CN109568607A - A kind of gadolinium Base Metal fullerene water dissolubility nitrene derivative and the preparation method and application thereof - Google Patents
A kind of gadolinium Base Metal fullerene water dissolubility nitrene derivative and the preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of gadolinium Base Metal fullerene water dissolubility nitrene derivatives and the preparation method and application thereof.The gadolinium Base Metal fullerene water dissolubility nitrene derivative is by paramagnetism gadolinium Base Metal fullerene GdaNb@C2nWith trinitride N3(CH2)mNH2Or N3(CH2)m‑1COOH is reacted by nitrene to be made, and general structure is as follows: GdaNb@C2n[N(CH2)mNH2]xOr GdaNb@C2n[N(CH2)m‑ 1COOM]xIn above structure general formula, a=1~3；B=0~3；N=30~45；M=2~6；X=8~30；M is H, NH4, Na or K.The present invention provides a kind of methods for preparing gadolinium Base Metal fullerene water dissolubility nitrene derivative through nitrene reaction.The gadolinium Base Metal fullerene water dissolubility nitrene derivative has good water solubility, also good paramagnetic properties are shown, it can be used as magnetic resonance imaging contrast, when for MRI image imaging, contrast enhancing effects highly significant, it is with important application prospects especially in terms of the diagnoses and treatment of MRI image guidance in medical consultations.
Description
Technical field
The invention belongs to carbon nanomaterial fields, and it is derivative to be related to a kind of paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene
Object and its preparation method and application, such gadolinium Base Metal fullerene water dissolubility nitrene derivative can be used as magnetic resonance imaging (MRI)
Contrast agent.
Background technique
With high longitudinal relaxation rate (R1), the paramagnetic metal fullerene T of low bio-toxicity1Type MRI contrast agent has developed
Nearly 20 years.Wherein, gadolinium Base Metal fullerene MRI contrast agent is most commonly in document report as molecular image probe.These MRI are visited
Needle is the Gd@C of the reaction single step such as hydroxylating, amination, Bingel-Hirsch or Prato or multi step modification60、Gd@C82、
ScxGd3-xN@C80、Gd3N@C80、Gd3N@C84Derivative.In these derivatives, Gd@C82(OH)40Label cell makees molecule for the first time
Probe application is in MRI cell imaging；Gd@C82O6(OH)16(NHCH2CH2COOH)8Protein-coupled receptor makees identification fluorescence egg for the first time
White molecular probe；In conjunction with the Gd of identification glioma small peptide IL-133N@C80(OH)26(CH2CH2COOH)16And Gd3N@C80O12
(OH)10(NH2)7(NO2)2It is successively reported and makees the tumour diagnosis and treatment reagent of Clinics and Practices function integration.In addition, Gd@C82O14
(OH)14(NH2)6Label-free fluorescent dye can constitute MRI- fluorescent dual module state molecular image probe, can also make antioxidant
ROS type free base is removed, has tumor suppression potentiality.Currently, paramagnetism gadolinium Base Metal fullerene derivate makees nanometer diagnosis and treatment examination
There are bottleneck, key is that lacking economical rationality large-scale prepares novel paramagnetism gadolinium Base Metal fowler for the application study of agent
The synthetic method of alkene soluble derivative leads to be difficult to provide sufficient products application in subsequent biological effect research.
The object of the invention is that the excessive nitrine chemical combination using the reaction technology for exempting from solvent strategy, directly to be in a liquid state
The paramagnetism gadolinium Base Metal fullerene of object disperse solid, reacts through nitrene, so that it is rich to invent a kind of paramagnetic gadolinium Base Metal
Strangle alkene soluble derivative and preparation method thereof.This is derivative for the paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene of Development of Novel
Object is used as MRI contrast agent and provides a brand-new Research Thinking.
Summary of the invention
The invention solves first technical problem be to provide a kind of bonded hydrophily function of the external side chain terminal of carbon cage
The gadolinium Base Metal fullerene water dissolubility nitrene derivative of group, the derivative have good water-soluble and paramagnetic performance, and its
There is the group with reactivity in side chain terminal.
The invention solves second technical problem be to provide and a kind of prepare the paramagnetic gadolinium Base Metal fullerene
The method of water-soluble nitrene derivative.
