CN1966088A - Magnetic resonance imaging contrast using arabinogalactan as carrier - Google Patents

Abstract

The invention discloses a magnetic resonance imaging contrast agent with arabinogalactan as a carrier. The contrast agent is composed of ethylenediaminetetraacetic acid or diethylenetriaminepentaacetic acid mono-N-hydroxysuccinimide active ester or ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid bisanhydride through a short linking arm and Aminated Arabinogalactan reaction, linking ethylenediaminetetraacetic acid or diethylenetriaminepentaacetic acid to the Arabinogalactan molecule through the formation of amide bonds, further combined with paramagnetic metal ions manganese, iron or lanthanide rare earth elements The divalent or trivalent ions coordinate to obtain complexes. They have high relaxation efficiencies, apparent liver selectivity, and fairly low acute toxicity. The contrast agent of the present invention can also be used in X-ray CT or gamma scintillation imaging diagnosis technology besides being used for magnetic resonance imaging diagnosis.

Description

Magnetic resonance imaging contrast agent based on arabinogalactan

technical field

The invention relates to a magnetic resonance imaging contrast agent, in particular to a liver-targeting magnetic resonance imaging contrast agent with arabinogalactan as a carrier.

Background technique

Magnetic resonance imaging (MRI) is another universally recognized medical achievement after X-ray CT, which has had a huge impact on medical practice. In clinical imaging, more than 35% of diagnoses require the use of contrast agents in order to improve the signal contrast between lesion and normal tissue. Magnetic resonance contrast agents are a class of diagnostic drugs that can shorten imaging time, improve imaging contrast and clarity, and display the functional status of tissues and organs. The contrast agents currently used in clinical magnetic resonance imaging diagnosis are mainly small molecule gadolinium or manganese complexes: Gd-DTPA (Magnevist, Magnevist), Gd-DOTA (Dotarem, Dotalin), Mn-DPDP (Teslascan, Thailand). Leying), Gd-DTPA-BMA (Omniscan, Omniscan), Gd-HP-DO3A (Prohance, Prohance), Gd-BOPTA (MultiHance, Modis), etc., these small molecule contrast agents have an effect on the brain and central nervous system Nervous system has a good imaging effect, but its extracellular distribution and rapid renal metabolism limit its application, especially for some organs in the body such as the liver and kidney. requirements. Therefore, the development of contrast agents with low cost, low toxicity, high relaxation efficiency, and selectivity or targeting to specific tissues or organs is the current development direction of magnetic resonance contrast agents.

In recent years, the mainstream research and development of contrast agents at home and abroad are diethylenetriaminepentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecyl-1,4,7 , 10-tetraacetic acid (1,4,7,10-tetraazacyclododecane-N, N′, N″, N-tetraacetic acid, hereinafter referred to as DOTA) is chemically modified to produce various types of contrast agents, among which macromolecular It is a main development direction. Introducing small molecular weight contrast agents Gd-DTPA and Gd-DOTA into the polymer backbone or covalently coupling with natural polymers and artificially synthesized polymers can form macromolecular contrast agents. Time, improve relaxation efficiency; According to the characteristics of the macromolecule itself or introducing a group with affinity to a certain tissue or organ of the human body into the macromolecule, it can also enhance the selectivity and targeting of tissues and organs. It has been used in The biomacromolecular carriers studied by magnetic resonance imaging contrast agents include antibodies, serum albumin, polysaccharides, red blood cells, hormones, polyamino acids, etc. As one of the four major biomacromolecules, sugars are widely distributed in nature. The site of action of drugs with polysaccharides as carriers is on the cell surface, so the interference of such drugs on the entire cell and the entire body is much smaller than that of drugs that directly enter the cell membrane and cytoplasm. The side effects of drugs as carriers are less than those of other drugs; and there are receptors for specific polysaccharides in different cells of the organism, and specific polysaccharides can be targeted to specific parts of the body through receptors. This targeting can not only further reduce Small side effects, and can reduce the dosage of polysaccharide drugs. In recent years, carbohydrates have attracted widespread attention as targeting and carrier molecules in the design and synthesis of MRI contrast agents: CMD-Gd-DTPA (Bioconjugate Chemistry, Bioconjugate Chem ., 1997.8, 605-610) [Gd]DTPA-dextran (Bioconjugate Chemistry, BioconjugateChem., 2004.11, 1361-1369), containing D-galactosyl (Chinese patent CN1,166,987, A) and Arabidoplastin Sugar (Chemical Journal of Higher Schools, 2002, 23, 1837) and other contrast agents.

