CN109821031A - The synthesis and application of fluoro- 19 magnetic resonance imaging contrast of carboxylic acid glycine betaine amphoteric ion polymer - Google Patents
The synthesis and application of fluoro- 19 magnetic resonance imaging contrast of carboxylic acid glycine betaine amphoteric ion polymer Download PDFInfo
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- CN109821031A CN109821031A CN201910101973.7A CN201910101973A CN109821031A CN 109821031 A CN109821031 A CN 109821031A CN 201910101973 A CN201910101973 A CN 201910101973A CN 109821031 A CN109821031 A CN 109821031A
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- carboxylic acid
- glycine betaine
- acid glycine
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Abstract
The present invention relates to a kind of fluoro- 19 magnetic resonance imaging contrasts of carboxylic acid glycine betaine amphoteric ion polymer, belong to magnetic resonance imaging contrast field.Polymer shown in the present invention, wherein a-e is integer independent.Preparation method is simple, yield is high, easily separated.The method of the present invention is simple and efficient, the contrast agent of preparation have Superhydrophilic, high sensitivity, good biocompatibility, can quantitative detection, can be applied to in-vivo imaging.
Description
Technical field
The present invention relates to a kind of synthesis of fluoro- 19 magnetic resonance imaging contrast of carboxylic acid glycine betaine amphoteric ion polymer and answer
With belonging to magnetic resonance imaging contrast field.
Background technique
Magnetic resonance imaging (Magnetic resonance imaging, MRI) has the safety of noninvasive radiationless damage,
Proton can be covered to arbitrary orientation tomoscan (cross section, sagittal plane, coronal-plane and various inclined-planes etc.) technology flexibility
The advantage of the multi-parameters such as density, relaxation, chemical shift feature and high spatial resolution and high contrast, currently, the magnetic of proton
Resonance image-forming (1H MRI) technology is widely used in clinical medicine the imaging to the screening of disease and pathological tissues.In addition,
MRI is also applied to basic life science research field more and more, to illustrate disease development mechanism, ancillary drug
The visual research of exploitation and disease treatment.
Currently, clinically apply be mainly based upon proton magnetic resonance imaging (1H MRI), theoretically1H MRI can be examined
Each position of Whole Body is looked into, and the aerial image of a 3 D stereo is provided.But clinical practice is found, due to internal water
Molecule it is widely distributed, leading to it, there are strong background interferences, and obtained imaging effect is excessively poor in this case, thus
Affect the judgement to diagnostic result.Better imaging effect in order to obtain, people begin one's study various developers, wish
Hoping can exist by developer in the aggregation of target site, enhance the contrast of different tissues location detection signal and improve not
With the resolution ratio of soft-tissue imaging.Fortunately,19F MRI very well overcomes1The defect of H MRI.First, no endogenous
Background interference.Relative to1H MRI locks into strong background caused by immanent hydrone in body and interferes, in body only
There is micro (< 10-6M fluorine) be present in bone and tooth in the form of solid-state fluorine compounds (T 2 →0), it is far below19F MRI's
Detection limit, avoids continuous sampling and compares using the image difference before and after contrast agent, and this is to use superparamagnetic (such as at other
Iron oxide) and the molecular imaging of paramagnetic metal (such as gadolinium) in necessary to.Therefore, the exogenous fluoride of high density is in the poly- of target spot
Collection is19F MRI provides the feasibility of high s/n ratio (SNR) imaging.Second, high sensitivity.19The spin quantum number of F isI =
1/2, gyromagnetic ratio (γ) with1H core is close to (40.08 MHz/Tvs.42.58MHz/T), sensitivity is1The 83% of H.Third, nothing are put
Penetrating property.19F is that a kind of natural abundance is 100% stable isotope, is to be not necessarily to isotope enrichment in use, in use process without
Radioactivity protection.4th, chemical shift range is big.The chemical shift range of organic fluoride is about 400 ppm, and1H signal is only
20 ppm or so.19F outermost layer has 7 electronics, and1Only one electronics of H outermost layer, therefore19The chemical shift of F and relaxation speed
Rate is more sensitive to the variation of chemical bond and microenvironment, thus19F MRI can provide internal drug existing forms and focal area is micro-
Other methods such as environment (such as pH value, oxygen concentration, viscosity) are difficult to the information obtained, and diagnosis of these information for disease
It is most important (for example, as tumour can develop drug resistance to chemicotherapy under anoxia state) with treatment.5th, it can quantitative detection.
