CN1810293A - Magnetic resonance imaging contrast medium based on metal fullerene and its prepn process - Google Patents

Magnetic resonance imaging contrast medium based on metal fullerene and its prepn process Download PDF

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CN1810293A
CN1810293A CN 200510002948 CN200510002948A CN1810293A CN 1810293 A CN1810293 A CN 1810293A CN 200510002948 CN200510002948 CN 200510002948 CN 200510002948 A CN200510002948 A CN 200510002948A CN 1810293 A CN1810293 A CN 1810293A
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metal fullerene
preparation
magnetic resonance
resonance imaging
aqueous slkali
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王春儒
舒春英
白春礼
甘利华
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Institute of Chemistry CAS
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Abstract

The magnetic resonance imaging contrast medium based on metal fullerene has the molecular expression of Gd@C82OHx(NH2CH2CH2COOH)y.Gd@C82OHx(HNCH2CH2SO3H)y, where x=16-22 and y=6-8. The preparation process is the neucleophilic addition reaction between metal fullerene material Gd@C82 and the alkali solution of beta-alanine or amino ethyl sulfuric acid to form the water- soluble metal fullerene derivative with decorating carboxyl radical or sulfo radical. The preparation process is simple and mild, and may be used in industrial production. The water- soluble derivative of the present invention has magnetic resonance imaging efficiency obviously higher than available Gd-divinyl triamino penta acetic acid chelate.

