CN102336838A - Paramagnetic metal complex and synthetic method and application thereof - Google Patents
Paramagnetic metal complex and synthetic method and application thereof Download PDFInfo
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- CN102336838A CN102336838A CN2011101742359A CN201110174235A CN102336838A CN 102336838 A CN102336838 A CN 102336838A CN 2011101742359 A CN2011101742359 A CN 2011101742359A CN 201110174235 A CN201110174235 A CN 201110174235A CN 102336838 A CN102336838 A CN 102336838A
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Abstract
The invention provides a paramagnetic metal complex and a synthetic method and application thereof. The paramagnetic metal complex is an arabinogalactan-modified 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacethyl paramagnetic metal complex. A magnetic resonance imaging contrast agent prepared from the paramagnetic metal complex has high stability, water solubility and relaxation rate and is targeted to liver and kidney, so that targeted imaging is realized, and the imaging contrast and definition are improved. The paramagnetic metal complex has a good effect on raising the early diagnosis levels of diseases of liver and kidney organs, is about 2 times the relaxation rate of dotarem, has very long targeted radiography imaging time, can be easily prepared into a solution with required concentration for intravenous injection, is suitable for sterilizing and disinfecting with a hot pressing method, can be selectively identified by an asialoglycoprotein receptor on a liver parenchyma surface, and has high selectivity on livers of human beings or other mammals.
Description
Technical field
The invention belongs to a kind of paramagnetic metal complex and compound method and application, relate in particular to 1,4,7 of a kind of arabogalactan modification, 10-tetraazacyclododecanand-1,4,7,10-tetraacethyl paramagnetic metal complex and compound method and application.
Background technology
Nuclear magnetic resonance (Magnetic Resonance Imaging; MRI) technology is owing to have feature and advantage such as high image contrast, multiparameter imaging, undamaged safety inspection, arbitrary orientation tomoscan; At aspects such as medical diagnosis and bodily fuctions's researchs abundant information can be provided; Make its instrument that becomes routine inspection gradually, become one of important means of clinical diagnosis, and in the new branch of science molecular imaging, also bringing into play important effect.(Chem.Rev.，1987，87，901，Coord.Chem.Rev.，2007，251，2428)。
Magnetic resonance imaging contrast is one type of diagnostic agent that can shorten imaging time, raising image contrast and sharpness, display organization organ dysfunction state, need use contrast medium above 30% diagnosis.Now clinical magnetic resonance imaging contrast commonly used such as magnevist Magnevist (Gd-DTPA), how its clever Dotarem (Gd-DOTA) waits that RT is short in vivo, does not have tissue perhaps organ selectivity or target property.At present one of research direction of magnetic resonance imaging contrast is high molecular and organ, tissue target tropism's a contrast medium (Radiology, 1997,203,297) in the world.Wherein organ target property contrast medium can make contrast medium be enriched in specific organ or tissue, and the time length is longer, thereby realizes targeted imaging, improves image contrast and sharpness, and radiography is effective, and dosage is low, and toxicity is little.
In recent years, the main flow of contrast agent research and exploitation is to diethylenetriamine pentaacetic acid (Diethylenetriaminepentaacetic acid is hereinafter to be referred as DTPA) and 1,4,7 both at home and abroad; 10-tetraazacyclododecanand-1,4,7,10-tetraacethyl (1,4; 7,10-tetraazacyclododecane-N, N ', N "; N ' " tetraacetic acid is hereinafter to be referred as DOTA) carry out chemically modified, make various types of contrast medium, wherein macromoleization is a main developing direction.Because its relaxation efficient of Gd-DOTA is proved and is better than Gd-DTPA, and kinetic stability is high, is to find the most stable rare earth compounding so far, become the focus of people's research gradually simultaneously.Macromolecular contrast agent and magnevist, how small molecules contrast medium such as its spirit is compared, and the former molecular dimension is bigger, and it is slower to see through capillary vessel speed, and the SR of molecule is lower, can improve relaxation efficient, reduces dosage, reduces toxicity.And can make contrast medium be enriched in particular organization by polysaccharide, polypeptide, antibody, the equimolecular special biochemical property of VITAMINs, thus realize targeted imaging, improve image contrast and sharpness.The macromolecular contrast agent of foreign study is that small molecules contrast medium Gd-DTPA, Gd-DOTA introducing high polymer main chain or covalent coupling are formed to the macromolecular carrier of natural polymer, synthetic mostly; Like BSA-Gd-DTPA, polylysine-Gd-DTPA and with the polylysine-Gd-DTPA of poly glycol monomethyl ether modification.