For1H MRI contrast agent by change local organization in water proton relaxation rate, enhancing normally with lesions position contrast
Method can provide the physiology and pathological information of body, but be difficult to accomplish quantitative detection and quantitative research.19The signal of F MRI
Intensity is in a linear relationship with content, therefore can provide the distribution containing fluorine molecule, form and quantitative information in vivo, is suitble to chemistry raw
Object research, drug development, disease quantitative Diagnosis and personalized drug therapy etc..In addition, for the research system of various concentration
Suitable research method can neatly be selected: for19The high system of F magnetic resonance signal intensity, can directly pass through19F MRI
The system is studied with intuitive imaging modality；For19The low system of F magnetic resonance signal intensity, can pass through19F MRS is with spectroscopy
Mode study the system.
In short,19F MRI has many advantages, such as non-invasive, high without endogenous background interference and spatial resolution, biology at
The fields such as picture and medical diagnosis on disease receive more and more attention.19F MRI will not only become a kind of in other mode imaging technologies
Extremely effective supplementary means, and as a kind of image probe with high spatial resolution, it will be early stage human diseases
Huge effect is played in diagnosis and adjuvant treatment.Therefore, efficiently19The research and development of F MRI contrast agent have great importance.
Summary of the invention
The object of the present invention is to provide a kind of fluoro- 19 magnetic resonance imaging contrasts of carboxylic acid glycine betaine amphoteric ion polymer
Synthesis and application, can satisfy19The needs of F MRI development.Preparation method of the present invention is simple, yield is high, easily separated.Especially originally
Invention preparation contrast agent have Superhydrophilic, high sensitivity, good biocompatibility, can quantitative detection, can be applied in vivo at
Picture.
Fluoro- 19 magnetic resonance imaging contrast of carboxylic acid glycine betaine amphoteric ion polymer provided by the invention has following chemistry
General structure, wherein a-e is integer independent, and a-e is 1-5 respectively；The integer that n is 5-300；
Fluoro- 19 magnetic resonance imaging contrast of carboxylic acid glycine betaine amphoteric ion polymer provided by the invention is with carboxylic acid beet
(its synthetic method is shown in that applicant applies on the same day: carboxylic acid glycine betaine type contains the ethyl methacrylate monomer of alkali amphoteric ion structure
Fluorine compounds and its synthetic method and application) it is raw material.Ethyl methacrylate with carboxylic acid glycine betaine amphoteric ion structure
Monomer, in solvent dimethylformamide by with reversible addition chain-transferring agent (RAFT, such as phenyl-(2- ethoxy) thio carbon
Acid esters) reaction, initiator is azodiisobutyronitrile (AIBN), and reaction carries out 24 h of reaction, reaction in 68-72 DEG C of oil bath
After, DMF dissolution is added, (3500 Da of molecular cut off) is fitted into bag filter, with 72 h of deionized water dialysis, every 12 h
Replacement is primary.Later, freeze-drying obtains free radical polyalcohol.Molar ratio by adjusting monomer and chain-transferring agent is adjusted
Control:
Carboxylic acid glycine betaine amphoteric ion polymer provided by the invention has carboxylic acid glycine betaine structure on each unit, can be in water
It can quickly be dissolved in solution, obtain evenly dispersed solution, prepare carboxylic acid glycine betaine amphoteric ion polymer19F MRI makes
Shadow agent.