Arabinogalactan (Arabinogalactan, AG) is a neutral polysaccharide composed of arabinose and galactose. It is the most abundant in the woody part of larch trees, up to 25%. It is also found in other plants such as corn, potato, angelica, radish, etc. It contains a certain amount of arabinogalactan, and there is a very mature extraction technology at present. Arabinogalactan has the characteristics of large molecular weight, good solubility, and long residence time in the blood, and there is an asialoglycoprotein receptor AGPr on the surface of animal liver parenchymal cells that specifically recognizes galactose residues, which can be used as Carrier of contrast media. In the previous work (Acta Chemical Journal of Higher Schools 2002, 23, 1837), DTPA was directly linked to arabinogalactan through ester bonds, and then coordinated with gadolinium ions. This contrast agent has high relaxation efficiency and good liver targeting, but it is prone to cross-linking during the synthesis process, and the formed ester bonds are prone to hydrolysis, which leads to a decrease in the relaxation efficiency of the contrast agent and the presence of Breakdown of free gadolinium increases the risk of toxicity.

Contents of the invention

The object of the present invention is to provide a magnetic resonance imaging contrast agent with arabinogalactan as a carrier. The magnetic resonance imaging contrast agent is connected by amide bonds, and is modified with arabinogalactan (Ethylenediaminetetraacetic acid, hereinafter referred to as EDTA) or DTPA macromolecular ligands and paramagnetic metal ions manganese, iron or lanthanum respectively. It is a paramagnetic metal complex obtained by coordinating divalent or trivalent ions of rare earth elements at a molar ratio of 1:1; the paramagnetic metal complex has the following structure:

Where m=0 or m=1, when m=0, it is the EDTA macromolecular ligand modified by arabinogalactan; when m=1, it is the DTPA macromolecular ligand modified by arabinogalactan.

n=18-25 is the number of small molecule ligands linked to each arabinogalactan molecule.

M is a trivalent ion of paramagnetic metal ion manganese, iron or lanthanide rare earth elements. Preferred trivalent ions of lanthanide rare earth elements are: Gd ³⁺ , Dy ³⁺ or Nd ³⁺ .

2≤i≤6，i为整数。R is

2≤i≤6, i is an integer.

The EDTA or DTPA macromolecule ligand modified by the arabinogalactan has the following structure:

Where m=0 or m=1, when m=0, it is the EDTA macromolecular ligand modified by arabinogalactan; when m=1, it is the DTPA macromolecular ligand modified by arabinogalactan.

n=18-25 is the number of small molecule ligands linked to each arabinogalactan molecule.

R is 2≤i≤6, i is an integer.

According to the characteristics that arabinogalactan contains D-galactose end group and can be selectively recognized by the asialoglycoprotein receptor on the surface of mammalian liver parenchyma, EDTA or DTPA is combined with aminated arabinogalactin through a short linking arm Glycans are linked via amide bonds to form arabinogalactan-modified EDTA or DTPA macromolecular ligands, and then the ligands are coordinated with paramagnetic metal ions to obtain good water solubility, high relaxation efficiency, and selectivity for the liver. Magnetic resonance imaging contrast agents of paramagnetic metal complexes modified with arabinogalactan.