Arabogalactan (Arabinogalactan; AG) neutral polysaccharide of forming by pectinose and semi-lactosi; Wooden part content in the fallen leaves pine tree is the abundantest; Up to 25%, also contain a certain amount of arabogalactan in other plant such as corn, yam, Radix Angelicae Sinensis, the radish etc., at present existing very sophisticated extractive technique.Arabogalactan has that molecular weight is big, solvability good, and there is the asialoglycoprotein receptor AGPr of specificity identification galactose residue in the hepatic parenchymal cells surface of animal, can be used as the carrier of contrast medium.(SCI, 2002,23,1837. Chinese patent CN1 in the work in this scientific research group past; 966,088, A); Gd-DTPA is connected through ester bond with arabogalactan, and the contrast medium of formation has higher relaxation efficient and liver target property preferably, but is prone to take place crosslinked in the building-up process; And the ester bond that forms is prone to hydrolysis takes place, and causes this contrast medium relaxation efficient low, and has the situation that decomposites free gadolinium and then increase toxicity.
Summary of the invention
In order to overcome the shortcoming that existing macromolecular contrast agent exists, the present invention provides a kind of paramagnetic metal complex and compound method and application.
A kind of paramagnetic metal complex is 1,4,7 of arabogalactan modification, 10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl paramagnetic metal complex is with 1 of arabogalactan modification; 4,7,10-tetraazacyclododecanand-1,4; 7,10-tetraacethyl part and paramagnetic metal ion, by the paramagnetic metal complex that mol ratio coordination in 1: 1 obtains, it has following structure:
In the formula, AG is an arabogalactan; N is the number of the micromolecular compound that connects on each arabogalactan molecule, n=27～36; M
M+Be paramagnetic metal ion, be metallic element Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Mo, Ru, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Lu+2 or+3 valency ions;
R is
2≤i≤6, and i is an integer.
1,4,7 of a kind of arabogalactan modification provided by the invention, 10-tetraazacyclododecanand-1,4,7, the compound method of 10-tetraacethyl paramagnetic metal complex includes following steps:
(1) arabogalactan being dissolved in temperature is in 0 ℃ the 6mol/L sodium hydroxide solution, stirs to add Monochloro Acetic Acid after 30 minutes, and the mass ratio of Monochloro Acetic Acid and arabogalactan is 2.2: 1; Elevated temperature to 60 ℃ stirring 1 hour; Methanol extraction filters, dialysis; Freeze-drying obtains carboxymethylated arabogalactan; Structural formula is following:
N=30～45th, the number of the small molecules part that connects on each arabogalactan molecule;
(2) at room temperature the carboxymethylated arabogalactan of institute's synthetic in (1) is dissolved in the deionized water,, dropwise adds 2-oxyethyl group-1-ethoxy carbonic acyl radical-1 of 0.3mol/L with the pH=3 of hydrochloric acid soln accent solution; The methanol solution of 2-EEDQ adds 2-oxyethyl group-1-ethoxycarbonyl acyl-1 afterwards, 2-EEDQ (EEDQ); Dropwise add quadrol under the stirring state, the mass ratio of EEDQ and carboxymethylated arabogalactan is 1.8: 1, and the mass ratio of quadrol and carboxymethylated arabogalactan is 2.8: 1; Stirring at room 5 hours, methanol extraction filters; Dialysis, freeze-drying obtains aminating arabogalactan; Structure is following:
N=27～36th, the number of the small molecules part that connects on each arabogalactan molecule;
R is
2≤i≤6, and i is an integer;
(3) with 1,4,7,10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl (DOTA) is dissolved in the water, and adds N-hydroxy thiosuccinimide (S-NHS) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) respectively in 4 ℃; DOTA, S-NHS, the mass ratio of EDCHCl are 2: 1: 1; Regulate pH=5.5, stirred 40 minutes, obtain the active ester solution of DOTA.