The invention solves third technical problem be to provide the paramagnetic gadolinium Base Metal fullerene water-soluble nitrogen
Application of guest's derivative as magnetic resonance imaging contrast.
The technical solution taken by the invention to solve the above technical problem is illustrated below.
It on the one hand, is by suitable the present invention provides a kind of paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative
Magnetic gadolinium Base Metal fullerene GdaNb@C2nWith trinitride N3(CH2)mNH2Or N3(CH2)m-1COOH is reacted by nitrene to be made,
General structure is as follows:
GdaNb@C2n[N(CH2)mNH2]xOr GdaNb@C2n[N(CH2)m-1COOM]x
In above structure general formula, a=1~3；B=0~3；N=30~45；M=2~6；X=8~30；M is H, NH4、Na
Or K.
Paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative molecular of the present invention is with paramagnetism gadolinium fund
Category Fullerene Carbon cage is core, and carbon cage is outer to make linking arm at least provided with 8 hydrophilic side-chains, each linking arm pass through nitrogen bridge with
Carbon cage is bonded, and linking arm is the short straight saturated carbon chains that several carbon atoms are constituted and end is also bonded hydrophilic functional group-NH2Or
Person-COOM therefore ensures that entire derivative molecular has water solubility.The number of linking arm can be according to different trinitride and gadolinium base
Metal fullerene kind determines, water-soluble very poor or even completely insoluble in water when linking arm number is lower than 8；Work as connection
When the number of arm is higher than 30, the carbon basket structure of product is very unstable, or even cage is caused out to lead to interior packet metal leakage；Therefore it connects
The number of arm is preferably between 8~30, for Gd@C82For derivative, particularly preferred 14~24.
Paramagnetism gadolinium Base Metal fullerene of the present invention is that each molecule is had by what 60~90 carbon atoms formed
Spherical or near-spherical structure and inside include 1-3 Gd atom either GdaNbElementide, the paramagnetism gadolinium fund
Belonging to fullerene is preferably Gd@C82、Gd@C60、Gd2@C80、Gd3N@C80Or Gd3N@C84, more preferable Gd@C82、Gd3N@C80Or Gd3N@
C84, and with Gd@C82It is optimal.
Trinitride of the present invention, molecular structure are the saturated fat normal carbon chain of carbochain carbon atoms number 2~6
And bonded the azido (- N in one end3) and bonded hydrophilic the amino (- NH in another end2) or carboxyl (- COOH), general structure be
N3(CH2)mNH2Or N3(CH2)m-1COOH, preferably 2- azidoethylamine, 2- triazoacetic acid, 3- azidopropylamine, 3- nitrine
Base propionic acid, 4- azido butyric acid or 6- azido caproic acid.
It is well known technology that with the compound containing azido group cycloaddition reaction, which can occur, for fullerene, but rarely seen related paramagnetic
Property gadolinium Base Metal fullerene nitrene reaction occur prepare the report of soluble derivative.
On the other hand, paramagnetic gadolinium Base Metal fullerene water-soluble nitrogen is prepared through nitrene reaction the present invention provides a kind of
The method of guest's derivative.
The paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivant structure general formula is GdaNb@C2n[N(CH2)mNH2]xOr GdaNb@C2n[N(CH2)m-1COOH]x, the preparation method includes the following steps:
(1) by gadolinium Base Metal fullerene GdaNb@C2nWith trinitride N3(CH2)mNH2Or N3(CH2)m-1COOH feed intake respectively in
Reactor stirs under atmosphere of inert gases, the ratio between amount of substance of the gadolinium Base Metal fullerene and trinitride be 1:100~
1000；
(2) the solid-liquid reaction system that step (1) obtains is risen to 40~80 by room temperature first with 2-5 DEG C/min heating rate
DEG C, 0.5~2 hour is kept the temperature, then rises to 110~150 DEG C again with 0.5-2 DEG C/min heating rate, 10~48 hours is kept the temperature, stops
It only heats, entire reaction process is by TLC tracing and monitoring；
(3) washing of reaction product addition organic solvent A, filtering, the most of unreacted trinitride of removal, residue water
It extracts, extracting solution filtering, drying obtain cured crude product；
(4) crude product is redissolved in water, is dialysed using the bag filter of MW=500-10000, freeze-drying, is obtained pure suitable
The solid product of magnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative.