The steps and conditions of a preparation method of a magnetic resonance imaging contrast agent of the present invention are as follows:

a) Dissolve EDTA or DTPA in a mixed solution of acetonitrile and triethylamine, the volume ratio of acetonitrile and triethylamine is 12:13, raise the temperature to 55°C, after EDTA or DTPA is completely dissolved, add N, N' at the same time -Dicyclohexylcarbodiimide (hereinafter referred to as DCC) and N-hydroxysuccinimide (hereinafter referred to as HONSu), the molar ratio of EDTA or DTPA to DCC is 1:1.4, and the molar ratio of DCC to HONSu is 1:1 , stirred at room temperature for 1.5h, filtered to obtain EDTA or DTPA mono-N-hydroxysuccinimide active ester solution (hereinafter referred to as EDTA-ONSu solution or DTPA-ONSu solution), the structure of EDTA-ONSu or DTPA-ONSu is as follows:

m=1, DTPA monoactive ester;

m=0, EDTA monoactive ester

b) Dissolving arabinogalactan in 6mol/L NaOH solution at 0°C, and then adding monochloroacetic acid, the molar ratio of monochloroacetic acid to monosaccharide in arabinogalactan is 3.2:1, Stir at 60°C for 50 minutes, precipitate with methanol, filter, and dry in vacuum to obtain carboxymethylated arabinogalactan. It has the following structure:

n=26-35 is the number of small molecule ligands linked to each arabinogalactan molecule.

c) dissolving the carboxymethylated arabinogalactan obtained in step b) in deionized water, adjusting the pH to 3 with HCl, and adding 2-ethoxy-1-ethoxycarbonyl-1 dropwise, The methanol solution of 2-dihydroquinoline (hereinafter referred to as EEDQ) is added dropwise with ethylenediamine under the stirring situation, the molar ratio of carboxylate in EEDQ and the carboxymethylated arabinogalactan is 2: 1, ethylenediamine The molar ratio of carboxylate to carboxymethylated arabinogalactan was 10:1, stirred at room temperature for 4 hours, precipitated with methanol, filtered, and vacuum-dried to obtain aminated arabinogalactan. Its structure is as follows:

n=18-25 is the number of small molecule ligands linked to each arabinogalactan molecule.

R is 2≤i≤6, i is an integer.

d) Dissolve the aminated arabinogalactan obtained in step c) in deionized water, add the EDTA-ONSu solution or DTPA-ONSu solution in step a), EDTA-ONSu or DTPA-ONSu and aminated arabinogalactan The molar ratio of amino groups in lactan is 2:1, adjust pH=10 with NaOH, stir at room temperature for 24 hours, remove acetonitrile under reduced pressure, use semi-permeable membrane dialysis method for separation and purification, deionized water dialysis for 5-7 days, The water was changed 2 to 3 times a day, and the solution in the osmotic bag was rotary evaporated at 55° C., and freeze-dried to obtain arabinogalactan-modified EDTA or DTPA macromolecule ligands. Its structural formula is as follows:

Wherein m is 0 or 1, when m=0, it is the EDTA macromolecular ligand modified by arabinogalactan, and when m=1, it is the DTPA macromolecular ligand modified by arabinogalactan.

n=18-25 is the number of small molecule ligands linked to each arabinogalactan molecule.

R is 2≤i≤6, i is an integer.

e) The arabinogalactan modified EDTA or DTPA macromolecule ligands obtained in step d) are respectively coordinated with divalent or trivalent ions of manganese, iron or lanthanide rare earth elements to obtain arabinogalactan Sugar-carrier magnetic resonance imaging contrast agents.

In order to ensure that the EDTA or DTPA macromolecular ligands modified by arabinogalactan coordinate with the divalent or trivalent ions of manganese, iron or lanthanide rare earth elements in a 1:1 molar ratio, more than 20% of the ratio can be added Divalent or trivalent ions of manganese, iron or lanthanide rare earth elements, and then dialysis to remove excess divalent or trivalent ions of manganese, iron or lanthanide rare earth elements to obtain paramagnetic metal complexes modified by arabinogalactan Magnetic resonance imaging contrast agents.