(4) under 4 ℃ of temperature, the aminated arabogalactan in (2) is dissolved in the deionized water, regulates pH 7.5～8.5 with sodium hydroxide solution, the drips of solution that obtains is added in the active ester solution of the DOTA in (3); Aminated arabogalactan and DOTA active ester mass ratio are 1: 3, under room temperature, stir 24 hours, and dialysis concentrates; Freeze-drying obtains 1,4,7 of arabogalactan modification; 10-tetraazacyclododecanand-1,4,7,10-tetraacethyl macromolecular ligand; Structural formula is following:
N=27～36th, the number of the small molecules part that connects on each arabogalactan molecule.
R is
2≤i≤6, and i is an integer.
(5) at ambient temperature with 1,4,7 of the arabogalactan modification that obtains in (4), 10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl macromolecular ligand and metallic element Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Mo, Ru, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy or Lu+2 or+3 valency ions are dissolved in respectively in the water, using the NaOH adjust pH is 5.5; The amount of substance of DOTA is 1: 1.2 with the amount of substance ratio of above-mentioned metals ion in the DOTA macromolecular ligand that arabogalactan is modified, in stirred overnight at room temperature, and dialysis; Concentrate, freeze-drying obtains 1 of arabogalactan modification; 4,7,10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl paramagnetic metal complex.
Arabogalactan of the present invention modify 1,4,7,10-tetraazacyclododecanand-1,4,7, the application of 10-tetraacethyl paramagnetic metal complex, it is as the magnetic resonance imaging contrast of preparation to people or other mammiferous livers, kidney.
1,4,7 of arabogalactan modification of the present invention, 10-tetraazacyclododecanand-1,4,7,10-tetraacethyl paramagnetic metal complex can be processed injection or powder injection with the method for routine.
The contrast medium of the present invention's preparation can use according to ordinary method.
The dosage of contrast medium of the present invention can because of the kind of paramagnetic metal complex with very big variation is arranged as the tissue of diagnosis object or organ and diagnositc equipment type different; Generally; The injection consumption preferably 0.05 arrives 0.5mmol for the people of diagnosis main body or every kg body weight 0.001 to 5.0mmol of other mammalian body.
Contrast medium part among the present invention can also form heavy metal complex like plumbous, bismuth or gold with heavy metal ion, is used to prepare ultrasonic imaging or X-ray CT, PET or forms the contrast medium of radiometal complex as radiotherapy medicine or scintillography with radioactive metal ion.
Beneficial effect: the present invention provides a kind of paramagnetic metal complex and compound method and application.Clinical magnetic resonance imaging contrast commonly used has higher toxicity like many its spirits now, and RT is short in the body, and accretion rate is fast in vivo, and utilization ratio is low, does not have tissue or organ selectivity, especially tissue or organ is lacked problems such as selectivity.
A kind of magnetic resonance imaging contrast of paramagnetic metal complex preparation is provided with the present invention; The characteristics that kept corresponding many carboxylics of polyamines title complex; Thereby have satisfactory stability property, a water-soluble and relaxation rate; Simultaneously liver, kidney are had target property, thereby realize targeted imaging, improve image contrast and sharpness.Early diagnosis level to the disease that improves liver, kidney organ has good result.Compare with many its spirits of wide clinical application, this type contrast medium has following advantage:
(1) relaxation efficient is high, compare with clinical many its spirits of generally using, and be about 2 times of many its spirits.
(2) imaging effect is good, and susceptibility is high, and imaging time is long.Compare with many its spirits, the picture signal of gained behind the injection target property magnetic resonance imaging contrast, sharpness and contrast gradient also obviously improve.Many its spirits can only be kept at most 30 minutes in vivo, and targeted contrast agent can make contrast medium be enriched in tissue or the organ, and the target contrast imaging is chronic.
(3) have good water-solublely, be easy to be mixed with the intravenous injection of desired concn solution.
(4) aqueous stability is suitable for the pressure sintering sterilization.
(5) liver had selectivity preferably: behind intravenous injection this type of contrast medium, can obviously improve liver position image contrast (confirmation of Wistar rat imaging experiment) a little less than clinical dosage.
(6) this polysaccharide side chain contains D-semi-lactosi end group, can be by the asialoglycoprotein receptor selectivity identification on liver parenchyma surface.
(7) have and keep stable concentration in vivo relatively for a long time, make liver obtain imaging window steady in a long-term.
