radioactive metal nuclide is used for being combined with radionuclide, and R2 is a coupling agent which is benzylamine, cyclohexylmethylamine or butylamine. The invention also provides a preparation method and application of the compound. The compound has very high affinity with prostate cancer specific membrane antigen (PSMA), and compared with existing PSMA treatment and imaging agents, the compound has the advantages that high swelling uptake is maintained, radioactive excretion of in-vivo non-target regions is accelerated, non-specific uptake of glands is reduced, and treatment and imaging of tumors are facilitated; and meanwhile, when the developing agent is marked by nuclide, the effect of integrating tumor diagnosis and treatment can be achieved, and the PSMA inhibitor is particularly suitable for treatment, diagnosis, staging and the like of prostate cancer.

Description

technical field [0001] The invention belongs to the technical field of radiopharmaceuticals and their preparation, and in particular relates to a PSMA inhibitor integrated with diagnosis and treatment, a compound, a preparation method and application thereof. Background technique [0002] Prostate cancer is one of the most common and high-incidence malignant tumors in middle-aged and elderly men. According to cancer statistics in 2018, it ranks first in the incidence of male malignant tumors and second in the fatality rate. Although the incidence of prostate cancer in China is far lower than that in European and American countries, with the continuous increase of aging population and changes in living habits in China, the incidence and mortality of this disease in China have shown a trend of rapid growth in the past ten years. Due to the relatively large differences in the symptoms of prostate cancer, there are no significant clinical symptoms in the early stage of the disea...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07F5/06C07F15/03C07B59/00A61K51/04A61P35/00A61K103/40A61K103/30A61K103/32A61K103/00A61K101/02
CPCC07D401/12C07F5/069C07F15/03A61K51/0482A61P35/00C07B59/004C07B2200/05
Inventor 周彤张晓军杨兴
Owner 北京瑞达福明科技有限公司
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