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<18>F-labeled EGFR positron imaging agent as well as preparation method and application thereof

A semi-preparation and reaction technology, applied in the field of 18F-labeled EGFR positron imaging agent and its preparation, to achieve fast clearance in vivo, good specificity, and good tracer effect

Active Publication Date: 2021-08-03
NANFANG HOSPITAL OF SOUTHERN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, studies have shown that EGFR-TKIs are mutation-sensitive, and not all patients with high EGFR expression can benefit. Therefore, the screening of EGFR-TKIs-sensitive patients is a clinical problem that needs to be solved urgently

Method used

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  • &lt;18&gt;F-labeled EGFR positron imaging agent as well as preparation method and application thereof
  • &lt;18&gt;F-labeled EGFR positron imaging agent as well as preparation method and application thereof
  • &lt;18&gt;F-labeled EGFR positron imaging agent as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] The compound shown in embodiment 1 formula (III) ( 18 Preparation method of F-labeled EGFR positron imaging agent precursor)

[0088] 4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline (formula (V), 40.00g, 1eq), DMF (N,N-dimethylformazol Amide, 200mL), potassium carbonate (35.38g, 2eq), propargylamine (8.48g, 1.2eq), stirred at 90°C for 2.5h. After the reaction was monitored by TLC (thin-layer chromatography), the temperature was lowered to room temperature (20-30° C.), and 400 mL of water was added and stirred evenly. Filter and wash twice with 400 mL of water. The filter cake was spin-dried to obtain 24.5 g of a silver-white solid product (formula (VI)), with a yield of 57.8%.

[0089] In the reaction flask, add 4-propargylamino-6,7-bis(2-methoxyethoxy)quinazoline (formula (VI), 0.42g, 1.0eq), copper sulfate pentahydrate (0.018g , 0.05eq), sodium erythorbate (0.026g, 0.1eq), 2mL each of water and tert-butanol, then add azidoethyl toluenesulfonate (0.332g, 1.0eq), and s...

Embodiment 2

[0091] The compound shown in embodiment 2 formula (IV) ( 18 The preparation method of F-marked EGFR positron imaging agent standard substance)

[0092] 4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline (formula (V), 40.00g, 1eq), DMF (N,N-dimethylformazol Amide, 200mL, 5V), potassium carbonate (35.38g, 2eq), propargylamine (8.48g, 1.2eq), stirred at 90°C for 2.5h. After TLC (thin-layer chromatography) monitors the completion of the reaction, the temperature is lowered to room temperature (20-30° C.), and 400 mL (10 V) of water is added and stirred evenly. Filter and wash twice with 400ml of water. The filter cake was spin-dried to obtain 24.5 g of a silver-white solid product (formula (VI)), with a yield of 57.8%.

[0093] In the reaction flask, add 4-propargylamino-6,7-bis(2-methoxyethoxy)quinazoline (formula (VI), 2.70g, 1.0eq), copper sulfate pentahydrate (0.40g , 0.2eq), sodium ascorbate (1.78g, 1.1eq), water and DCM (dichloromethane) each 27mL, then added 2-fluoroethane az...

Embodiment 3

[0095] The compound shown in embodiment 3 formula (II) ( 18 F-marked EGFR positron imaging agent) preparation method

[0096] (1) Use a medical cyclotron to bombard H 2 18 O, pass 18 O(p,n) 18 F nuclear reaction produces 500mCi 18 F, and conduct in anion exchange column, measure activity and use 1.5mL mixed solution (15.0mg 4,7,13,16,21,24-hexaoxo-1,10-diazabicyclo[8.8.8]20 Hexane (K 2.2.2. ) plus 4.5mg K 2 CO 3 dissolved in 0.15mL water and 1.35mL acetonitrile) will 18 F is rinsed into the reaction bottle;

[0097] (2) Continuously blow high-purity helium into the reaction bottle, azeotropically remove water at 110°C for 3 minutes, and dry; dissolve 5 mg of precursor in 1 mL of anhydrous DMSO solution, add to the reaction bottle, and react at 110°C for 15 minutes.

[0098] (3) After cooling the reaction solution, carry out semi-preparative HPLC separation to obtain 18 F-labeled EGFR positron imaging agent, the separation conditions are: the chromatographic column is ...

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Abstract

The invention belongs to the technical field of medicinal chemistry and nuclear pharmacy, and discloses an <18>F-labeled EGFR positron imaging agent as well as a preparation method and application thereof. The <18>F-labeled EGFR positron imaging agent has a structure as shown in a formula (II) which is described in the specification. The tracing effect is good, the specificity is relatively good, and high-expression or variant tumors of an epidermal factor receptor (EGFR) can be positively recognized. Meanwhile, the compound is good in in-vitro stability, is mainly metabolized through intestines, galls and kidneys, is quick to remove in vivo, is low in background uptake of background visceral organs and tissues such as muscles, bones, hearts, lungs and livers, and can be used for tumor PET imaging agents, EGFR expression level detection agents and EGFR inhibitor screening agents.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and nuclear pharmacy, and specifically relates to 18 F-labeled EGFR positron imaging agent and its preparation method and application. Background technique [0002] Positron Emission Tomography (PET) is currently the best imaging device for monitoring the occurrence and development of tumors in vivo. , biochemical process for non-invasive, three-dimensional, dynamic research, PET can be applied to the diagnosis of tumors, benign and malignant differentiation, malignant tumor staging, typing and early diagnosis and identification of tumor recurrence and metastasis, the selection of treatment options and the effect of chemotherapy and radiotherapy Detection and observation of tumor change process and monitoring of prognosis. [0003] Epidermal growth factor receptor (EGFR) is a huge transmembrane glycoprotein with a molecular weight of about 180kDa and has ligand-induced tyrosine prote...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07B59/00A61K51/04A61K101/02
CPCC07D403/12C07B59/002A61K51/0459C07B2200/05Y02P20/55
Inventor 黄顺韩彦江胡孔珍吴湖炳唐刚华
Owner NANFANG HOSPITAL OF SOUTHERN MEDICAL UNIV
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