For the case where the total charge number after complex formation is not zero, physiologically compatible cations, especially Na ⁺ , Ca ²⁺ , Cu ²⁺ , Zn ²⁺ , NH ₄ ⁺ or organic derivatives of NH ₄ ⁺ can be used: N-methylglucamine, amino acid or alcohol amine to balance its charge.

The paramagnetic metal complex magnetic resonance imaging contrast agent modified by arabinogalactan in the present invention can be made into an injection. For example, the injection can be modified with the arabinogalactan of the present invention with sodium chloride injection, glucose injection, glucose and sodium chloride injection or distilled water or other carriers specified in "The Pharmacopoeia of the People's Republic of China" (1990 edition). The paramagnetic metal complex or its salt is prepared into a solution with a concentration of 0.001-1.0mol/L, particularly preferably a solution of 0.1-0.5mol/L, and is mixed with a physiologically compatible acid such as hydrochloric acid or a physiologically compatible base including N-methylglucamine, tromethamine, amino acids and other organic bases or ammonia water, sodium hydroxide, sodium carbonate, sodium bicarbonate and other inorganic bases to adjust the pH value to between 6.5 and 8.0. Usually, 0.1-15% of the mass of arabinogalactan-modified paramagnetic metal complexes is added to the preparation, which is arabinogalactan-modified EDTA or DTPA macromolecule ligand, or arabinogalactan-modified EDTA Or the physiologically compatible salt of DTPA macromolecular ligand, or the EDTA or DTPA macromolecular complexes modified by calcium, magnesium, copper, zinc arabinogalactan or the arabinogalactan of calcium, magnesium, copper, zinc Physiologically compatible salts of sugar-modified EDTA or DTPA macromolecular complexes to ensure complete coordination of paramagnetic metal ions such as Gd ³⁺ . In addition, antioxidants such as ascorbic acid or sodium and calcium salts of ascorbic acid need to be added, which do not affect the preparation, storage and use of the preparation. Another way is to combine the paramagnetic metal complex modified by arabinogalactan of the present invention with 0.1 to 15% of the mass of the paramagnetic metal complex modified by arabinogalactan. EDTA or DTPA macromolecular ligands and salts thereof, or calcium, magnesium, copper, zinc arabinogalactan-modified EDTA or DTPA macromolecular complexes or physiologically compatible salts of these complexes, pH regulators, Antioxidants and other required ingredients are formulated into dry solid preparations, namely powder for injection or powder for injection, which are diluted to the required concentration with carriers such as sodium chloride injection or distilled water before use.

The contrast agent of the present invention can be used in a conventional method. This method is to give a paramagnetic metal complex modified by arabinogalactan to a diagnostic object including a human body or other mammals, and then perform magnetic resonance imaging analysis to obtain enhanced magnetic resonance imaging. Imaging diagram. The administration amount of the contrast agent of the present invention may vary greatly due to the molecular weight of the paramagnetic complex, the tissue or organ to be diagnosed and the type of diagnostic equipment. Generally, the dosage of the injection is 0.001-5.0 mmol per kilogram body weight of the human body or other mammals as the subject of diagnosis, preferably 0.05-0.5 mmol per kilogram body weight.

Beneficial effects of the present invention:

1. The relaxation efficiency of this type of contrast agent is significantly higher than that of small molecule contrast agents commonly used in clinical practice, and is about 2 times that of small molecule contrast agents.

2. This type of contrast agent has good water solubility and is easy to prepare into a solution of required concentration for intravenous injection.

3. Good selectivity to the liver: after intravenous injection of this type of contrast agent slightly lower than the clinical dose (0.1mmolGd/kg), the imaging contrast of the liver can be significantly improved (confirmed by Wistar rat imaging experiments).

