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Non-ionic multi-nuclear magnetic resonance imaging contrast medium taking tetrabenzoylmethane as interconnect and preparation method thereof

A technology of nuclear magnetic resonance imaging and tetrabenzoylmethane, which is applied in the direction of nuclear magnetic resonance/magnetic resonance imaging contrast agents, chemical instruments and methods, compounds containing elements of group 3/13 of the periodic table, etc., can solve the problem of long residence time, relaxation High relaxation efficiency, slow metabolism, etc., to achieve the effect of reducing the flexibility of the linker, improving the relaxation efficiency, and good water solubility

Active Publication Date: 2015-03-25
JIANGXI INST OF RARE EARTHS CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, Gd-DOTA (Dotarem, Dotalin) and Gd-HP-DO3A (ProHance, Proxians), however, the disadvantage of this type of contrast agent is that it is slowly metabolized in the human body and has a long residence time, which may cause side effects such as chronic poisoning , thus limiting the application of this type of contrast agent; recently Zhao Guiyan's group constructed (Gd-DO3A) 3 -TAB's triple-nuclear contrast agent (Two multinuclear GdIII macrocyclic complexes as contrast agents with high relaxation and stability using rigid linkers, Inorg.Chim.Acta, 2013, 146–152) makes the relaxation efficiency higher than that of clinical contrast agents

Method used

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  • Non-ionic multi-nuclear magnetic resonance imaging contrast medium taking tetrabenzoylmethane as interconnect and preparation method thereof
  • Non-ionic multi-nuclear magnetic resonance imaging contrast medium taking tetrabenzoylmethane as interconnect and preparation method thereof
  • Non-ionic multi-nuclear magnetic resonance imaging contrast medium taking tetrabenzoylmethane as interconnect and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Step 1: Synthesis of tetrakis-(4-(bromoacetyl)phenyl)methane

[0051] Under nitrogen protection, dissolve 0.8g tetraphenylmethane in 30mLCS 2 In, add 2.5g 2-bromoacetyl bromide, then add 1.7gAlCl 3 , reflux, react at 50°C for 28h, pour off CS 2 , add 25g ice water, 7mL concentrated hydrochloric acid, 25mL dichloromethane and stir until the black solid is completely dissolved; layered extraction, add water and saturated sodium chloride to wash, dry over anhydrous sodium sulfate, pass through a silica gel column, the mobile phase is dichloromethane: n-Hexane = 20:1, and finally 1.4 g of white foamy solid tetrakis-(4-(bromoacetyl)phenyl)methane was obtained.

[0052] Step 2: Tetrakis(4-(2-tris-(4,7,10-triacetate tert-butylcarboethoxy)1,4,7,10-tetraazacyclododecylacetyl)phenyl) Methane synthesis

[0053] Add 1.6g of tri-tert-butyl 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triethyl to a 20mL reaction tube Ester · Hydrogen bromide hydrochloride ( t Bu-DO3A·HB...

Embodiment 2

[0061] Step 1: Synthesis of tetrakis-(4-(bromoacetyl)phenyl)methane

[0062] Under nitrogen protection, dissolve 1.6g tetraphenylmethane in 60mLCS 2 In, add 5g of 2-bromoacetyl bromide, and finally add 3.4g of AlCl 3 , reflux, react at 50°C for 25h, pour off the CS 2 , add 50g ice water, 13mL concentrated hydrochloric acid, 50mL dichloromethane and stir until the black solid is completely dissolved; layered extraction, add water and saturated sodium chloride to wash, dry over anhydrous sodium sulfate, pass through a silica gel column, the mobile phase is dichloromethane: n-Hexane=20:1, and finally 2.6 g of white foamy solid tetrakis-(4-(bromoacetyl)phenyl)methane was obtained.

[0063]Step 2: Tetrakis(4-(2-tris-(4,7,10-triacetate tert-butylcarboethoxy)1,4,7,10-tetraazacyclododecylacetyl)phenyl) Methane synthesis

[0064] Add 3.2 g of tri-tert-butyl 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) tris to a 50 mL round bottom flask Acetate · hydrogen bromide hydrochlo...

Embodiment 3

[0078] Step 1: Synthesis of tetrakis-(4-(bromoacetyl)phenyl)methane

[0079] Under nitrogen protection, dissolve 2g tetraphenylmethane in 75mLCS 2 In, add 6.3g of 2-bromoacetyl bromide, and finally add 4.3g of AlCl 3 , reflux, react at 55°C for 24h, pour off the CS 2 , add 65g ice water, 16mL concentrated hydrochloric acid, 65mL dichloromethane and stir until the black solid is completely dissolved; layered extraction, add water and saturated sodium chloride to wash, dry over anhydrous sodium sulfate, pass through a silica gel column, and the mobile phase is dichloromethane: n-Hexane=20:1, and finally 3.4 g of white foamy solid tetrakis-(4-(bromoacetyl)phenyl)methane was obtained.

[0080] Step 2: Tetrakis(4-(2-tris-(4,7,10-triacetate tert-butylcarboethoxy)1,4,7,10-tetraazacyclododecylacetyl)phenyl) Methane synthesis

[0081] Add 3.4 g of tri-tert-butyl 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) tris to a 50 mL round bottom flask Acetate · hydrogen bromide hydr...

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Abstract

The invention provides a non-ionic multi-nuclear magnetic resonance imaging contrast medium taking tetrabenzoylmethane as interconnect and a preparation method thereof, belonging to a magnetic resonance imaging contrast medium. The contrast medium is prepared by covalently linking four DO3A groups with rigid connection group tetrabenzoylmethane and then coordinating paramagnetic metal ions Gd<3+>, wherein besides four nitrogen atoms in the DO3A and three carboxylic groups on a ring, an acetyl carbonyl group in the tetrabenzoylmethane also participate in the coordinating of paramagnetic ions; due to the formation of the coordination bond, the coordination stability of the paramagnetic ions and compounds can be enhanced, the interconnect flexibility between DO3A chelating groups and a connection center can also be reduced, the rotation of the DO3A and the paramagnetic ions is consistent with that of the whole molecule, the relevant rotation time of the paramagnetic ions can be objectively prolonged, and the relaxation efficiency of the contrast medium can be improved. The total relaxation efficiency of the contrast medium can achieve 37.2mM<-1>s<-1>.

Description

technical field [0001] The invention belongs to magnetic resonance imaging contrast agents, in particular to a non-ionic multinuclear magnetic resonance imaging contrast agent with tetrabenzoylmethane as a linker and a preparation method thereof. Background technique [0002] In recent years, Magnetic Resonance Imaging (MRI) has become one of the commonly used clinical diagnostic methods. Compared with conventional CT, magnetic resonance imaging has the advantages of no radiation, non-invasiveness, and high spatial resolution. Currently, more than 35% of clinical MRIs require the use of MRI contrast agents. With the development and clinical application of new magnetic imaging techniques, such as functional magnetic resonance imaging (Functional MRI) and perfusion magnetic resonance imaging (Perfusion MRI), the research and development of MRI contrast agents has become an increasingly important field. Magnetic resonance imaging contrast agent is a kind of diagnostic drug th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/00A61K49/06
CPCY02P20/55
Inventor 杨卫张雯雯徐经纬赵桂燕方新秀
Owner JIANGXI INST OF RARE EARTHS CHINESE ACAD OF SCI
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