CN101002950A - Magnetic resonace imaging contrast medium with glycyrrhizic acid as carrier - Google Patents
Magnetic resonace imaging contrast medium with glycyrrhizic acid as carrier Download PDFInfo
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Abstract
An MRI contrast medium using glycyrrhizic acid as its carrier is prepared through reaction between the mono-N-hydroxy succinimide (and monocyclic acid anhydride) of EDTA (or biethyltriamino pentacetate) and aminated glycyrrhizic acid, and coordinating with paramagnetic metal ions to obtain a match. It has high elaxation efficiency and selectivity to liver, and lower acute toxin. It can also be used for X-ray CT and gamma-ray flash imaging technique.
Description
Technical field
The present invention relates to a kind of magnetic resonance imaging contrast, being specifically related to glycyrrhizic acid is the novel magnetic resonance imaging contrast of carrier.
Background technology
In recent years, along with magnetic resonance angiography (magnetic resonance angiography, MRA), functional mri (functional MRI), perfusion mri (perfusion MRI), the development of diffusion-weighted nuclear magnetic resonance new MRI technology such as (diffusion weighted MRI) and popularizing in clinical diagnostic applications, the research and development of magnetic resonance imaging contrast (MRI contrast agents) has become a research field that becomes more and more important.Magnetic resonance imaging contrast is the diagnostic agent that a class can shorten imaging time, raising image contrast and definition, display organization organ dysfunction state.The contrast agent that is used for the clinical magnetic resonance imaging diagnosis at present is mainly the coordination compound of micromolecule gadolinium or manganese: Gd-DTPA (Magnevist, magnevist), Gd-DOTA (Dotarem, many its spirits), Gd-DTPA-BMA (Omniscan, Ou Naiying), Gd-HP-DO3A (Prohance, general network shows to be thought), Gd-BOPTA (MultiHance, Mo Disi) etc., these micromolecule contrast agent have good imaging effect to brain and central nervous system etc., renal metabolism has limited its application but its extracellular distribution reaches faster, particularly to more intravital internal organs of animal such as liver, the radiography effect of kidney is not ideal enough, can not satisfy the requirement of organ and tissue selectivity.Small-molecular weight contrast agent Gd-DTPA, Gd-DOTA are introduced high polymer main chain or can form macromolecular contrast agent with the macromolecule covalent coupling of natural polymer, synthetic, the biomacromolecule carrier that has been used at present magnetic resonance imaging contrast research has antibody, serum albumin, polysaccharide, erythrocyte, hormone, polyamino acid etc., and these macromolecular contrast agents have in vivo advantages such as long, relaxation efficient height of the time of staying and consumption are few.Yet, the macromolecular contrast agent in these researchs since in vivo overstand cause decompositing the risk of free gadolinium probably.Therefore, develop cheap, toxicity is little, relaxation usefulness is high and particular organization or organ are had the contrast agent of selectivity or targeting, is the developing direction of present magnetic resonance contrast agent.
Target administration has advantages such as curative effect height, drug dose is few, toxic and side effects is little, aspect the development of magnetic resonance imaging contrast, introducing by the targeting group can improve the enrichment concentration of magnetic resonance imaging contrast in target tissue, generation strengthens drug effect and reduces dosage the selectivity of particular organization or organ.Multiple hepatic disease such as hepatocarcinoma, hepatitis is commonly encountered diseases and frequently-occurring disease at home and abroad, thereby can do early stage the inspection to liver and gall diseases, research with magnetic resonance imaging contrast of liver and gall targeting has caused extensive concern: for example Mn-DPDP (Teslascan, safe happy shadow), contain vitamin B
6(Chinese patent, CN1,125,142, A), arabinogalactan (SCI, 2002,23,1837) etc.