4. This kind of contrast agent aqueous solution has good thermal stability and is suitable for sterilization and disinfection by hot pressing.

5. The polysaccharide side chain contains D-galactose end group, which can be selectively recognized by the asialoglycoprotein receptor on the surface of the liver parenchyma.

6. This type of contrast agent can maintain a stable concentration in the body for a relatively long time, so that the liver can obtain a long-term stable imaging window.

7. Good selectivity to the liver of human or other mammals.

Animal imaging experiment: Bruker MRI, 30cm coil, 4.7T magnetic field, T ₁ weighted multi-slice-multi-echo imaging method, repetition time TR: 300ms, echo time TE: 13.6ms, scan area: 5.5 ×5.5cm ² , scanning matrix: 128×128. Take male Wistar rats with a body weight of 190-210 g, anesthetize them with 10% urethane at a rate of 1.0 mL/100 g body weight, test the axial _T1- weighted image of the abdominal cavity of the animal, and inject the above-mentioned contrast agent solution intravenously at a dose of 0.093 mmol/kg body weight for imaging , Sampling and observation every 3 minutes, and continuous observation for more than 90 minutes. The imaging results showed that the enhancement effect of this kind of contrast agent slightly lower than the clinical dose on the liver magnetic resonance signal was significantly better than that of Gd-DTPA, and the enhancement effect remained good throughout the experimental period (Figure 2). This contrast enhancement demonstrates the good liver selectivity of this type of contrast agent.

Description of drawings

Figure 1 The enhancement effect of rat kidney signal over time after injection of arabinogalactan-modified gadolinium diethylenetriaminepentaacetate complex contrast agent (hereinafter referred to as Gd-DTPA-CMAGA)

Figure 2 The enhancement effect of rat liver signal over time after injection of contrast agent Gd-DTPA-CMAGA

Figure 3 is the axial _T1- weighted image of rat kidney before and 20 minutes after injection of contrast agent Gd-DTPA-CMAGA

Figure 4 is the axial _T1- weighted images of rat liver before and 20 min after injection of contrast agent Gd-DTPA-CMAGA

Detailed ways

Example 1

Preparation of arabinogalactan by ethylenediamine-modified gadolinium diethylenetriaminepentaacetate complex (Gd-DTPA-CMAGA) contrast agent for magnetic resonance imaging

a) 1g of DTPA was dissolved in a mixed solution of 4.8ml of acetonitrile and 5.4ml of triethylamine, and the temperature was raised to 55°C. After DTPA was completely dissolved, 0.371g of DCC and 0.207g of HONSu were added at the same time, stirred at room temperature for 1.5h, and filtered to obtain DTPA- ONSu solution.

b) Dissolve 6g of arabinogalactan in 50ml of 6mol/L NaOH solution at 0°C, then add 12.3g of monochloroacetic acid, stir at 60°C for 50min, precipitate with methanol, filter, and dry in vacuo to obtain carboxymethyl sylated arabinogalactan.

c) Dissolve 6 g of carboxymethylated arabinogalactan in deionized water, adjust the pH to 3 with 1 mol/L HCl, add 9.3 g of EEDQ methanol solution dropwise, and add 12.5 ml of ethylenediamine dropwise while stirring, Stir at room temperature for 4 hours, precipitate with methanol, wash, and dry in vacuo to obtain aminated arabinogalactan.

d) Dissolve 1 g of the aminated arabinogalactan in c in 25 ml of deionized water, add 10 ml of the DTPA-ONSu solution in step a, adjust the pH to 10 with 6 mol/L NaOH, stir at room temperature for 24 hours, and pump under reduced pressure Acetonitrile was removed, dialyzed for 5 days, the solution in the osmotic bag was rotary evaporated at 55° C. to a small volume, and freeze-dried to obtain the arabinogalactan-modified DTPA macromolecular ligand (hereinafter referred to as DTPA-CMAGA).