Carboxylic acid glycine betaine amphoteric ion polymer provided by the invention19The characteristics of F MRI contrast agent, is:
1) it can be kept in the complex biologicals sample such as blood plasma and tissue (heart, liver, spleen, lung, kidney) homogenate19The letter of F NMR signal
It makes an uproar more in a linear relationship than with concentration.
2) it can keep stable in the complex biologicals sample such as blood plasma and tissue (heart, liver, spleen, lung, kidney) homogenate19F core
Magnetic resonance relaxation effect.
3) it can be remained unchanged in the complex biologicals sample such as blood plasma and tissue (heart, liver, spleen, lung, kidney) homogenate19F core
Magnetic Resonance Spectrum half-peak breadth.
4) quantitative detection can be carried out in the complex biologicals sample such as blood plasma and tissue (heart, liver, spleen, lung, kidney) homogenate.
5) it can be kept in the complex biologicals sample such as blood plasma and tissue (heart, liver, spleen, lung, kidney) homogenate19F MRI signal
With the linear relationship of concentration.
6) high sensitivity detects very strong after capable of injecting in vivo19F MRI signal.
In short, the present invention provides the synthetic method and application of a kind of carboxylic acid glycine betaine amphoteric ion polymer, Ke Yiman
Foot19The needs of F MRI development.Preparation method of the present invention is simple, yield is high, easily separated.Contrast agent especially prepared by the present invention
With Superhydrophilic, high sensitivity, good biocompatibility, can quantitative detection, can be applied to in-vivo imaging.
Detailed description of the invention
1 nuclear-magnetism fluorine stave of Fig. 1 polymer P sign.
2 nuclear-magnetism fluorine stave of Fig. 2 polymer P sign.
3 nuclear-magnetism fluorine stave of Fig. 3 polymer P sign.
The agent of Fig. 4 P3-b polymeric contrast can be kept in blood plasma and tissue (heart, liver, spleen, lung, kidney) homogenate19F NMR
The signal-to-noise ratio of signal and concentration are in a linear relationship.
Relaxation effect of Fig. 5 P3-b polymeric contrast agent in blood plasma and tissue (heart, liver, spleen, lung, kidney) homogenate.
Fig. 6 P3-b amphoteric ion polymer contrast agent is in blood plasma19The linear relationship of F MRI signal and concentration.
In Fig. 7 P3-b amphoteric ion polymer contrast agent body19F MRI signal.
Specific embodiment
Below by specific embodiment, the invention will be further described, but the scope of protection of the present invention is not limited thereto.
Apply on the same day referring to applicant, method described in entitled " fluorination tertiary amine compound and synthetic method and its application "
Obtain starting tertiary amine compound, wherein on the same day application of the method for new synthesis fluorination secondary amine compound referring particularly to applicant, name
Referred to as: fluorination secondary amine compound and its synthetic method and application.
The synthetic method of ethyl methacrylate monomer with carboxylic acid glycine betaine amphoteric ion structure is shown in applicant on the same day
Application, title are as follows: " carboxylic acid glycine betaine type fluorochemical and its synthetic method and application ".
The synthesis of 1 polymer P 1 of embodiment
Reversible addion-fragmentation chain transfer polymerization (RAFT) chain-transferring agent phenyl-(2- hydroxyl second is sequentially added in shlenk reaction tube
Base) sulfocarbonate (0.1 mM), N- (2- fluoro ethyl)-N- (ethyl 2-methacrylate)-sarcosine monomer (20
MM), initiator azodiisobutyronitrile (AIBN) (0.01 mM) and 3 mL solvent dimethylformamides (DMF), vacuumize/lead to argon
After three, gas circulations, airtight reactor tube reacts 24 h in 68-72 DEG C of oil bath.After reaction, DMF dissolution is added,
(3500 Da of molecular cut off) is fitted into bag filter, and with 72 h of deionized water dialysis, every 12 h replacement is primary.Later, freezing is dry
It is dry to obtain P1 polymer.P1 polymer is characterized using fluorine spectrum, as a result as shown in Fig. 1.