Radix Glycyrrhizae (Glycyrrhiza uralensis Fisch) is the pulse family herbaceos perennial, and main product is a kind of broad-spectrum Chinese crude drug in the Inner Mongol, Gansu and other places.(Glycyrrhizic acid is the main active of the root and rhizome of Radix Glycyrrhizae GL) to glycyrrhizic acid, the content in Radix Glycyrrhizae about 7～10%.Research both at home and abroad confirms that all there is the binding site (Acta Biochimica et Biophysica Sinica of glycyrrhizic acid in hepatic parenchymal cells film surface, Biochim.Biophys.Acta, 1991.1066,77-82), and the moderate (molecular weight: 822.92) of glycyrrhizic acid molecular weight, structure is single, is liver target magnetic resonance contrast agent carrier preferably.The structural formula of glycyrrhizic acid is as follows:
Summary of the invention
The purpose of this invention is to provide a kind of novel, high relaxation rate, stable, low toxicity, to some organ or tissue of human body particularly liver have the magnetic resonance imaging contrast of targeting.
Glycyrrhizic acid of the present invention is that the magnetic resonance imaging contrast of carrier is ethylenediaminetetraacetic acid (the Ethylenediaminetetraacetic acid that modifies with glycyrrhizic acid, hereinafter to be referred as EDTA) or diethylenetriamine pentaacetic acid (Diethylenetriaminepentaacetic acid, hereinafter to be referred as DTPA) part respectively with paramagnetic metal ion, the paramagnetic metal complex that obtains by mol ratio coordination in 1: 1; Described paramagnetic metal ion is: Gd
3+, Mn
2+, Fe
3+, Fe
2+, V
4+, V
3+, Cu
2+, Cr
2+, Co
2+, Co
3+, Ni
2+, Dy
3+
Described paramagnetic metal complex has following structure:
Wherein m=0 or 1 is the EDTA part that glycyrrhizic acid is modified when m=0; It when m=1 the DTPA part that glycyrrhizic acid is modified;
M is paramagnetic metal ion: Gd
3+, Mn
2+, Fe
3+, Fe
2+, V
4+, V
3+, Cu
2+, Cr
2+, Co
2+, Co
3+, Ni
2+, Dy
3+
R is CH
2
i, 2≤i≤6, i is an integer.
EDTA or DTPA part that described glycyrrhizic acid is modified have following structure:
Wherein m=0 or m=1 are the EDTA part that glycyrrhizic acid is modified when m=0; It when m=1 the DTPA part that glycyrrhizic acid is modified;
R is CH
2
i, 2≤i≤6, i is an integer.
The binding site that has glycyrrhizic acid according to hepatic parenchymal cells film surface, and the glycyrrhizic acid molecular weight is moderate, characteristics such as structure is single, EDTA or DTPA are connected via amido link with the amination glycyrrhizic acid by the linking arm of a weak point, form EDTA or DTPA part that glycyrrhizic acid is modified, with this part and paramagnetic metal ion coordination, can obtain good water solubility, relaxation efficient height then, liver is had the optionally paramagnetic metal complex magnetic resonance imaging contrast of glycyrrhizic acid modification.
The step and the condition of the preparation method of a kind of magnetic resonance imaging contrast of the present invention are as follows:
A) EDTA or DTPA are dissolved in the mixed solution of acetonitrile and triethylamine, the volume ratio of acetonitrile and triethylamine is 12: 13, be warming up to 55 ℃, after treating that EDTA or DTPA are molten entirely, add N simultaneously, N '-dicyclohexylcarbodiimide (hereinafter to be referred as DCC) and N-hydroxy-succinamide (hereinafter to be referred as HONSu), the mol ratio of EDTA or DTPA and DCC is 1.4: 1, the mol ratio of DCC and HONSu is 1: 1, stirring at room 1.5h, filter single N-hydroxy-succinamide active ester solution of EDTA or the single N-hydroxy-succinamide active ester solution (hereinafter to be referred as EDTA-ONSu solution or DTPA-ONSu solution) of DTPA; EDTA-ONSu or DTPA-ONSu structure are as follows:
M=1, the single active ester of DTPA,
M=0, the single active ester of EDTA;
B) under-15 ℃ of conditions, glycyrrhizic acid is dissolved among the THF, adds DCC then, the mol ratio of glycyrrhizic acid and DCC is 1: 3, add HONSu after stirring 30min, the mol ratio of glycyrrhizic acid and HONSu is 1: 3, behind-15 ℃ of stirring 3h, room temperature continues to stir 24h, leach behind the 1,3-Dicyclohexylurea in the gained solution impouring absolute ether, collect white solid, respectively wash three times with dehydrated alcohol, absolute ether, vacuum drying gets the active fat (hereinafter to be referred as GL-ONSu) of glycyrrhizic acid.It has following structure:
C) GL-ONSu that obtains in the step b) is dissolved among the DMF, is added drop-wise to that (ethylenediamine is dissolved in DMF in the big excessive diamine; Hexamethylene diamine is dissolved in DMSO), the mol ratio of diamine and GL-ONSu is 30: 1～100: 1, in 60 ℃ of reaction 24h, pour among the THF after liquid volume is evaporated to 1/3, spend the night separatory in 4 ℃ of placements, layer oily matter splashes in the dehydrated alcohol of stirring, collects white precipitate.Dehydrated alcohol, absolute ether respectively wash three times, and vacuum drying, product obtain the amination glycyrrhizic acid through column chromatographic isolation and purification.Its structure is as follows:
R is CH
2
i, 2≤i≤6, i is an integer.