e) Dissolve 0.5 g of DTPA-CMAGA in d in 10 ml of deionized water, add 3 ml of 0.2 mol/L GdCl ₃ solution (more than 20% of the ratio), adjust the pH value to 5.5 with 1 mol/L NaOH, and stir overnight at room temperature, Dialyze, exchange the aqueous solution outside the dialysis bag until its longitudinal relaxation time _T1 is greater than 3000ms, and freeze-dry to obtain the Gd-DTPA-CMAGA magnetic resonance imaging contrast agent.

Example 2

Preparation of Arabinogalactan as a Contrast Agent for Magnetic Resonance Imaging via Manganese Diethylenetriaminepentaacetate Complex Modified with Ethylenediamine

a) Step a) in the same example 1.

b) Same as step b) in Example 1.

c) Same as step c) in Example 1.

d) Same as step d) in Example 1.

e) Dissolve 0.5g of the arabinogalactan-modified DTPA macromolecule ligand in d in 10ml of deionized water, add 3ml of 0.2mol/L MnCl _solution (more than 20% of the ratio), adjust the pH with 1mol/L NaOH The value is 5.7, stirred overnight at room temperature, dialyzed, exchanged the aqueous solution outside the dialysis bag until its longitudinal relaxation time _T1 is greater than 3000ms, freeze-dried to obtain the manganese diethylenetriaminepentaacetic acid complex of arabinogalactan modified by ethylenediamine Magnetic resonance imaging contrast agents.

Example 3

Preparation of arabinogalactan as a contrast agent for magnetic resonance imaging via ethylenediamine-modified gadolinium ethylenediaminetetraacetate complexes

a) 0.743g EDTA was dissolved in a mixed solution of 4.8ml acetonitrile and 5.4ml triethylamine, and the temperature was raised to 55°C. After the EDTA was completely dissolved, 0.371g DCC and 0.207g HONSu were added at the same time, stirred at room temperature for 1.5h, and filtered to obtain EDTA- ONSu solution.

b) Same as step b) in Example 1.

c) Same as step c) in Example 1.

d) Dissolve 1 g of the aminated arabinogalactan in c in 25 ml of deionized water, add 10 ml of the EDTA-ONSu solution in step a, adjust the pH to 10 with 6 mol/L NaOH, stir at room temperature for 24 hours, and pump under reduced pressure Acetonitrile was removed, dialyzed for 5 days, the solution in the osmotic bag was rotary evaporated at 55°C to a small volume, and freeze-dried to obtain the arabinogalactan-modified EDTA macromolecule ligand.

e) Dissolve 0.5g of the EDTA macromolecule ligand modified by arabinogalactan in d in 10ml of deionized water, add _3ml of 0.2mol/L GdCl solution (more than 20% of the ratio), adjust the pH with 1mol/L NaOH Value is 5.5, stirred overnight at room temperature, dialyzed, exchanged the aqueous solution outside the dialysis bag until its longitudinal relaxation time T ₁ is greater than 3000ms, and freeze-dried to obtain arabinogalactan through ethylenediamine modified ethylenediaminetetraacetic acid gadolinium complex magnetic Resonance imaging contrast agents.

Example 4

Preparation of Arabinogalactan as Magnetic Resonance Imaging Contrast Agent by Ethylenediamine Modified Manganese EDTA Complex

a) Step a) in the same example 3.

b) Same as step b) in Example 1.

c) Same as step c) in Example 1.

d) Step d) in the same example 3.

e) Dissolve 0.5g of the EDTA macromolecule ligand modified by arabinogalactan in d in 10ml of deionized water, add 3ml of 0.2mol/L MnCl _solution (more than 20% of the ratio), adjust the pH with 1mol/L NaOH The value is 5.7, stirred overnight at room temperature, dialyzed, exchanged the aqueous solution outside the dialysis bag until the longitudinal relaxation time _T1 is greater than 3000ms, and freeze-dried to obtain the ethylenediaminetetraacetic acid manganese complex of arabinogalactan modified by ethylenediamine.