(8) 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, by forming images after the above-mentioned contrast agent solution of 0.094mmol/kg body weight dosage intravenous injection, the every sampling at a distance from 3min observed once, more than the day-night observation 90min.Imaging results shows, a little less than the arabogalactan of clinical dosage modify 1,4; 7; 10-tetraazacyclododecanand-1,4,7; The increase effect that the magnetic resonance imaging contrast of 10-tetraacethyl paramagnetic metal complex preparation produces the liver magnetic resonance signal obviously is superior to the Gd-DOTA of clinical dosage, and the whole experimental phase keeps good reinforced effects (like Fig. 2) always.The raising of this contrast gradient has demonstrated the good liver selectivity of this type of contrast medium.
Description of drawings
1,4,7 of Fig. 1 injection arabogalactan modification of the present invention, 10-tetraazacyclododecanand-1,4,7, the time dependent reinforced effects figure of rat kidney signal behind the magnetic resonance imaging contrast of 10-tetraacethyl paramagnetic metal complex preparation.
1,4,7 of Fig. 2 injection arabogalactan modification, 10-tetraazacyclododecanand-1,4,7, the time dependent reinforced effects figure of rat liver signal behind the magnetic resonance imaging contrast of 10-tetraacethyl paramagnetic metal complex preparation.
Fig. 3 injection arabogalactan of the present invention modify 1,4,7,10-tetraazacyclododecanand-1,4,7, before the magnetic resonance imaging contrast of 10-tetraacethyl paramagnetic metal complex preparation with injection 30min after rat axle position kidney T
1The weighting image pattern
Fig. 4 injection arabogalactan modify 1,4,7,10-tetraazacyclododecanand-1,4,7, before the magnetic resonance imaging contrast of 10-tetraacethyl paramagnetic metal complex preparation with injection 30min after rat axle position liver T
1The weighting image pattern.
Embodiment
Embodiment 1
Arabogalactan is through ethylene diamine-modified 1,4,7,10-tetraazacyclododecanand-1,4,7, the preparation of 10-tetraacethyl Gd coordination compound
(1) under 0 ℃ of condition, the 6g arabogalactan is dissolved in the NaOH solution of 50mL 6mol/L, stir adding 13.2g Monochloro Acetic Acid after 30 minutes; Elevated temperature to 60 ℃ stirring 1 hour, methanol extraction filters; Dialysis, freeze-drying gets carboxymethylated arabogalactan;
(2) the carboxymethylated arabogalactan of 6g is dissolved in the 60mL deionized water, transfers pH=3, dropwise add 2-oxyethyl group-1-ethoxy carbonic acyl radical-1 of 0.3mol/L (145mL) with 1mol/L HCl; The methanol solution of 2-EEDQ dropwise adds 16.8g quadrol, stirring at room 5h under the stirring state; Methanol extraction filters, dialysis; Freeze-drying gets the amination arabogalactan;
(3) 2g DOTA is dissolved in the 20mL deionized water; Under 4 ℃, add 1g N-hydroxy thiosuccinimide and 1g 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride respectively, regulate pH=5.5; Stirred 40 minutes, and obtained DOTA active ester solution.
(4) the aminated arabogalactan among the 1g (2) is dissolved in the 25mL deionized water, uses 1molL
-1NaOH transfers pH=8.5, and the drips of solution that obtains is added in the active ester solution of the DOTA in (3), and aminated arabogalactan and DOTA active ester mass ratio are 1: 3, under room temperature, stir 24h; Dialysed 3 days, with solution in the osmotic bag at 55 ℃ of rotary evaporations to small volume, freeze-drying, arabogalactan modify 1; 4,7,10-tetraazacyclododecanand-1; 4,7, the macromolecular ligand of 10-tetraacethyl.
(5) at ambient temperature, with 1,4,7 of the arabogalactan modification that obtains among the 1g (4), 10-tetraazacyclododecanand-1,4,7,10-tetraacethyl macromolecular ligand and 0.2mol/LGdCl
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned GdCl of DOTA in the DOTA macromolecular ligand that arabogalactan is modified
3Metal Gd ionic amount of substance ratio is 1: 1.2, and using 1mol/L NaOH adjust pH is 5.5, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange dialysis tubing is until its longitudinal relaxation time T
1Greater than 3000ms, concentrate, freeze-drying gets 1,4,7 of arabogalactan modification, 10-tetraazacyclododecanand-1,4,7,10-tetraacethyl macromole Gd coordination compound.