D) the amination glycyrrhizic acid that obtains in the step c) is dissolved in the deionized water, add EDTA-ONSu solution or DTPA-ONSu solution in the step a), the mol ratio of EDTA-ONSu or DTPA-ONSu and amination glycyrrhizic acid is 6: 1～60: 1, transfer pH=10 with NaOH, in stirring at room 24h, rotary evaporation is removed acetonitrile, adopt the semipermeable membrane dialysis method to separate purification, deionized water dialysis 5～7 days is changed water every day 2～3 times, and lyophilizing gets EDTA or the DTPA part that glycyrrhizic acid is modified.Its structural formula is as follows:
Wherein m=0 or 1 is the EDTA part that glycyrrhizic acid is modified when m=0, is the DTPA part that glycyrrhizic acid is modified when m=1;
R is CH
2
i, 2≤i≤6, i is an integer.
E) EDTA that the glycyrrhizic acid that obtains in the step d) is modified or DTPA part respectively with paramagnetic metal ion, by mol ratio coordination in 1: 1, can obtain the magnetic resonance imaging contrast that glycyrrhizic acid is a carrier; Described paramagnetic metal ion is: Gd
3+, Mn
2+, Fe
3+, Fe
2+, V
4+, V
3+, Cu
2+, Cr
2+, Co
2+, Co
3+, Ni
2+, Dy
3+
For the glycyrrhizic acid that obtains is the novel magnetic resonance imaging contrast of carrier, characterizes, and sees Table 1.Table 1 is chemical compound GLA, the productive rate of DTPA-GLA and structural characterization data.
For the non-vanishing situation of total electrical charge number behind the formation coordination compound, the cation of available physiological compatibility is Na particularly
+, Ca
2+, Cu
2+, Zn
2+, NH
4 +Or NH
4 +Organic derivative: N-methyl glucoside amine, aminoacid or hydramine come balance its institute electrically charged.
The paramagnetic metal complex magnetic resonance imaging contrast that glycyrrhizic acid among the present invention is modified can be made injection.Such as, injection can be used sodium chloride injection, glucose injection, the solution that the paramagnetic metal complex that dextrose ﹠ sodium chloride injection or distilled water or other are gone up regulation at the Pharmacopoeia of the People's Republic of China (nineteen ninety version) carrier is modified glycyrrhizic acid of the present invention or its salt are mixed with concentration 0.001-1.0mol/L, particularly preferably be the solution of 0.1-0.5mol/L, and comprise N-methyl glucoside amine with the sour example hydrochloric acid of physiological compatibility or the alkali of physiology intermiscibility, slow blood amine, organic base or ammonia such as aminoacid, sodium hydroxide, sodium carbonate, inorganic bases such as sodium bicarbonate are regulated between pH value to 6.5～8.0.Usually in preparation, add the salt of the physiological compatibility of EDTA that the glycyrrhizic acid of EDTA that the glycyrrhizic acid of the salt of physiological compatibility of EDTA that EDTA that 0.1～15% the glycyrrhizic acid that is equivalent to paramagnetic metal complex quality that glycyrrhizic acid modifies modifies or DTPA part or glycyrrhizic acid modify or DTPA part or calcium, magnesium, copper, zinc modifies or DTPA coordination compound or calcium, magnesium, copper, zinc modifies or DTPA coordination compound, to guarantee that paramagnetic metal ion is such as Gd
3+Coordination fully.Also need add the additive that the sodium, calcium salt etc. of antioxidant such as ascorbic acid or ascorbic acid do not influence the preparation preparation, store and use in addition.Other required compositions such as the salt of the EDTA that the glycyrrhizic acid of another kind of way EDTA that to be paramagnetic metal complex that glycyrrhizic acid of the present invention is modified modify with 0.1～15% the glycyrrhizic acid that is equivalent to paramagnetic metal complex quality that glycyrrhizic acid modifies or DTPA part and its salt or calcium, magnesium, copper, zinc is modified or the physiological compatibility of DTPA coordination compound or these coordination compounds, pH regulator agent, antioxidant are mixed with dried solid preparation, be powder pin or injectable powder, be diluted to desired concn with carriers such as sodium chloride injection or distilled water before using.