Further, in the step (1), trinitride has to be between specified model relative to the feed ratio of gadolinium Base Metal fullerene
Within enclosing, i.e., the ratio between amount of substance is 100~1000:1.When specifying feed ratio 100:1 lower limit lower than this, reaction system is easily rapid
Solidify and be difficult to continue carry out and derivative addition number it is few, cause to be difficult to obtain water-soluble products；When more than the 1000:1 upper limit,
Subsequent processing is cumbersome, and is not easy to obtain the product of purifying；Within the scope of specified feed ratio can relatively low cost, high yield acquisition
Water-soluble paramagnetism gadolinium Base Metal fullerene nitrene derivative.
Further, in the step (2), temperature control operation is extremely crucial, and when being lower than 110 DEG C, reaction is difficult to occur and be formed
Water-soluble products when more than 150 DEG C, react excessively violent, there is very big risk out of control, preferably 110~150 DEG C of temperature control range,
More preferable 110~120 DEG C.
Further, in the step (3), conventional reagent is can be used in washing, such as ether, methylene chloride, chloroform, acetic acid
Ethyl ester etc., the most of unreacted trinitride of removal.
Further, in the step (4), refining methd is so purified, processing mode step using being freeze-dried after dialysis
It is less and easy to operate.
Paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene is prepared through nitrene reaction the present invention also provides another kind to spread out
The method of biology, the paramagnetism gadolinium Base Metal fullerene nitrene derivant structure general formula are GdaNb@C2n[N(CH2)m- 1COOM]x, the M is Na or K or NH4, the preparation method includes the following steps:
(a) by gadolinium Base Metal fullerene GdaNb@C2nWith trinitride N3(CH2)m-1COOH is fed intake respectively in reactor, lazy
Property atmosphere under stir, the ratio between amount of substance of the gadolinium Base Metal fullerene and trinitride be 1:100~1000；
(b) the solid-liquid reaction system that step (1) obtains is risen to 40~80 by room temperature first with 2-5 DEG C/min heating rate
DEG C, 0.5~2 hour is kept the temperature, is then warming up to 110~150 DEG C again with 0.5-2 DEG C/min, keeps the temperature 10~48 hours, stops adding
Heat, entire reaction process is by TLC tracing and monitoring；
(c) washing of reaction product addition organic solvent B, filtering, the most of unreacted trinitride of removal, residue redissolve
In alkaline solution, the alkaline solution is NaOH or KOH aqueous solution or ammonium hydroxide, dialysed using MW=500-10000 bag filter,
It is dry, obtain the solid product of pure paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative.
Further, in the step (a), trinitride has to be between specified model relative to the feed ratio of gadolinium Base Metal fullerene
Within enclosing, i.e., the ratio between amount of substance is 100~1000:1.When specifying feed ratio 100:1 lower limit lower than this, reaction system is easily rapid
Solidify and be difficult to continue carry out and derivative addition number it is few, cause to be difficult to obtain water-soluble products；When more than the 1000:1 upper limit,
Subsequent processing is cumbersome, and is not easy to obtain the product of purifying；Within the scope of specified feed ratio can relatively low cost, high yield acquisition
Water-soluble paramagnetism gadolinium Base Metal fullerene nitrene derivative.
Further, in the step (b), temperature control operation is extremely crucial, and when being lower than 110 DEG C, reaction is difficult to occur and be formed
Water-soluble products when more than 150 DEG C, react excessively violent, there is very big risk out of control, preferably 110~150 DEG C of temperature control range,
More preferable 110~120 DEG C.
Further, in the step (c), conventional reagent is can be used in washing, such as ether, methylene chloride, chloroform, acetic acid
Ethyl ester etc., the most of unreacted trinitride of removal.The present invention by step (3) and (c) in organic solvent organic solvent A and
Organic solvent B indicates that purpose, which is only that, distinguishes different steps, and being not offered as organic solvent A and organic solvent B must use
Different solvents, in fact the two is respectively independent, and those skilled in the art, which can according to need, to be selected.
Further, in the step (c), alkaline solution is preferably the NaOH or KOH of concentration > 0.1mol/L and≤1mol/L
Aqueous solution or ammonium hydroxide, NaOH the or KOH aqueous solution of more preferable 0.5mol/L.
Further, paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative obtained by step (c), can be by folded
Nitrogen object and paramagnetism gadolinium Base Metal fullerene kind, to regulate and control the number of side chains number and the width of distribution.