Embodiment 2 arabogalactans are through ethylene diamine-modified 1,4,7,10-tetraazacyclododecanand-1,4,7, the preparation of 10-tetraacethyl Gd coordination compound
(4) use 1molL
-1NaOH transfers pH=7.5;
(5) MnCl
2Solution substitutes GdCl
3Solution; Remaining is with embodiment 1.
Embodiment 3 arabogalactans are through ethylene diamine-modified 1,4,7,10-tetraazacyclododecanand-1,4,7, the preparation of 10-tetraacethyl Gd coordination compound
(4) use 1molL
-1NaOH transfers pH=8.0;
(5) FeCl
3Solution substitutes GdCl
3Solution; Remaining is with embodiment 1.
Embodiment 4 arabogalactans are through ethylene diamine-modified 1,4,7,10-tetraazacyclododecanand-1,4,7, the preparation of 10-tetraacethyl Gd coordination compound
(4) use 1molL
-1NaOH transfers pH=7.5;
(5) FeCl
3Solution substitutes GdCl
3Solution; Remaining is with embodiment 1.
Embodiment 5 arabogalactans are through ethylene diamine-modified 1,4,7,10-tetraazacyclododecanand-1,4,7, the preparation of 10-tetraacethyl Gd coordination compound
(4) use 1molL
-1NaOH transfers pH=7.5;
(5) DyCl
3Solution substitutes GdCl
3Solution; Remaining is with embodiment 1.
Embodiment 6 arabogalactans are through ethylene diamine-modified 1,4,7,10-tetraazacyclododecanand-1,4,7, the preparation of 10-tetraacethyl Gd coordination compound
(4) use 1molL
-1NaOH transfers pH=8.0;
(5) CuCl
2Solution substitutes GdCl
3Solution; Remaining is with embodiment 1.
Embodiment 7 arabogalactans are through ethylene diamine-modified 1,4,7,10-tetraazacyclododecanand-1,4,7, the preparation of 10-tetraacethyl Gd coordination compound
(4) use 1molL
-1NaOH transfers pH=8.0;
(5) TiCl
2Solution substitutes GdCl
3Solution; Remaining is with embodiment 1.
1,4,7 of arabogalactan modification, 10-tetraazacyclododecanand-1,4,7, the usage of the magnetic resonance imaging contrast of 10-tetraacethyl paramagnetic metal complex is following:
Embodiment 8 get that the arabogalactan of the embodiment 1 of 0.1 gram modifies 1,4,7; 10-tetraazacyclododecanand-1,4,7; The magnetic resonance imaging contrast of 10-tetraacethyl paramagnetic metal complex preparation; Be dissolved in the conventional sodium chloride injection, using slow blood amine to regulate the pH value is 6.5, processes 0.001 mol magnetic resonance imaging contrast.
Embodiment 9 get that the arabogalactan of the embodiment 2 of 0.1 gram modifies 1,4,7; 10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl paramagnetic metal complex is dissolved in the conventional VISOSE injection liquid; Using slow blood amine to regulate the pH value is 8.0, processes 0.01 mol magnetic resonance imaging contrast.
Embodiment 10 get that the arabogalactan of the embodiment 3 of 0.1 gram modifies 1,4,7; 10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl paramagnetic metal complex is dissolved in conventional sodium-chlor-VISOSE injection liquid; Using slow blood amine to regulate the pH value is 6.5, processes 0.1 mol magnetic resonance imaging contrast.
Embodiment 12 get that the arabogalactan of the embodiment 4 of 0.1 gram modifies 1,4,7; 10-tetraazacyclododecanand-1,4,7; 10-tetraacethyl paramagnetic metal complex is dissolved in the distilled water for injection, and using slow blood amine to regulate the pH value is 8.0, processes 0.5 mol magnetic resonance imaging contrast.
Embodiment 13 get that the arabogalactan of the embodiment 5 of 0.1 gram modifies 1,4,7; 10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl paramagnetic metal complex is dissolved in the conventional VISOSE injection liquid; Using slow blood amine to regulate the pH value is 8.0, processes 0.01 mol magnetic resonance imaging contrast.
