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Therapeutic drug targeting fibroblast activating protein and preparation method thereof

A therapeutic drug and a fibroblast-oriented technology, which is applied in the field of therapeutic drugs targeting fibroblast activation protein and its preparation and labeling, and can solve the problems of unsatisfactory therapeutic use, inability to achieve mass production and distribution, and short half-life

Pending Publication Date: 2021-11-09
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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  • Therapeutic drug targeting fibroblast activating protein and preparation method thereof
  • Therapeutic drug targeting fibroblast activating protein and preparation method thereof
  • Therapeutic drug targeting fibroblast activating protein and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Preparation of compound DOTA-tEB-FAPI02

[0033] Synthesis of compound 4:

[0034] Add COOH-PEG to the N,N-dimethylformamide of compound 3 (1.0mmol) 2 -COOH (1.50mmol), HATU (1.0mmol) and N,N-diisopropylethylamine (3.0mmol), stirred at room temperature overnight, and the completion of the reaction was monitored by HPLC. The solvent was distilled off under reduced pressure to obtain a crude product. The crude product was reverse-phase columnized and freeze-dried to obtain pure compound 4 with a yield of 67%. Among them, the mass spectrum of compound 3 is shown in figure 1 .

[0035] Synthesis of compound 5:

[0036] Put compound 4 (0.1mmol), HATU (0.1mmol) and N,N-diisopropylethylamine (0.3mmol), FAPI small molecule inhibitor compound 1 (0.1mmol) and 5mL N,N into a 50mL flask respectively. -Dimethylformamide, react at room temperature, and monitor the completion of the reaction by HPLC. The solvent was distilled off under reduced pressure to obtain a cr...

Embodiment 2

[0042] Example 2. Preparation of 177Lu-DOTA-tEB-FAPI02 complex:

[0043] Dissolve 50 micrograms of the compound DOTA-tEB-FAPI02 prepared by the method in Example 1 in 20 microliters of DMSO, add 200 microliters of buffer solution (pH=5.5), oscillate to dissolve it completely, and add about 5 mCi 177 LuCl 3. The mixture was shaken and heated at 95°C for 30 min. Cool to room temperature after the reaction. Take a C18 separation column, wash it slowly with 10mL of absolute ethanol, and then with 10mL of water. After diluting the labeling solution with 10mL water, load the sample on the separation column, first remove the unlabeled solution with 10mL water 177 Lu ions, and then rinsed with 0.3mL 10mM HCl ethanol solution to obtain the product. The eluate was diluted with normal saline and sterile filtered to obtain 177 Injection of Lu-DOTA-tEB-FAPI02. HPLC quality control results such as Figure 4 shown.

experiment example

[0044] Experimental example. Analysis and application effect

[0045] 1. HPLC analysis and identification

[0046] 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).

[0047] 2, 177 Experiments of Lu-DOTA-tEB-FAPI02 complex in normal mice and U87 tumor-bearing model mice.

[0048] Prepared by the method of Example 2 with a purity greater than 95% 177 Lu-DOTA-tEB-FAPI02, in normal mice and U87 tumor-bearing model mice, injected 1.3MBq via tail vein 177 Lu-tEB-FAPI. Pharmacokinetics and SPECT imaging were tested at different time points after in...

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Abstract

The invention provides a therapeutic prodrug compound targeting fibroblast activating protein. The structure of the therapeutic prodrug compound is shown as a formula (I). The invention also provides a therapeutic drug targeting the fibroblast activating protein, the therapeutic drug is a complex obtained by taking the compound as shown in the formula (I) as a ligand and labeling with therapeutic nuclide, and the structure of the therapeutic drug is shown in the formula (II). The invention also provides a preparation method of the prodrug compound and the therapeutic drug, and an application of the prodrug compound and the therapeutic drug in preparation of the therapeutic drug for FAP protein high-expression tumors. According to the therapeutic drug targeting the fibroblast activation protein, the circulating half-life period of the fibroblast activation protein inhibitor modified by truncated Evans blue can be remarkably prolonged, and tumor uptake enrichment and retention time can be prolonged.

Description

technical field [0001] The invention relates to the fields of nuclear medicine and molecular imaging, in particular to a therapeutic 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 on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078C07K1/06C07K1/13C07K1/02A61P35/00A61K51/08A61K51/04
CPCC07K5/06139A61K51/0485A61K51/08A61P35/00
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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