The third aspect, the present invention provides the paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivatives as magnetic
The application of resonance image-forming contrast agent.
In the paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative molecular that the present invention obtains, carbon cage surface passes through
Bonded-the NH in the multiple ends of nitrogen-atoms bridging2Or the hydrophilic side-chains of-COOM, so that entire Cage molecules have water solubility, simultaneously
Also good paramagnetic properties are shown, therefore can be used as magnetic resonance imaging contrast.In addition, by means of side chain terminal there is reaction to live
Property-NH2Or-COOM functional group, it can be used as reaction intermediate, pass through the bonded such as paramagnetic of amidation coupling reaction, light, enzyme mark
The large biological molecules such as all kinds of markers and carbohydrate, nucleic acid, polypeptide, antibody such as note, thus the nanometer diagnosis and treatment examination of constructing function
Agent, to be applied to nanometer Clinics field.
Compared with prior art, the beneficial effects of the present invention are:
(A) it is the suitable of side chain carbochain length, number and chain end alkene hydrophilic group inequality that compound provided by the invention, which is one,
Magnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative, this can greatly expand the product of metal fullerene soluble derivative
Library.
(B) the paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative new method of large scale preparation provided by the invention
The characteristics of: synthesis technology is easy, efficient, and method for purifying and separating is simple, it is easy to accomplish heavy industrialization preparation.
(C) reaction system of solid-liquid phase reaction method provided by the invention is without adding organic solvent dispersion paramagnetism gadolinium fund
Belong to fullerene, the trinitride itself of the liquid as reactant is close with derivative polarity, and is conducive to it and is scattered in liquid phase reactor
System, and higher adduct number purpose derivative is finally generated, until generating water-soluble derivative products.
(D) present invention obtains the external side chain end of carbon cage of paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative
There is the group-NH with reactivity in end2Or-COOM, it is each magnetic, light, enzyme etc. can be coupled by amidation condensation reaction
The biologically functional molecules such as class marker and carbohydrate, nucleic acid, polypeptide, antibody.
(E) present invention obtain paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative have it is good water-soluble
Property, good paramagnetic properties are also shown, can be used as magnetic resonance imaging contrast, when for MRI image imaging, contrast enhancing effects
Highly significant, it is with important application prospects especially in terms of the diagnoses and treatment of MRI image guidance in medical consultations.
Detailed description of the invention
Gd@C in Fig. 1 embodiment 182(NCH2CH2COOH)22The MALDI-TOF MS spectrogram of aqueous solution.
Gd@C in Fig. 2 embodiment 182(NCH2CH2COOH)22The FT-IR spectrogram of powder.
Gd@C in Fig. 3 embodiment 182(NCH2CH2COOH)22The thermogravimetric analysis spectrogram of powder.
Gd@C in Fig. 4 embodiment 382(NCH2CH2NH2)16The FT-IR spectrogram of powder.
Fig. 5 .Gd@C82(NCH2COOH)24(A) and Gd@C82(NCH2CH2COOH)22(B) proton longitudinal relaxation rate.
Specific embodiment
Following embodiment helps to further understand the present invention, but the scope of the present invention is not limited to the implementation enumerated
Example.
Experimental method described in following embodiment is conventional method；The reagent and material commercially obtain
?.Wherein, Gd@C82From Xiamen, good fortune is taken in the fresh material Science and Technology Ltd., and purity is higher than 99.0%.
Embodiment 1: preparation Gd@C82With the soluble derivative Gd@C of nitrine propionic acid82(NCH2COOH)22
By 10mg Gd@C82With the N of liquid3CH2CH2Stoichiometrically 1:500's COOH successively feeds intake in three mouthfuls of reaction flasks,
Nitrogen protection, stirring；60 DEG C are to slowly warm up to 2 DEG C/min heating rate first, 1 hour is kept the temperature, then again with 0.5 DEG C/min
Heating rate rises to 120 DEG C, keeps the temperature 48 hours, stops heating；Add ethyl acetate washing, filtering, residue deionized water
It is extracted repeatedly to colourless, it is extracting solution filtering, dry, obtain solidification crude product；It redissolves in deionized water, uses MW=3500 bag filter
Dialysis, membrane filtration, freeze-drying obtain pure paramagnetism Gd@C82The solid product of polyalanine soluble derivative.