Contrast agent of the present invention can use according to a conventional method, and this method is to comprising the paramagnetic metal complex that human body or other mammal glycyrrhizic acid are modified with diagnosis object, carrying out magnetic resonance imaging analysis then, the nuclear magnetic resonance figure that is enhanced.The dosage of contrast agent of the present invention can because of the molecular weight of paramagnetic complex with bigger variation is arranged as the tissue of diagnosis object or organ and diagnostic device type different.In general, the injection consumption is as the human body of diagnosis main body or every kg body weight 0.001～5.0mmol of other mammalian body, preferably every kg body weight 0.05～0.5mmol.
Beneficial effect of the present invention:
1. the relaxation efficient of this type of contrast agent is about 1.5 times of micromolecule contrast agent apparently higher than the clinical micromolecule contrast agent that generally uses.
2. this type of contrast agent can be mixed with the intravenous injection of desired concn solution.
3. liver had selectivity preferably: behind intravenous injection this type of contrast agent, can obviously improve liver position image contrast (confirmation of Wistar rat imaging experiment) a little less than clinical dosage (0.1mmolGd/kg).
4. this type of contrast agent aqueous solution Heat stability is good is suitable for the pressure sintering sterilization.
5. this type of contrast agent can keep stable concentration in vivo relatively for a long time, makes liver obtain imaging window steady in a long-term.
6. people or other mammiferous liver had good selectivity.
The animal imaging experiment: use Brooker company magnetic resonance imager, the 30cm coil, T is adopted in 4.7T magnetic field
1Weighting multi-disc-many echo-wave imagings mode, repetition time TR:300ms, echo time TE:13.6ms, scanning area: 5.5 * 5.5cm
2, scan matrix: 128 * 128.Get the Wistar rat of male body weight 190～210g, press 1.0mL/100g body weight anesthesia with 10% urethane after, axle position, test animal abdominal cavity T
1The weighting picture is pressed imaging after the above-mentioned contrast agent solution of 0.097mmol/kg body weight dosage intravenous injection, every 3min sampling observation once, and more than the Continuous Observation 90min.Imaging results shows, a little less than this type of contrast agent of clinical dosage the reinforced effects that the liver magnetic resonance signal produces obviously is better than Gd-DTPA, and keeps good reinforced effects (as Fig. 2) in the whole experimental stage always.The raising of this contrast has demonstrated the good liver selectivity of this type of contrast agent.
Description of drawings
Fig. 1 injects the time dependent reinforced effects of contrast agent (hereinafter to be referred as Gd-DTPA-GLA) back rat kidney signal of the DTPA-Gd coordination compound of glycyrrhizic acid modification.
The time dependent reinforced effects of rat liver signal behind Fig. 2 injection of contrast medium Gd-DTPA-GLA.
Fig. 3 be before the injection of contrast medium Gd-DTPA-GLA and 60min after rat axle position kidney T
1The weighting picture.
Fig. 4 be before the injection of contrast medium Gd-DTPA-GLA and 60min after rat liver axle position T
1The weighting picture.
Table 1 is chemical compound GLA, the productive rate of DTPA-GLA and structural characterization data.
