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4-nitro glyoxaline compound, preparation and use thereof

A technology of nitroimidazoles and compounds, applied to nitroimidazole complexes and their precursors, in the application field of tumor imaging agents, to achieve high tumor absolute uptake value, increase tumor uptake value, and reduce liver uptake. Effect

Inactive Publication Date: 2009-07-22
BEIJING NORMAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the currently reported 99m Tc-labeled azamacrocyclic compounds mainly form 99m TCO 2 Form complexes, while 99m TcO, 99m TcN and 99m Tc(CO) 3 Azamacrocyclic complexes of the form

Method used

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  • 4-nitro glyoxaline compound, preparation and use thereof
  • 4-nitro glyoxaline compound, preparation and use thereof
  • 4-nitro glyoxaline compound, preparation and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Synthesize compound NIEC provided by the invention according to the synthetic route shown below:

[0035]

[0036] The reagents used are:

[0037] (a) EtOTFA, Et 3 N and MeOH;

[0038] (b) 2-bromoethanol, K 2 CO 3 and CH 3 CN;

[0039] (c)CH 3 SO 2 Cl, CH 2 Cl 2 and Et 3 N;

[0040] (d) Compound 1, K 2 CO 3 and CH 3 CN;

[0041] NaOH and MeOH

[0042] Specific steps are as follows:

[0043] Synthesis of Tri-TFA cyclam (compound 1):

[0044] In a dry 50mL three-necked flask, cyclam (1.0g, 5.0mmol) and triethylamine (0.69mL, 5.0mmol) were dissolved in 20mL of anhydrous methanol, nitrogen protection was introduced and the reaction solution was kept at 0 with an ice-water bath. ~5°C, then add ethyl trifluoroacetate (6.0mL, 50.0mmol) dropwise, continue the dropwise addition for ten minutes, stir the reaction for 7 hours, remove the solvent by suspension evaporation, pass the residue through a small silica gel column, and use ethyl acetate as eluent to o...

Embodiment 2

[0053] preparation 99m TcO-NIEC complex

[0054] 1) 99m Preparation of TcO-GH

[0055] Weigh 25 mg of GH ligand, dissolve it completely with 0.5 mL of normal saline, add 0.5 mL of SnCl 2 2H 2 O (1mg / mL, 0.1M HCI), adjust the pH=7~7.5, add 0.5mL of freshly rinsed 99m TCO 4 - The solution (approximately 10 mCi) was heated in a water bath at 40° C. for 10 minutes, then cooled to room temperature, and prepared as a precursor for the ligand exchange method.

[0056] 2) 99m Preparation of TcO-NIEC

[0057] Dissolve 20 mg of the compound NIEC ligand in 20 mL of methanol, take out 0.15 mL and put it into a penicillin vial, adjust the pH value to 13 with 1.0 mL of pH=13, that is, 0.1 M NaOH buffer solution, and add 0.15 mL of 99m For Tc-GH solution, the mixture was heated in a boiling water bath for 45 minutes, filtered through a filter membrane, and the labeling rate was above 95%.

Embodiment 3

[0059] preparation 99m TcN-NIEC complex

[0060] (1) Intermediate [ 99m TcN] 2+ preparation of

[0061] Can be prepared in two ways 99m TcN intermediates, namely

[0062] Take 1~2mL99m TCO 4 - Add the fresh eluent to the DTCZ kit, shake well, and heat in a boiling water bath for 15 minutes to obtain the intermediate [ 99m TcN] 2+ ;

[0063] or

[0064] Take 1~2mL 99m TCO 4 - Add the fresh eluent into the SDH kit, shake well, and let it stand at room temperature for 15 minutes to obtain the intermediate [ 99m TcN] 2+ .

[0065] (2) 99m Preparation of TcN-NIEC

[0066] Take 0.1mL of the ligand solution NIEC prepared above and put it into a penicillin vial, adjust the pH value of the NIEC ligand solution to 13 with 1.0mL of 0.1M NaOH buffer solution, and then add 0.1mL[ 99m TcN] 2+ Intermediate, heated in a boiling water bath for 40min. The marking rate is above 95%.

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Abstract

The invention provides hydrophilic complexes marked by radioactive nuclide for hypoxic tumors; and the precursor of the complexes is a 1, 4, 8, 11-tetraazacyclotetradecane-contained 4-nitromidazole compound with the structural formula as shown on the right. The invention also provides the preparation methods of the complexes and the precursor thereof, as well as the application of the complexes as potential tumor hypoxia imaging agents; and the tumor hypoxia imaging agent of the complexes have good hydrophilic property and relatively high uptake value in tumors, particularly the complexes such as TcO-NIEC and TcN-NIEC have high absolute uptake value in tumors, low L / NT value, relatively high tumor / muscle ratio and tumor / blood ratio, effectively solve the problem that the current tumor hypoxia imaging agent has the defects of low absolute uptake value and high L / NT value, thus being likely to become new tumor hypoxia imaging agents with better performance.

Description

technical field [0001] The present invention relates to a class of radionuclide-labeled nitroimidazole complexes and their precursors for hypoxic tumors, and also relates to their preparation methods and their application in imaging agents for human or animal organs or tissues, especially The application in tumor imaging agent belongs to the fields of radiopharmaceuticals and nuclear medicine. Background technique [0002] Tissue hypoxia is a main feature of many clinically important diseases. Hypoxic cells are common in animal and human solid tumors, but hypoxic cells are not sensitive to radiotherapy and chemotherapy, so they often become an important cause of tumors that are difficult to cure and easy to relapse. reason. Detecting the oxygen level of the tumor before and after the treatment of tumor patients can evaluate the curative effect and help formulate the treatment plan. [0003] The use of non-invasive methods to determine tumor hypoxia has been widely valued. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07F13/00A61K51/04A61K103/10
Inventor 王学斌王凤龙张现忠张俊波陆洁唐志刚刘键
Owner BEIJING NORMAL UNIVERSITY
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