Description

A kind of magnetic resonance imaging contrast and preparation method based on metal fullerene
Technical field
The present invention relates to a kind of magnetic resonance imaging contrast.
The invention still further relates to the preparation method of above-mentioned magnetic resonance imaging contrast.
Background technology
Nuclear magnetic resonance (MRI) technology has now developed into a kind of common means in the clinical treatment diagnosis, is diagnosing tumour one of effective method the most.In order to strengthen contrast and the definition between pathological tissues and the normal structure image, need to select suitable contrast medium to show anatomical features.These contrast mediums overwhelming majority utilizes the paramagnetic characteristic of metal ion.Gd 3+Because have over paramagnetism, its complex is the present general and the most effective most widely used class contrast medium.Nearest result of study shows, Gd@C 82(OH) 40MRI radiography efficient be clinical used Gd-DTPA[diethylene triamine pentaacetic acid, DTPA] 20 times of chelate contrast agent.This table of discovery Benq can be used for making MRI contrast agent efficiently in the soluble derivative of metal fullerene.But Gd@C in acid and neutral solution 82(OH) xEasily be agglomerated into bulky grain, will run into the angiemphraxis problem as in animal or human's body, using.
Summary of the invention
The object of the present invention is to provide a kind of magnetic resonance imaging contrast based on metal fullerene.
Another purpose of the present invention is to provide a kind of method for preparing above-mentioned contrast agent.
For achieving the above object, the magnetic resonance imaging contrast based on metal fullerene provided by the invention is metal fullerene Gd@C 82Soluble derivative, its expression formula is:
Gd@C 82(OH) x(NH 2CH 2CH 2COOH) y(x=16 in the formula～22, y=6～8);
Or Gd@C 82(OH) x(HNCH 2CH 2SO 3H) y(x=16 in the formula～22, y=6～8).
The method of the above-mentioned contrast agent of preparation provided by the invention, be to utilize the aqueous slkali of metal fullerene and Beta-alanine or taurine that nucleophilic addition directly takes place, and the realization cage is modified the preparation of carboxyl or sulfonic soluble derivative outward, and key step is:
(a) prepare the aqueous slkali (concentration is 0.2-0.5mol/L) of Beta-alanine or taurine, and add the ethanol of 4 times of amounts of this aqueous slkali volume;
(b) under the room temperature, the aqueous slkali of step a is added drop-wise in the toluene solution of metal fullerene, the mol ratio of its Beta-alanine or taurine and metal fullerene is 100-300: 1, obtain mixture solution;
(c) under the room temperature, the mixture solution stirring reaction that step b is obtained 3-5 days, separatory concentrates, the polydextran gel phase that fixes, deionized water is done mobile phase, collects the component of pH=6-7, obtains the soluble derivative (AAD-EMF) of target product-metal fullerene.
For improving the purity of metal fullerene, preferably in advance metal fullerene to be purified, the available method commonly used of purifying is as contain the carbon ash of metal fullerene by the preparation of direct-current arc electric discharge, with Carbon bisulfide (CS 2), organic solvent extraction such as dimethyl formamide (DMF), toluene separate to purify in conjunction with high performance liquid chromatography and obtain the toluene solution of highly purified metal fullerene, carry out prepared in reaction AAD-EMF with this toluene solution then.
Compare with other prior art, the present invention has following characteristics:
1. the present invention utilizes the nucleophilic characteristic of amino of Beta-alanine or taurine and the Gd@C of electron deficiency 82These characteristics of nucleophilic addition take place, and at room temperature make Gd@C in a large number through single step reaction 82Carboxylated or sulfonated derivant, thereby have simple economy, the easy to operate and advantage being convenient to accomplish scale production.
2. the present invention need can not allow out of phase material generation nucleophilic addition with phase transfer catalyst, has reduced Financial cost to a great extent.
3. it is excessive far away that the present invention can make wherein cheap a kind of reactant according to the stoichiometric proportion that reaction equation provides, thereby make Gd@C 82Can fully react, reach the purpose of saving material, reducing cost.
4. the MRI contrast agent (AAD-EMF) based on metal fullerene of the present invention preparation has radiography efficient and is better than now clinical used Gd-DTPA, and sedimentary characteristics do not take place in neutral aqueous solution.
Description of drawings
Fig. 1 a is the position view of pH=6-7 component (brown colour band) on chromatographic column of collecting in the preparation process of the present invention.
Fig. 1 b is the structural representation of the cage of the present invention soluble derivative (AAD-EMF) that is modified with the metal fullerene of carboxyl outward.
Fig. 2 for the dynamic Laser scattering particle size distribution figure of the AAD-EMF of the present invention preparation (pH=7, pH=9), this material has narrower particle size distribution in pH scope more widely, especially under neutrallty condition, its particle size distribution is 25-250nm.
(pH=7 pH=9), has further confirmed the uniformity of particle size distribution to atomic force microscope (AFM) picture of AAD-EMF on Muscovitum that Fig. 3 a and Fig. 3 b prepare for the present invention.
Fig. 4 for the AAD-EMF of the present invention preparation with the external t1 weighting of other contrast agent under same concentration as comparison diagram.
The specific embodiment
Embodiment 1: take by weighing 11mg NaOH, the 24.3mg Beta-alanine adds the 2mL dehydrated alcohol after adding the 0.5mL water dissolution, and this mixed liquor dropwise is added to the Gd@C of about 5mL through purifying 82In the toluene solution of (about 1.3mg), room temperature stirred 5 days down, and separatory separates then, and unreacted Gd@C removes 2 times with toluene wash in lower floor 82, with sephadex G-25 phase that fixes, make eluant behind the concentrating under reduced pressure with high purity water, the brown component of collecting pH=6-7 is Gd@C of the present invention 92Carboxylated soluble derivative (AAD-EMF).
Figure A20051000294800051
According to the stoichiometric proportion shown in the last equation 1, if (B) the excessive far away reactant A complete reaction as far as possible that makes.OH in the alkali -Also can with Gd@C 82Nucleophilic addition takes place, yellowish green Gd@C 82Toluene solution can become colourlessly gradually, and following pure water layer becomes brown.
Embodiment 2: with the Gd@C through purifying 82(about 1.3mg) is mixed with toluene solution, and the alkaline concentration of taurine is 0.2mol/L, also nucleophilic addition can take place, and room temperature stirred 5 days down, and all the other conditions are with embodiment 1.
Embodiment 3: with the nitrogen containing metal fullerene Gd that has the radiography effect through the another kind of purifying 3N@C 80Nucleophilic addition also can take place in the aqueous slkali that (about 1.3mg) is mixed with toluene solution and Beta-alanine or taurine, the mol ratio of Beta-alanine in the present embodiment or taurine and metal fullerene is that 100: 1 room temperature stirred 3 days down, and all the other conditions are with embodiment 1.