The specific embodiment
Embodiment 1
Glycyrrhizic acid is by the preparation of ethylene diamine-modified DTPA-Gd coordination compound (Gd-DTPA-GLA) magnetic resonance imaging contrast
A) 8g DTPA is dissolved in the mixed solution of 10ml acetonitrile and 11.3ml triethylamine, is warming up to 55 ℃, treat DTPA complete molten after, add 2.87g DCC and 1.66g HONSu simultaneously, stirring at room 1.5h, filter DTPA-ONSu solution.
B) under-15 ℃ of conditions, the 5.06g glycyrrhizic acid is dissolved among the 40ml THF, add 3.81gDCC then, add 2.13g HONSu behind the stirring 30min, behind-15 ℃ of stirring 3h, room temperature continues to stir 24h, leach behind the 1,3-Dicyclohexylurea in the gained solution impouring 100ml absolute ether, collect white solid, dehydrated alcohol, absolute ether respectively wash three times, vacuum drying gets GL-ONSu.
C) the 2.23g GL-ONSu that obtains in the step b) is dissolved among the 12ml DMF, slowly be added drop-wise in the DMF solution that 28ml contains the 13.3ml ethylenediamine, stir 24h in 60 ℃, pour among the 80ml THF after liquid volume is evaporated to 1/3, spend the night in 4 ℃ of placements, separatory, layer oily matter splash in the 100ml dehydrated alcohol of stirring, collect white precipitate.Dehydrated alcohol, absolute ether respectively wash three times, and vacuum drying then through column chromatographic isolation and purification, gets product amination glycyrrhizic acid.
D) the amination glycyrrhizic acid in the 1g step c) is dissolved in the 15ml deionized water, add the DTPA-ONSu solution among the 9.7ml step a, transfer pH=10 with 6mol/L NaOH, in stirring at room 24h, rotary evaporation is removed acetonitrile, adopts the semipermeable membrane dialysis method to separate purification, deionized water dialysis 5 days, change water every day 3 times, lyophilizing gets the DTPA part (hereinafter to be referred as DTPA-GLA) that glycyrrhizic acid is modified.
E) DTPA-GLA in the 0.52g step d) is dissolved in the 10ml deionized water, adds 3.75ml0.2mol/L GdCl
3Solution is 6.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the Gd-DTPA-GLA magnetic resonance imaging contrast.
Embodiment 2
Glycyrrhizic acid is by the preparation of the magnetic resonance imaging contrast of ethylene diamine-modified diethylenetriamine pentaacetic acid manganese complex
A) with a in the example 1.
B) with b in the example 1.
C) with c in the example 1.
D) with d in the example 1.
E) DTPA-GLA in the 0.52g step d) is dissolved in the 10ml deionized water, adds 3.75ml0.2mol/L MnCl
2Solution is 6.5 with 1mol/L NaOH adjust pH, dialysis, and the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets glycyrrhizic acid by ethylene diamine-modified diethylenetriamine pentaacetic acid manganese complex magnetic resonance imaging contrast.
Embodiment 3
Glycyrrhizic acid is by the preparation of the magnetic resonance imaging contrast of ethylene diamine-modified ethylenediaminetetraacetic acid Gd coordination compound
A) 5.93g EDTA is dissolved in the mixed solution of 10ml acetonitrile and 11.3ml triethylamine, is warming up to 55 ℃, treat EDTA complete molten after, add 2.87g DCC and 1.66g HONSu simultaneously, stirring at room 1.5h, filter EDTA-ONSu solution.
B) with b in the example 1.
C) with c in the example 1.
D) GLA in the 1g step c) is dissolved in the 25ml deionized water, add the EDTA-ONSu solution among the 9.7ml step a, transfer pH=10 with 6mol/L NaOH, in stirring at room 24h, rotary evaporation is removed acetonitrile, dialysed 5 days, with solution in the osmotic bag at 55 ℃ of rotary evaporations to small size, lyophilizing gets the EDTA part that glycyrrhizic acid is modified..
E) the EDTA part that glycyrrhizic acid in the 0.44g step d) is modified is dissolved in the 10ml deionized water, adds 3.75ml 0.2mol/L GdCl
3Solution is 6.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets glycyrrhizic acid by ethylene diamine-modified ethylenediaminetetraacetic acid Gd coordination compound magnetic resonance imaging contrast.
