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Diagnostic medicine targeting fibroblast activation protein and preparation method of diagnostic medicine

A fibroblast-oriented and activated protein technology, which is applied in the field of diagnostic drugs targeting fibroblast activated protein and its preparation markers, can solve the problems of restricting diagnostic applications in clinical promotion, low yield at one time, and inability to meet therapeutic purposes. Effect of Improving Visual Effects

Inactive Publication Date: 2021-11-05
YANTAI LANNACHENG BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

because 68 Ga 3+ Produced by a generator, the output is low at one time, and the half-life is short (only 68min), which makes it impossible to achieve mass production and distribution, which greatly limits its diagnostic application in clinical promotion
In addition, due to the rapid metabolism and elution of FAPI, the effective dose at the tumor site is low and the retention time is too short, which cannot meet the needs of therapeutic use

Method used

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  • Diagnostic medicine targeting fibroblast activation protein and preparation method of diagnostic medicine
  • Diagnostic medicine targeting fibroblast activation protein and preparation method of diagnostic medicine
  • Diagnostic medicine targeting fibroblast activation protein and preparation method of diagnostic medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: the preparation of compound NOTA-FAPI02

[0027] In a 25 mL flask, compound 1 (0.1 mmol), compound 2 NOTA-NHS (0.1 mmol) and N,N-diisopropylethylamine (0.3 mmol) were sequentially put into 5 mL of N,N-dimethylformamide. The reaction system was stirred at room temperature and monitored by HPLC until the end of the reaction (r.t. was 10.851 minutes). The crude product was reversed-phase columnized and freeze-dried to obtain the pure compound NOTA-FAPI02 with a yield of 54%. figure 1 is the mass spectrum of compound NOTA-FAPI02.

[0028] The synthetic route of above-mentioned steps is as follows:

[0029]

Embodiment 2

[0030] Embodiment 2. Preparation of 18FAl-NOTA-FAPI02 complex:

[0031] Dissolve 50 micrograms of the compound NOTA-FAPI02 prepared by the method in Example 1 in 50 microliters of 0.1M buffer solution (pH=4) and 300uL of acetonitrile, and add 3 microliters of 10mM AlCl 3 solution, and add 50 µl to it 18 f - Aqueous solution (10-30mCi), fully mixed and heated to 105-110 degrees Celsius for 10 minutes. Take a C18 separation column, wash it slowly with 10mL of absolute ethanol, and then with 10mL of water. Dilute the cooled labeling solution with 10mL of water and transfer it to the separation column, first use 10mL of water to remove unlabeled 18F ions, and then rinse the product with 50% ethanol / normal saline. The eluent is diluted with physiological saline, and sterile filtered to obtain the injection solution of the 18FAl-NOTA-FAPI02 complex.

experiment example

[0032] Experimental example. Analysis and application effect

[0033] 1. HPLC analysis and identification

[0034] The HPLC system was as follows: SHIMADZULC-20A; C18 chromatographic column (YMC, 3 μm, 4.6×150 mm) was used for analysis. Detection wavelength 254nm, flow rate 1mL / min, eluting gradient: 0-3 minutes: 10% acetonitrile (0.1% TFA) and 90% water (0.1% TFA) remain unchanged; 3-16 minutes: increase to 90% acetonitrile (0.1% TFA) and 10% water (0.1% TFA); 16-18min: reduce to 10% (0.1% TFA) and 90% water (0.1% TFA); 18-20min: maintain 10% acetonitrile (0.1% TFA ) and 90% water (0.1% TFA).

[0035] In summary, the present invention provides a diagnostic drug targeting fibroblast activation protein, which improves the clinical availability of FAPI imaging agents.

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Abstract

The invention provides a diagnostic prodrug compound targeting fibroblast activating protein. The structure of the diagnostic prodrug compound is represented by a formula (I). The invention also provides a diagnostic medicine targeting a fibroblast activation protein, wherein the diagnostic medicine is a complex obtained by taking the compound represented by the formula (I) as a ligand and labeling the compound with 18FAl, and the structure of the diagnostic medicine is represented by the formula (II). The invention also provides a preparation method of the precursor compound and the diagnostic medicine, and an application of the precursor compound and the diagnostic medicine in preparation of nuclide imaging medicines for FAP protein high-expression tumors. According to the diagnostic nuclide medicine targeting the fibroblast activation protein, 18F nuclide which can be stably produced and has a long half-life period is adopted to replace 68Ga, the imaging effect of targeted FAP protein nuclide can be improved, and the nuclide medicine has the potential of being clinically popularized and applied.

Description

technical field [0001] The invention relates to the fields of nuclear medicine and molecular imaging, in particular to a diagnostic drug targeting fibroblast activation protein and a preparation marker thereof. Background technique [0002] Fibroblast activation protein (FAP) is a membrane serine peptidase expressed on the surface of activated fibroblasts in the tumor stroma. Studies have shown that over 90% of epithelial malignant tumors have high expression of fibroblast activation protein on the surface of stromal fibroblasts. Therefore, FAP has become an important target for tumor imaging and therapy. [0003] At present, radionuclide-labeled fibroblast activation protein inhibitor (FAPI), represented by quinolinic acid derivatives, has made important progress in the field of precise tumor imaging. For example, metal nuclides 68 Ga-labeled FAPI has achieved more than 30 different types of tumor-specific PET imaging. because 68 Ga 3+ Produced by a generator, the one...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P35/00A61K51/04A61K101/02
Inventor 陈小元徐鹏飞郭志德吴晓明文雪君
Owner YANTAI LANNACHENG BIOTECHNOLOGY CO LTD
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