Example 5

Preparation of Arabinogalactan by Gadolinium Complex of Diethylenetriaminepentaacetate Modified by Hexamethylenediamine

a) Step a) in the same example 1.

b) Same as step b) in Example 1.

c) Dissolve 6g of carboxymethylated arabinogalactan in deionized water, adjust the pH to 3 with 1mol/L HCl, add 9.3g of EEDQ methanol solution dropwise, add 15ml of hexamethylenediamine dropwise under stirring, and bring to room temperature Stir for 4 hours, precipitate with methanol, wash with methanol, and dry in vacuo to obtain aminated arabinogalactan.

d) Dissolve 1 g of the aminated arabinogalactan in c in 25 ml of deionized water, add 10 ml of the DTPA-ONSu solution in step a, adjust the pH to 10 with 6 mol/L NaOH, stir at room temperature for 24 hours, and pump under reduced pressure Acetonitrile was removed, dialyzed for 5 days, the solution in the osmotic bag was rotary evaporated at 55°C to a small volume, and freeze-dried to obtain the arabinogalactan-modified DTPA macromolecule ligand.

e) Dissolve 0.5g of the DTPA macromolecule ligand modified by arabinogalactan in d in 10ml of deionized water, add _3ml of 0.2mol/L GdCl solution (more than 20% of the ratio), adjust the pH with 1mol/L NaOH The value is 5.5, stirred at room temperature overnight, dialyzed, exchanged the aqueous solution outside the dialysis bag until its longitudinal relaxation time T ₁ is greater than 3000ms, freeze-dried to obtain the gadolinium diethylenetriaminepentaacetic acid complex of arabinogalactan modified by hexamethylenediamine Magnetic resonance imaging contrast agents.

Example 6

Preparation of Arabinogalactan as Magnetic Resonance Imaging Contrast Agent by Diethylenetriaminepentaacetic Manganese Complex Modified by Hexamethylenediamine

a) Step a) in the same example 1.

b) Same as step b) in Example 1.

c) Same as step c) in Example 5.

d) Same as step d) in Example 5.

e) Dissolve 0.5g of the arabinogalactan-modified DTPA macromolecule ligand in d in 10ml of deionized water, add 3ml of 0.2mol/L MnCl _solution (more than 20% of the ratio), adjust the pH with 1mol/L NaOH The value is 5.7, stirred overnight at room temperature, dialyzed, exchanged the aqueous solution outside the dialysis bag until its longitudinal relaxation time _T1 is greater than 3000ms, and freeze-dried to obtain the manganese diethylenetriaminepentaacetic acid complex of arabinogalactan modified by hexamethylenediamine Magnetic resonance imaging contrast agents.

Example 7

Preparation of Arabinogalactan as Magnetic Resonance Imaging Contrast Agent by Hexamethylenediamine Modified Gadolinium EDTA Complex

a) Step a) in the same example 3.

b) Same as step b) in Example 1.

c) Same as step c) in Example 5.

d) Dissolve 1 g of the aminated arabinogalactan in c in 25 ml of deionized water, add 10 ml of the EDTA-ONSu solution in step a, adjust the pH to 10 with 6 mol/L NaOH, stir at room temperature for 24 hours, and pump under reduced pressure Acetonitrile was removed, dialyzed for 5 days, the solution in the osmotic bag was rotary evaporated at 55°C to a small volume, and freeze-dried to obtain the arabinogalactan-modified EDTA macromolecule ligand.

e) Dissolve 0.5g of the EDTA macromolecule ligand modified by arabinogalactan in d in 10ml of deionized water, add _3ml of 0.2mol/L GdCl solution (more than 20% of the ratio), adjust the pH with 1mol/L NaOH The value is 5.5, stirred at room temperature overnight, dialyzed, exchanged the aqueous solution outside the dialysis bag until the longitudinal relaxation time _T1 is greater than 3000ms, and freeze-dried to obtain the gadolinium complex of arabinogalactan modified by hexamethylenediamine.