Embodiment 4
Glycyrrhizic acid is by the preparation of the magnetic resonance imaging contrast of ethylene diamine-modified ethylenediaminetetraacetic acid manganese complex
A) with a in the example 3.
B) with b in the example 1.
C) with c in the example 1.
D) with d in the example 3.
E) the EDTA part that glycyrrhizic acid in the 0.44g step d) is modified is dissolved in the 10ml deionized water, adds 3.75ml 0.2mol/L MnCl
2Solution is 6.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets glycyrrhizic acid by ethylene diamine-modified ethylenediaminetetraacetic acid manganese complex.
Glycyrrhizic acid is by the preparation of the magnetic resonance imaging contrast of the DTPA-Gd coordination compound of hexamethylene diamine modification
A) with a in the example 1.
B) with b in the example 1.
C) the 2.23g GL-ONSu that obtains in the step b) is dissolved among the 12ml DMF, slowly be added drop-wise in the DMSO solution that 28ml contains the 26.3ml hexamethylene diamine, stir 24h in 60 ℃, pour in the 500ml acetone after liquid volume is evaporated to 1/3, collect white precipitate.Dehydrated alcohol, absolute ether respectively wash three times, and then through column chromatographic isolation and purification, vacuum drying obtains product.
D) the amination glycyrrhizic acid in the 1g step c) is dissolved in the 25ml deionized water, adds the DTPA-ONSu solution among the 8.2ml step a, transfer pH=10 with 6mol/L NaOH, in stirring at room 24h, rotary evaporation is removed acetonitrile, dialyses 5 days, and lyophilizing gets the DTPA macromolecular ligand that glycyrrhizic acid is modified.
E) the DTPA part that glycyrrhizic acid in the 0.56g step d) is modified is dissolved in the 10ml deionized water, adds 3.75ml 0.2mol/L GdCl
3Solution is 6.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the DTPA-Gd coordination compound magnetic resonance imaging contrast that glycyrrhizic acid is modified by hexamethylene diamine.
Embodiment 6
Glycyrrhizic acid is by the preparation of the magnetic resonance imaging contrast of the diethylenetriamine pentaacetic acid manganese complex of hexamethylene diamine modification
A) with a in the example 1.
B) with b in the example 1.
C) with c in the example 5.
D) with d in the example 5.
E) the DTPA part that glycyrrhizic acid in the 0.56g step d) is modified is dissolved in the 10ml deionized water, adds 3.75ml 0.2mol/L MnCl
2Solution is 6.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the diethylenetriamine pentaacetic acid manganese complex magnetic resonance imaging contrast that glycyrrhizic acid is modified by hexamethylene diamine.
Embodiment 7
Glycyrrhizic acid is by the preparation of the magnetic resonance imaging contrast of the ethylenediaminetetraacetic acid Gd coordination compound of hexamethylene diamine modification
A) with a in the example 3.
B) with b in the example 1.
C) with c in the example 5.
D) the amination glycyrrhizic acid in the 1g step c) is dissolved in the 25ml deionized water, adds the EDTA-ONSu solution among the 8.2ml step a, transfer pH=10 with 6mol/L NaOH, in stirring at room 24h, rotary evaporation is removed acetonitrile, dialyses 5 days, and lyophilizing gets the EDTA part that glycyrrhizic acid is modified.
E) the EDTA part that glycyrrhizic acid in the 0.48g step d) is modified is dissolved in the 10ml deionized water, adds 3.75ml 0.2mol/L GdCl
3Solution is 6.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the ethylenediaminetetraacetic acid Gd coordination compound that glycyrrhizic acid is modified by hexamethylene diamine.
Embodiment 8
Glycyrrhizic acid is by the preparation of the magnetic resonance imaging contrast of the ethylenediaminetetraacetic acid manganese complex of hexamethylene diamine modification
A) with a in the example 3.
B) with b in the example 1.
C) with c in the example 5.
D) with d in the example 7.
E) the EDTA part that glycyrrhizic acid in the 0.48g step d) is modified is dissolved in the 10ml deionized water, adds 3.75ml 0.2mol/L MnCl
2Solution is 6.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the ethylenediaminetetraacetic acid manganese complex magnetic resonance imaging contrast that glycyrrhizic acid is modified by hexamethylene diamine.