Embodiment 14 get that the arabogalactan of the embodiment 6 of 0.1 gram modifies 1,4,7; 10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl paramagnetic metal complex is dissolved in conventional sodium-chlor-VISOSE injection liquid; Using slow blood amine to regulate the pH value is 6.5, processes 0.1 mol magnetic resonance imaging contrast.
Embodiment 14 get that the arabogalactan of the embodiment 7 of 0.1 gram modifies 1,4,7; 10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl paramagnetic metal complex is dissolved in conventional sodium-chlor-VISOSE injection liquid; Using slow blood amine to regulate the pH value is 6.5, processes 0.1 mol magnetic resonance imaging contrast.
Embodiment 15 gets the Wistar rat of male 190-210g body weight, press 1.0mL/100g body weight anesthesia with 10% urethane after, press the magnetic resonance imaging contrast that 0.1mmol/kg body weight dosage intravenous injection embodiment 1 prepares after, axle position, test animal abdominal cavity T
1The weighting picture, the every sampling at a distance from 3min observed once, more than the day-night observation 90min.Obtain the kidney of this magnetic resonance imaging contrast and the axle position T of liver
1The weighting picture is like Fig. 3 and 4.
Claims (3)
1. a paramagnetic metal complex is characterized in that, it is 1,4,7 of arabogalactan modification; 10-tetraazacyclododecanand-1,4,7,10-tetraacethyl paramagnetic metal complex is with 1 of arabogalactan modification; 4,7,10-tetraazacyclododecanand-1,4; 7,10-tetraacethyl part and paramagnetic metal ion, by the paramagnetic metal complex that mol ratio coordination in 1: 1 obtains, it has following structure:
In the formula, AG is an arabogalactan; N is the number of the micromolecular compound that connects on each arabogalactan molecule, n=27～36; M
M+Be paramagnetic metal ion, be metallic element Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Mo, Ru, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Lu+2 or+3 valency ions;
R is
2≤i≤6, and i is an integer.
2. the compound method of a kind of paramagnetic metal complex as claimed in claim 1 is characterized in that, step and condition are following: (1) is dissolved in temperature with arabogalactan is in 0 ℃ the 6mol/L sodium hydroxide solution; Stir and add Monochloro Acetic Acid after 30 minutes, the mass ratio of Monochloro Acetic Acid and arabogalactan is 2.2: 1, and elevated temperature to 60 ℃ stirred 1 hour; Methanol extraction filters, dialysis; Freeze-drying obtains carboxymethylated arabogalactan; Structural formula is following:
N=30～45th, the number of the small molecules part that connects on each arabogalactan molecule;
(2) at room temperature that the carboxymethylated arabogalactan of institute's synthetic in (1) is soluble in water, the pH=3 with hydrochloric acid soln accent solution adds 2-oxyethyl group-1-ethoxycarbonyl acyl-1 afterwards; 2-EEDQ (EEDQ) stirred after 30 minutes, dropwise added quadrol; The mass ratio of EEDQ and carboxymethylated arabogalactan is 1.8: 1, and the mass ratio of quadrol and carboxymethylated arabogalactan is 2.8: 1, stirs 5 hours; Methanol extraction filters, dialysis; Freeze-drying obtains aminating arabogalactan; Structure is following:
N=27～36th, the number of the small molecules part that connects on each arabogalactan molecule;
R is
2≤i≤6, and i is an integer;
(3) with 1,4,7,10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl (DOTA) is dissolved in the water, and adds N-hydroxy thiosuccinimide (S-NHS) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) respectively in 4 ℃; DOTA, S-NHS, the mass ratio of EDCHCl are 2: 1: 1; Regulate pH=5.5, stirred 40 minutes, obtain the active ester solution of DOTA.
(4) under 4 ℃ of temperature, the aminated arabogalactan in (2) is dissolved in the water, regulates pH 7.5～8.5 with sodium hydroxide solution, the drips of solution that obtains is added in the active ester solution of the DOTA in (3), and aminated arabogalactan and DOTA active ester mass ratio are 1: 3; Stirred 24 hours, and kept pH, concentrate dialysis 7.5～8.5; Freeze-drying obtains 1,4,7 of arabogalactan modification; 10-tetraazacyclododecanand-1,4,7,10-tetraacethyl macromolecular ligand; Structural formula is following:
N=27～36th, the number of the small molecules part that connects on each arabogalactan molecule;
R is
2≤i≤6, and i is an integer.