As shown in Figure 1, m/z is that quasi-molecular ions belongs to Gd@C at 1142 in MALDI-TOF MS82Carbon cage faced parent element, generally
Think, the metal fullerene external side chain of soluble derivative carbon cage is in MALDI-TOF MS experimentation because of the attached work of laser desorption
It is stripped with from metal fullerene carbon cage, without there is the molecular ion peak of derivative, there is only metal fullerene units
Quasi-molecular ions.Due to Gd@C82Insoluble in water phase, it can determine whether that the soluble derivative is exactly Gd C82Derivative.
As shown in Fig. 2, infrared spectroscopy is in 3420cm-1The strong absworption peak at place is attributed to O-H stretching vibration, 1720cm-1It inhales at place
It receives peak and belongs to C=O, 1100cm-1C-OH stretching vibration is belonged to, in 2930cm-1It is flexible that the weak absorbing peak at place belongs to C-H
Vibration, in 1640cm-1The strong absworption peak at place belongs to Gd@C82Remaining C=C stretching vibration in carbon cage.IR spectrogram proves Gd@
C82There is-COOH in polyalanine soluble derivative molecule.
As shown in figure 3, TG-DTG-DSC Synchronization Analysis the result shows that, Gd@C82Polyalanine soluble derivative molecule exists
110-515 DEG C of percent mass of temperature range is reduced to 35.33% from 93.89%, the percent mass of this section reduction
(57.80%) it is entirely due to Gd@C82External group-the NCH of polyalanine soluble derivative molecule2CH2The whole of COOH is lost
It loses, and 515 DEG C of whens remaining quality then belongs to Gd@C82Carbon cage, wherein carbon cage amount is 1142, the external side chain of whole (-
NCH2CH2COOH formula weight) is 87x, calculates x=21.47, obtains Gd@C accordingly82Polyalanine soluble derivative mean molecule
Formula is Gd@C82(NCH2CH2COOH)22。
Embodiment 2: preparation Gd@C82With the soluble derivative Gd@C of nitrine acetic acid82(NCH2COOH)24
By 10mg Gd@C82With the N of liquid3CH2COOH successively feeds intake in three mouthfuls of reaction flasks, nitrogen protection, stirring；First
80 DEG C are to slowly warm up to 2 DEG C/min heating rate, keeps the temperature 2 hours, then rises 120 DEG C again with 0.5 DEG C/min heating rate, is protected
Temperature 48 hours stops heating；Ether washing is added, remaining condition is the same as the embodiment of the present invention 1.Obtain pure paramagnetism Gd@C82
Polyglycine soluble derivative solid product.It is Gd@C that thermogravimetric analysis, which characterizes its Average molecular formula,82(NCH2COOH)24。
Embodiment 3: preparation Gd@C82With the soluble derivative Gd@C of nitrine ethamine82(NCH2CH2NH2)20
By 10mg Gd@C82With the N of liquid3CH2CH2NH2It successively feeds intake in three mouthfuls of reaction flasks, nitrogen protection, stirring；First
60 DEG C are to slowly warm up to 2 DEG C/min heating rate, 2 hours is kept the temperature, then rises to 125 DEG C again with 0.5 DEG C/min heating rate,
Heat preservation 48 hours stops heating；Add ethyl acetate washing；Remaining condition is the same as the embodiment of the present invention 1.Obtain pure paramagnetism
Gd@C82Polyethyene diamine soluble derivative Gd@C82(NCH2CH2NH2)20Solid product.