The paramagnetic metal complex magnetic resonance imaging contrast usage that glycyrrhizic acid is modified is as follows:
Embodiment 9
The Gd-DTPA-GLA that takes by weighing among the 0.1274g embodiment 1 is dissolved in the 15mL sodium chloride injection, be mixed with the solution that concentration is 10mmol/L, regulating pH value with slow blood amine is 6.5, and adds 0.001g DTPA-GLA in preparation, obtains the injection of contrast agent Gd-DTPA-GLA.Get the Wistar rat of male 190～210g body weight, press 1.0mL/100g body weight anesthesia with 10% urethane after, press the above-mentioned contrast agent solution of 0.093mmol/kg body weight dosage intravenous injection after, axle position, test animal abdominal cavity T
1The weighting picture, every 3min sampling observation once, more than the Continuous Observation 90min.Obtain the axle position T of this contrast agent kidney and liver
1Weighting picture such as Fig. 3 and 4.
Table one
| Chemical compound | Productive rate | Elementary analysis (%) (in the bracket is value of calculation) C H N | IR(cm -1) | 1HNMR (DMSO-d 6，δ) |
| ?GLA | ?70％ | 60.73(60.76)；8.41(8.44)；8.82(8.86) | 1657，1545 | 8.0 |
| ?DTPA-GLA | ?85％ | 52.06(52.09)；6.87(6.95)；10.08(10.12) | 1721，1654，1543，1389 | 8.0 |
Claims (1)
1, a kind of glycyrrhizic acid is the nuclear magnetic resonance of carrier, it is characterized in that: this contrast agent be the ethylenediaminetetraacetic acid part modified with glycyrrhizic acid or diethylenetriamine pentaacetic acid part respectively with paramagnetic metal ion, the paramagnetic metal complex that obtains by mol ratio coordination in 1: 1; Described paramagnetic metal complex has following structure:
Wherein m=0 or 1 is the ethylenediaminetetraacetic acid part that glycyrrhizic acid is modified when m=0; It when m=1 the diethylenetriamine pentaacetic acid part that glycyrrhizic acid is modified;
M is paramagnetic metal ion: Gd
3+, Mn
2+, Fe
3+, Fe
2+, V
4+, V
3+, Cu
2+, Cr
2+, Co
2+, Co
3+, Ni
2+, Dy
3+
R is CH
2
i, 2≤i≤6, i is an integer;
Ethylenediaminetetraacetic acid or diethylenetriamine pentaacetic acid part that described glycyrrhizic acid is modified have following structure:
Wherein m=0 or m=1 are the ethylenediaminetetraacetic acid part that glycyrrhizic acid is modified when m=0; It when m=1 the diethylenetriamine pentaacetic acid part that glycyrrhizic acid is modified;
R is CH
2
i, 2≤i≤6, i is an integer.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766188A (en) * | 2012-07-24 | 2012-11-07 | 上海交通大学 | Cholesterol derivative, chelate, recombinant high density lipoprotein and application thereof |
| CN102895678A (en) * | 2012-09-18 | 2013-01-30 | 浙江大学 | Liver-targeted magnetic resonance imaging contrast agent based on oleanolic acid and preparation method thereof |
-
2006
- 2006-12-29 CN CN2006101308848A patent/CN101002950B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766188A (en) * | 2012-07-24 | 2012-11-07 | 上海交通大学 | Cholesterol derivative, chelate, recombinant high density lipoprotein and application thereof |
| CN102766188B (en) * | 2012-07-24 | 2016-01-13 | 上海交通大学 | Cholesterol derivative, inner complex, rHDL and uses thereof |
| CN102895678A (en) * | 2012-09-18 | 2013-01-30 | 浙江大学 | Liver-targeted magnetic resonance imaging contrast agent based on oleanolic acid and preparation method thereof |
| CN102895678B (en) * | 2012-09-18 | 2014-06-04 | 浙江大学 | Liver-targeted magnetic resonance imaging contrast agent based on oleanolic acid and preparation method thereof |
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| Publication number | Publication date |
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| CN101002950B (en) | 2011-01-19 |
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