(5) at ambient temperature with 1,4,7 of the arabogalactan modification that obtains in (4), 10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl macromolecular ligand respectively with metallic element Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Mo, Ru, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy or Lu+2 or+3 valency ions are dissolved in the water; The amount of substance of DOTA is 1: 1.2 with the amount of substance ratio of above-mentioned metals ion in the DOTA macromolecular ligand that arabogalactan is modified, and stirs 24 hours, concentrates; Dialysis, freeze-drying obtains 1 of arabogalactan modification; 4,7,10-tetraazacyclododecanand-1; 4,7,10-tetraacethyl paramagnetic metal complex.
3. the application of a kind of paramagnetic metal complex as claimed in claim 1 is characterized in that, it is as the magnetic resonance imaging contrast of preparation to people or other mammiferous livers, kidney.
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| CN102727911A (en) * | 2012-07-09 | 2012-10-17 | 中国科学院长春应用化学研究所 | Diamino polyethylene glycol modified paramagnetic metal complex magnetic resonance imaging contrast agent |
| CN104069515A (en) * | 2014-06-27 | 2014-10-01 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex modified by aspartic acid-leucine copolymer as well as preparation and application of paramagnetic metal complex |
| CN104083778A (en) * | 2014-06-27 | 2014-10-08 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex modified by asparaginic acid-phenylalanine copolymer, preparation method and application of paramagnetic metal complex |
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| CN107973866A (en) * | 2017-12-15 | 2018-05-01 | 武汉工程大学 | Macrocyclic tetraaza manganese complex modification Chitosan Composites with high SOD enzyme activity and preparation method thereof |
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| CN116535538A (en) * | 2022-01-26 | 2023-08-04 | 北京大学 | Development and application of thoracic aortic aneurysm and aortic dissection early diagnosis probe |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102727911A (en) * | 2012-07-09 | 2012-10-17 | 中国科学院长春应用化学研究所 | Diamino polyethylene glycol modified paramagnetic metal complex magnetic resonance imaging contrast agent |
| CN102727911B (en) * | 2012-07-09 | 2013-07-24 | 中国科学院长春应用化学研究所 | Diamino polyethylene glycol modified paramagnetic metal complex magnetic resonance imaging contrast agent |
| CN104069515A (en) * | 2014-06-27 | 2014-10-01 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex modified by aspartic acid-leucine copolymer as well as preparation and application of paramagnetic metal complex |
| CN104083778A (en) * | 2014-06-27 | 2014-10-08 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex modified by asparaginic acid-phenylalanine copolymer, preparation method and application of paramagnetic metal complex |
| CN104083778B (en) * | 2014-06-27 | 2017-01-04 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex that aspartic acid-phenylalanine copolymer is modified and its preparation method and application |
| CN104069515B (en) * | 2014-06-27 | 2017-01-11 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex modified by aspartic acid-leucine copolymer as well as preparation and application of paramagnetic metal complex |
| CN107456583A (en) * | 2017-06-19 | 2017-12-12 | 南京科技职业学院 | A kind of magnetic resonance imaging contrast containing gadolinium and its preparation and application |
| CN107991277A (en) * | 2017-11-27 | 2018-05-04 | 陕西中药研究所 | Serotonin-magnetic particle compound and the method for being enriched with sialydated glycoproteins |
| CN107991277B (en) * | 2017-11-27 | 2020-10-16 | 陕西中药研究所(陕西医药信息中心) | Serotonin-magnetic particle composite and method for enriching sialylated glycoprotein |
| CN107973866A (en) * | 2017-12-15 | 2018-05-01 | 武汉工程大学 | Macrocyclic tetraaza manganese complex modification Chitosan Composites with high SOD enzyme activity and preparation method thereof |
| CN107973866B (en) * | 2017-12-15 | 2020-08-28 | 武汉工程大学 | Tetranitrogen macrocyclic manganese complex modified chitosan composite material with high SOD enzyme activity and preparation method thereof |
| CN116535538A (en) * | 2022-01-26 | 2023-08-04 | 北京大学 | Development and application of thoracic aortic aneurysm and aortic dissection early diagnosis probe |
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