As shown in figure 4, infrared spectroscopy is in 3385cm-1The strong absworption peak at place is attributed to N-H stretching vibration, 1388cm-1It inhales at place
It receives peak and belongs to NH bending vibration, 1037cm-1Belong to C-NH2Stretching vibration is in 2935,2850cm-1The weak absorbing peak at place belongs to
In C-H symmetric and anti-symmetric stretching vibration, in 1654cm-1The strong absworption peak at place belongs to Gd@C82Remaining C=C stretches in carbon cage
Contracting vibration.IR spectrogram proves Gd@C82There is-NH in polyethyene diamine soluble derivative molecule2。
Embodiment 4: preparation Gd@C82With the metal fullerene base polyglycine sodium soluble derivative Gd@C of nitrine acetic acid82
(NCH2COONa)14
By 10mg Gd@C82With the N of liquid3CH2Stoichiometrically 1:100's COOH successively feeds intake in three mouthfuls of reaction flasks, nitrogen
Gas shielded, mechanical stirring；40 DEG C are to slowly warm up to 2 DEG C/min heating rate first, 0.5 hour is kept the temperature, then again with 0.5
DEG C/min heating rate rises to 110 DEG C, 10 hours are kept the temperature, heating is stopped；Add ether washing, filtering, residue redissolve in
0.5mol/LNaOH solution is dialysed using MW=3500 bag filter, membrane filtration, freeze-drying, and purification, which obtains, contains Sodium Glycinate
Gd@C82The solid product of water-soluble nitrene derivative, it is Gd C that thermogravimetric analysis, which characterizes its Average molecular formula,82
(NCH2COONa)10。
Embodiment 5: preparation Gd@C82With the poly- glycoleucine sodium soluble derivative Gd@C of metal fullerene base of nitrine caproic acid82
(NCH2CH2CH2CH2CH2COONa)10
By 10mg Gd@C82With the N of liquid3CH2CH2CH2CH2CH2Stoichiometrically 1:250's COOH successively feeds intake in three
Mouth reaction flask, nitrogen protection, mechanical stirring；80 DEG C are to slowly warm up to 2 DEG C/min heating rate first, keeps the temperature 2 hours, then
140 DEG C are risen to 0.5 DEG C/min heating rate again, keeps the temperature 24 hours, stops heating；Add ethyl acetate washing, filtering, residual
Object is redissolved in 0.5mol/LNaOH solution, and membrane filtration is dialysed using MW=3500 bag filter, and freeze-drying, purification obtains gold
Belong to the poly- glycoleucine sodium soluble derivative of fowler alkenyl, it is Gd C that thermogravimetric analysis, which characterizes its Average molecular formula,82
(NCH2CH2CH2CH2CH2COONa)10。
Comparative example
Referring to embodiment 1, difference is: Gd@C82With the N of liquid3CH2CH2After COOH mixing, it is directly warming up to reflux temperature
Degree is reacted and is acutely carried out, and after about 30min-60min, system solidifies rapidly, and reaction is forced to terminate, and stops heating；Add acetic acid second
Ester washing, filtering, residue are extracted 3-5 times repeatedly with deionized water, and extracting solution filtering, concentration use MW=3500 bag filter
Dialysis, does not obtain Gd@C after membrane filtration, freeze-drying82Polyalanine soluble derivative Gd@C82(NCH2CH2COOH) x
Solid product.
Embodiment 6:Gd@C82Nitrene derivative makees the specific embodiment that Relaxivity is tested when MRI contrast agent
Relaxivity experiment carries out on 200,000,000 animal MRI instrument.Gd@C is respectively configured82(NCH2COOH)24With Gd@C82
(NCH2CH2COOH)22A series of various concentration samples.It is scanned using inversion recovery spin echo imaging sequence, sequential parameter
Are as follows: repetition time 10s, echo time 13.5ms, 3.5 × 3.5cm of imaging area2, piece thickness 1.0mm, data matrix 64 × 64,
A series of suitable TI values are selected between 0.05~15s.It is fitted by three parameter single exponential functions, obtains all samples to be tested
Longitudinal relaxation time T1.Pass through T when its serial various concentration1Value is fitted its proton longitudinal relaxation rate, that is, R1Value.Fig. 5 is Gd@C82
(NCH2COOH)24With Gd@C82(NCH2CH2COOH)22Longitudinal relaxation rate 1/T1Relative to its concentration trend chart, this variation
The slope of trend is its R1Value, it is as a result shown in table 1.In general, carbochain is shorter in linking arm, and relaxation rate is higher, adduct number
Mesh is more, and relaxation rate is higher.
Table 1
| Sample name | R1(mM-1S-1) |
| Gd@C82(NCH2COOH)24 | 26.29 |
| Gd@C82(NCH2CH2COOH)22 | 17.34 |
Claims (9)
1. a kind of paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative, is by paramagnetism gadolinium Base Metal fullerene
GdaNb@C2nWith trinitride N3(CH2)mNH2Or N3(CH2)m-1COOH is reacted by nitrene to be made, and general structure is as follows:
GdaNb@C2n[N(CH2)mNH2]xOr GdaNb@C2n[N(CH2)m-1COOM]x
In above structure general formula, a=1~3；B=0~3；N=30~45；M=2~6；X=8~30；M is H, NH4, Na or K.
2. paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative as described in claim 1, it is characterised in that: described
Paramagnetism gadolinium Base Metal fullerene be Gd@C82、Gd@C60、Gd2@C80、Gd3N@C80Or Gd3N@C84, more preferable Gd@C82、
Gd3N@C80Or Gd3N@C84, and with Gd@C82It is optimal.
3. paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative as claimed in claim 2, it is characterised in that: described
Paramagnetism gadolinium Base Metal fullerene be Gd@C82, x=14~24.
4. the paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative as described in one of claim 1-3, feature exist
In: the trinitride is 2- azidoethylamine, 2- triazoacetic acid, 3- azidopropylamine, 3- azido propionic acid, 4- azido
Butyric acid or 6- azido caproic acid.
5. a kind of prepare paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative described in claim 1 through nitrene reaction
Method, it is characterised in that:
When the general structure of the paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative is GdaNb@C2n[N(CH2)mNH2]xOr GdaNb@C2n[N(CH2)m-1COOH]xWhen, the preparation method includes the following steps:
(1) by gadolinium Base Metal fullerene GdaNb@C2nWith trinitride N3(CH2)mNH2Or N3(CH2)m-1COOH is fed intake respectively in reaction
Device stirs under atmosphere of inert gases, the ratio between amount of substance of the gadolinium Base Metal fullerene and trinitride be 1:100~
1000；
(2) the solid-liquid reaction system that step (1) obtains is risen to 40~80 DEG C by room temperature first with 2-5 DEG C/min heating rate,
Then heat preservation 0.5~2 hour rises to 110~150 DEG C again with 0.5-2 DEG C/min heating rate, keep the temperature 10~48 hours, stops
Heating, entire reaction process is by TLC tracing and monitoring；
(3) washing of reaction product addition organic solvent A, filtering, the most of unreacted trinitride of removal, residue are carried out with water
It extracts, extracting solution filtering, drying obtain cured crude product；
(4) crude product is redissolved in water, is dialysed using the bag filter of MW=500-10000, and freeze-drying obtains pure paramagnetism
Gadolinium Base Metal fullerene water dissolubility nitrene derivative solid product；
When the paramagnetism gadolinium Base Metal fullerene nitrene derivant structure general formula is GdaNb@C2n[N(CH2)m-1COOM]x,
Middle M is Na or K or NH4When, the preparation method includes the following steps:
(a) by gadolinium Base Metal fullerene GdaNb@C2nWith trinitride N3(CH2)m-1COOH is fed intake respectively in reactor, in indifferent gas
It is stirred under body atmosphere, the ratio between amount of substance of the gadolinium Base Metal fullerene and trinitride is 1:100~1000；
(b) the solid-liquid reaction system that step (1) obtains is risen to 40~80 DEG C by room temperature first with 2-5 DEG C/min heating rate,
Then heat preservation 0.5~2 hour rises to 110~150 DEG C again with 0.5-2 DEG C/min heating rate, keep the temperature 10~48 hours, stops
Heating, entire reaction process is by TLC tracing and monitoring；
(c) washing of reaction product addition organic solvent B, filtering, the most of unreacted trinitride of removal, residue are redissolved in alkali
Property solution, the alkaline solution is NaOH or KOH aqueous solution or ammonium hydroxide, uses the bag filter dialysis of MW=500-10000, dry
It is dry, obtain the solid product of pure paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative.
6. method as claimed in claim 5, it is characterised in that: the step (2) or (b) in, 40~80 DEG C heat preservation 0.5~2
After hour, it is to slowly warm up to 110~120 DEG C of insulation reactions.
7. such as method described in claim 5 or 6, it is characterised in that: the organic solvent A and organic solvent B are respectively independently selected
From one of following or any several mixing: ether, methylene chloride, chloroform, ethyl acetate.
8. such as method described in claim 5 or 6, it is characterised in that: in the step (c), alkaline solution be concentration >
NaOH the or KOH aqueous solution or ammonium hydroxide of 0.1mol/L and≤1mol/L.
9. paramagnetic gadolinium Base Metal fullerene water dissolubility nitrene derivative as described in claim 1 is made as magnetic resonance imaging
The application of shadow agent.
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