The synthesis of 2 polymer P 2 of embodiment
Reversible addion-fragmentation chain transfer polymerization (RAFT) chain-transferring agent phenyl-(2- hydroxyl second is sequentially added in shlenk reaction tube
Base) sulfocarbonate (0.1 mM), N- (2,2- bis-fluoro ethyls)-N- (ethyl 2-methacrylate)-sarcosine list
Body (30 mM), initiator azodiisobutyronitrile (AIBN) (0.01 mM) and 3 mL solvent dimethylformamides (DMF) are taken out true
After empty/logical three circulations of argon gas, airtight reactor tube reacts 24 h in 68-72 DEG C of oil bath.After reaction, it is added
DMF dissolution, is fitted into bag filter (3500 Da of molecular cut off), and with 72 h of deionized water dialysis, every 12 h replacement is primary.It
Afterwards, freeze-drying obtains P1 polymer.P2 polymer is characterized using fluorine spectrum, as a result as shown in Fig. 2.
The synthesis of 3 polymer P 3 of embodiment
Reversible addion-fragmentation chain transfer polymerization (RAFT) chain-transferring agent phenyl-(2- hydroxyl second is sequentially added in shlenk reaction tube
Base) sulfocarbonate (0.1 mM), N- (3,3,3- trifluoro propyl)-N- (ethyl 2-methacrylate)-sarcosine
(50 mM), initiator azodiisobutyronitrile (AIBN) (0.01 mM) and 3 mL solvent dimethylformamides (DMF), vacuumize/
After three circulations of logical argon gas, airtight reactor tube reacts 24 h in 68-72 DEG C of oil bath.After reaction, it is molten that DMF is added
Solution, is fitted into bag filter (3500 Da of molecular cut off), and with 72 h of deionized water dialysis, every 12 h replacement is primary.Later, cold
Jelly is dried to obtain P1 polymer.P3 polymer is characterized using fluorine spectrum, as a result as shown in Fig. 3.
According to the method in embodiment 3, the polymer of other available composition ratio.
The composition of 1. P3 series polymer of table
| Polymer | Chain-transferring agent: monomer | The degree of polymerization | Molecular weight distribution |
| P3-a | 1:5 | 5 | 1.5 |
| P3-b | 1:50 | 48 | 1.2 |
| P3-c | 1:60 | 58 | 1.8 |
| P3-d | 1:80 | 76 | 1.2 |
| P3-e | 1:100 | 89 | 2.1 |
| P3-f | 1:120 | 106 | 1.6 |
| P3-g | 1:150 | 146 | 2.1 |
| P3-h | 1:200 | 186 | 2.6 |
| P3-i | 1:250 | 238 | 2.2 |
| P3-j | 1:300 | 298 | 2.8 |
4 polymer P 3-b solution of embodiment19F NMR signal-to-noise ratio and concentration relationship are evaluated
Firstly, (the 10 % D in blood plasma and tissue homogenate2O is for locking field), the P3-b sample (0.5-50 of compound concentration gradient
mg/mL).Next, being utilized on Bruker Avance 400 (TopSpin 3.5) nuclear magnetic resonance equipment19F nuclear-magnetism is total
Vibration wave composes the signal-to-noise ratio of detectable concentration gradient sample, the relationship between Signal-to-Noise and contrast medium concentration is evaluated, such as 4 institute of attached drawing
Show, the agent of P3-b polymeric contrast can be kept in the complex biologicals sample such as blood plasma and tissue (heart, liver, spleen, lung, kidney) homogenate19F
The signal-to-noise ratio of NMR signal and concentration are in a linear relationship.