Claims (7)

1. the magnetic resonance imaging contrast based on metal fullerene is the soluble derivative of metal fullerene, and its expression formula is:
Gd@C 82(OH) x(NH 2CH 2CH 2COOH) y
Or Gd@C 82(OH) x(HNCH 2CH 2SO 3H) y
X=16 in the formula～22, y=6～8.
2. method for preparing the described magnetic resonance imaging contrast of claim 1, its key step is:
(a) compound concentration is the Beta-alanine of 0.2-0.5mol/L or the aqueous slkali of taurine;
(b) under the room temperature, the aqueous slkali of step a is added drop-wise in the toluene solution of metal fullerene, wherein the mol ratio of Beta-alanine or taurine and metal fullerene is 100-300: 1, obtain mixture solution;
(c) under the room temperature, the mixture solution stirring reaction that step b is obtained 3-5 days, separatory concentrates, the polydextran gel phase that fixes, deionized water is done mobile phase, collects the component of pH=6-7, obtains target product;
Described metal fullerene is Gd@C 82
3. the preparation method of claim 2 is characterized in that, is added with ethanol in the aqueous slkali of step a preparation, and alcoholic acid addition is 4 times of aqueous slkali volume.
4. the preparation method of claim 2 is characterized in that, aqueous slkali is NaOH, KOH solution.
5. the preparation method of claim 2 is characterized in that, the used metal fullerene of step b is through Carbon bisulfide, N, and dinethylformamide or toluene are purified.
6. the preparation method of claim 2 is characterized in that, the separatory among the step c with organic solvent washing after reconcentration.
7. the preparation method of claim 6 is characterized in that, organic solvent is a toluene.
CN 200510002948 2005-01-26 2005-01-26 Magnetic resonance imaging contrast medium based on metal fullerene and its prepn process Pending CN1810293A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100560138C (en) * 2007-02-02 2009-11-18 厦门大学 A kind of NMR contrast agent and preparation method thereof
CN102862977A (en) * 2012-09-06 2013-01-09 西南科技大学 Fullerenols metal salt derivative as well as preparation method and application thereof
CN106620727A (en) * 2016-10-08 2017-05-10 北京福纳康生物技术有限公司 Amino acid modified metallofullerene water-soluble nanoparticles as well as preparation method and application thereof
CN108530309A (en) * 2017-03-02 2018-09-14 北京福纳康生物技术有限公司 A kind of fullerene derivate and preparation method thereof and its application in chemotherapeutic protection
CN108853142A (en) * 2017-05-09 2018-11-23 北京福纳康生物技术有限公司 Water-soluble fullerene nano particle inhibits the application in tumour growth drug in preparation
CN109568607A (en) * 2018-12-30 2019-04-05 河南农业大学 A kind of gadolinium Base Metal fullerene water dissolubility nitrene derivative and the preparation method and application thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100560138C (en) * 2007-02-02 2009-11-18 厦门大学 A kind of NMR contrast agent and preparation method thereof
CN102862977A (en) * 2012-09-06 2013-01-09 西南科技大学 Fullerenols metal salt derivative as well as preparation method and application thereof
CN102862977B (en) * 2012-09-06 2015-01-28 西南科技大学 Fullerenols metal salt derivative as well as preparation method and application thereof
CN106620727A (en) * 2016-10-08 2017-05-10 北京福纳康生物技术有限公司 Amino acid modified metallofullerene water-soluble nanoparticles as well as preparation method and application thereof
CN108530309A (en) * 2017-03-02 2018-09-14 北京福纳康生物技术有限公司 A kind of fullerene derivate and preparation method thereof and its application in chemotherapeutic protection
CN108853142A (en) * 2017-05-09 2018-11-23 北京福纳康生物技术有限公司 Water-soluble fullerene nano particle inhibits the application in tumour growth drug in preparation
CN109568607A (en) * 2018-12-30 2019-04-05 河南农业大学 A kind of gadolinium Base Metal fullerene water dissolubility nitrene derivative and the preparation method and application thereof

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