Example 8

Preparation of Arabinogalactan as Magnetic Resonance Imaging Contrast Agent by Hexamethylenediamine Modified Manganese EDTA Complex

a) Step a) in the same example 3.

b) Same as step b) in Example 1.

c) Same as step c) in Example 5.

d) Same as step d) in Example 7.

e) Dissolve 0.5g of the EDTA macromolecule ligand modified by arabinogalactan in d in 10ml of deionized water, add 3ml of 0.2mol/L MnCl _solution (more than 20% of the ratio), adjust the pH with 1mol/L NaOH The value is 5.7, stirred at room temperature overnight, dialyzed, exchanged the aqueous solution outside the dialysis bag until its longitudinal relaxation time T ₁ is greater than 3000ms, freeze-dried to obtain arabinogalactan magnetic Resonance imaging contrast agents.

Arabinogalactan-modified paramagnetic metal complex magnetic resonance imaging contrast agent is used as follows:

Example 9

Weigh 0.2946g of Gd-DTPA-CMAGA in Example 1 and dissolve it in 15mL of sodium chloride injection, prepare a solution with a concentration of 10mmol/L, adjust the pH value to 6.5 with tromethamine, and add 0.001 g DTPA-CMAGA to obtain the injection of contrast agent Gd-DTPA-CMAGA. Take male Wistar rats with a body weight of 190-210 g, anesthetize them with 10% urethane at a rate of 1.0 mL/100 g body weight, inject the above-mentioned contrast medium solution intravenously at a dose of 0.093 mmol/kg body weight, and test the axial T1 _- weighted image of the abdominal cavity of the animal. Sampling and observation every 3 minutes, continuous observation for more than 90 minutes. Axial _T1- weighted images of the kidney and liver obtained with the contrast medium are shown in Figures 3 and 4.

Claims (2)

1. A magnetic resonance imaging contrast agent with arabinogalactan as a carrier, characterized in that: the magnetic resonance imaging contrast agent is connected by an amide bond and modified with arabinogalactan. The paramagnetic metal complex obtained by coordinating the macromolecular ligands of triaminepentaacetic acid with the divalent or trivalent ions of manganese, iron or lanthanide rare earth elements respectively in a molar ratio of 1:1; The paramagnetic metal complex has the following structure:

Where m=0 or m=1, when m=0, it is arabinogalactan-modified ethylenediaminetetraacetic acid macromolecule ligand; when m=1, it is arabinogalactan-modified diethylenetriaminepenta Acetate macromolecular ligand; n=18～25 is the number of small molecule ligands connected on each arabinogalactan molecule; M is a divalent or trivalent ion of paramagnetic metal ion manganese, iron or lanthanide rare earth elements, R is

2≤i≤6, i is an integer; The ethylenediaminetetraacetic acid or diethylenetriaminepentaacetic acid macromolecule ligand modified by arabinogalactan has the following structure: Where m=0 or m=1, when m=0, it is arabinogalactan-modified ethylenediaminetetraacetic acid macromolecule ligand; when m=1, it is arabinogalactan-modified diethylenetriaminepenta Acetate macromolecular ligand; n=18～25 is the number of small molecule ligands connected on each arabinogalactan molecule; R is 2≤i≤6, i is an integer. 2. A magnetic resonance imaging contrast agent with arabinogalactan as a carrier as claimed in claim 1, said paramagnetic metal ion manganese, iron or trivalent ions of lanthanide rare earth elements are preferably: ^{Gd3 +} , Dy ³⁺ or Nd ³⁺ .

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