5 polymer P 3-b solution of embodiment19F NMR relaxation time and concentration relationship are evaluated
Firstly, (the 10 % D in blood plasma and tissue homogenate2O is for locking field), it prepares P3-b sample (20 mg/mL).Next,
On Bruker Avance 400 (TopSpin 3.5) nuclear magnetic resonance equipment, using standard inversion recovery sequence (IR,
Inversion recovery) and Carr-Purcell-Meiboom-Gill (CPMG) pulse train, sample is indulged respectively
To the relaxation time (T 1) and lateral relaxation time (T 2) tested.According to index variation edit corresponding vdlist and
vclist。T 1Value can be immediately arrived at according to fitting report.T 2It is calculated according to formula:T 2=fitting cycle-index * (2D20+
P2).Relaxation time changes as shown in Fig. 5 with polymer concentration, and the agent of P3-b polymeric contrast can be in blood plasma and tissue homogenate
Etc. keep stable relaxation properties in complex biological samples system.
6 polymer P 3-b solution of embodiment19The detection of F MRI signal
Firstly, in blood plasma compound concentration gradient P3-b polymer samples (5-200 mg/mL).Utilize toy magnetic resonance
Imager (70/20 USR of Bruker BioSpec), detection19The signal strength of F MRI.19The signal strength and P3-b of F MRI
Relationship between polymer concentration is as shown in Fig. 6, P3-b amphoteric ion polymer19F magnetic resonance imaging contrast, can be in blood
It is kept in slurry19The linear relationship of F MRI signal and concentration.
After 7 polymer P 3-b solution tail vein injection of embodiment, in vivo19The detection of F MRI signal
In order to investigate the internal of contrast agent19F MRI imaging effect uses Balb/c white mouse (6-7 weeks, 20g)
It is studied.After 1 h of tail vein injection P3-b polymeric contrast agent aqueous dispersions, after mouse is carried out breathing anesthesia, benefit
It is imaged with toy magnetic resonance imager (70/20 USR of Bruker BioSpec), detection is internal19F MRI signal.Such as
Shown in attached drawing 7, it can be detected clearly in Mice Body19F MRI signal.
Claims (4)
1. a kind of fluoro- 19 magnetic resonance imaging contrast of carboxylic acid glycine betaine amphoteric ion polymer, it is characterised in that have followingization
Learn general structure, wherein a-e is integer independent, and a-e is 1-5 respectively；N is the integer of 5-300；
。
2. fluoro- 19 magnetic resonance imaging contrast of carboxylic acid glycine betaine amphoteric ion polymer as described in claim 1, feature
It is that it includes polymer P 1, carboxylic acid glycine betaine zwitterion polymerization shown in polymer P 2 and polymer P 3a- P3j
Object.
3. the synthesis of fluoro- 19 magnetic resonance imaging contrast of carboxylic acid glycine betaine amphoteric ion polymer as described in claim 1
Method, it is characterised in that it includes the steps that:
Using the ethyl methacrylate monomer with carboxylic acid glycine betaine amphoteric ion structure as raw material, that is, there is carboxylic acid glycine betaine two
The ethyl methacrylate monomer of property ionic structure, in solvent dimethylformamide by with reversible addition chain-transferring agent benzene
The reaction of base-(2- ethoxy) sulfocarbonate, initiator is azodiisobutyronitrile, and reaction carries out in 68-72 DEG C of oil bath
24 h are reacted, after reaction, DMF dissolution is added, is fitted into bag filter, 3500 Da of molecular cut off uses deionized water dialysis
72 h, every 12 h replacement are primary；Later, freeze-drying obtains free radical polyalcohol, by adjusting rubbing for monomer and chain-transferring agent
You are than being regulated and controled, and quickly dissolution, obtains evenly dispersed solution in aqueous solution, and it is poly- to prepare carboxylic acid glycine betaine amphoteric ion
Close object19F MRI contrast agent:
。
4. carboxylic acid glycine betaine amphoteric ion polymer as claimed in claim 1 or 219The application of F MRI contrast agent.
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