CN102274529B - Magnetic resonance imaging contrast agent and preparation method thereof - Google Patents

Abstract

The invention provides a magnetic resonance imaging contrast agent and a preparation method thereof, which is characterized in that the magnetic resonance imaging contrast agent is coordinated by a 3-hydroxypyridin-4-one hexadentate ligand and a paramagnetic metal ion in a molar ratio of 1:1. The metal complex of the obtained 3-hydroxypyridin-4-one hexadentate ligand, the preparation steps of which include the preparation of benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand; and then debenzyl by catalytic hydrogenation Obtain 3-hydroxypyridin-4-one hexadentate ligand; finally coordinate the obtained 3-hydroxypyridin-4-one hexadentate ligand with paramagnetic metal ion in a molar ratio of 1:1 to obtain 3-hydroxypyridine The step of the metal complex of the -4-ketone hexadentate ligand, that is, the magnetic resonance imaging contrast agent, has the advantages of high stability of the magnetic resonance contrast agent, small toxic and side effects on human tissues, high relaxation rate, good water solubility, and The preparation method is simple and easy to operate.

Description

A kind of magnetic resonance imaging contrast agent and preparation method thereof

technical field

The invention relates to a magnetic resonance contrast agent for early diagnosis of tumors, in particular to a magnetic resonance imaging contrast agent and a preparation method thereof.

Background technique

Magnetic resonance imaging (magnetic resonance imaging, MRI) has been widely used in the angiography of the head, nervous system, abdomen and blood vessels of the human body. It is particularly effective in detecting tissue necrosis, local ischemia and various malignant lesions, and can be used for early diagnosis. , in order to improve the effect of magnetic resonance imaging, it is usually necessary to use magnetic resonance imaging contrast agent. MRI contrast agents are a class of magnetic substances that can improve the sensitivity and specificity of MRI diagnosis, enhance signal contrast, and improve soft tissue signal resolution.

The contrast agents currently used in clinical magnetic resonance imaging are mainly small molecule gadolinium or manganese complexes: Gd-DTPA (Magnevist, Magnevist), Gd-DOTA (Dotarem, Duotaling), Mn-DPDP (Teslascan, Taylor These small molecule contrast agents have good imaging effects on the brain and central nervous system, etc., but their extracellular distribution and rapid renal metabolism limit their application, and cannot meet the requirements of tissue and organ selectivity. Stable, easy to decompose in the body to release toxic metal ions, low relaxation rate, poor water solubility.

Contents of the invention

The technical problem to be solved by the present invention is to provide a magnetic resonance contrast agent with high stability, high relaxation rate, good water solubility and little toxic and side effects on human tissues and its preparation method.

The technical scheme adopted by the present invention to solve the above-mentioned technical problems is: a magnetic resonance imaging contrast agent, which is composed of 3-hydroxypyridin-4-one hexadentate ligand and paramagnetic metal ion in a ratio of 1:1 The metal complex of the 3-hydroxypyridin-4-one hexadentate ligand obtained by molar ratio coordination, the metal complex has the following general structural formula:

The structure of the 3-hydroxypyridin-4-one hexadentate ligand is as follows:

Wherein R ₁ =H, CH ₃ ; R ₂ =H, C _1-3 hydrocarbon group, (CH ₂ ) _2-6 OH, (CH ₂ ) _2-6 OCH ₃ , (CH ₂ CH ₂ O) _1-3 H; n=1-3; Y is a trivalent group, its structure is as follows:

M is a paramagnetic metal ion Fe, La, Eu, Gd or Dy.

The paramagnetic metal ion is gadolinium Gd.

A method for preparing a magnetic resonance imaging contrast agent, comprising the following steps:

(1) Preparation of benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand

Mix tricarboxylic acid with benzyl-protected 3-hydroxypyridin-4-one bidentate ligand containing free amino group, 1,3-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and dissolve in In N,N-dimethylformamide, the obtained first mixed solution was stirred at room temperature for at least 2 days and then filtered, the filtrate was evaporated to remove the solvent under reduced pressure, and the obtained concentrate was separated and purified by silica gel column chromatography to obtain The white solid is a benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand;

(2) Preparation of 3-hydroxypyridin-4-one hexadentate ligand

After dissolving the benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand obtained in step (1) in methanol, add palladium carbon and concentrated hydrochloric acid to obtain a second mixed solution, and react in a hydrogen atmosphere with a pressure of 4.2mPa After 3 hours, filter and evaporate, remove the solvent in the second mixed solution to obtain a solid residue, add methanol to the solid residue until the solid residue is completely dissolved, then add acetone until the precipitate no longer separates out, and collect the precipitate The precipitate was vacuum-dried to obtain a white powder product, namely -3-hydroxypyridin-4-one hexadentate ligand;

(3) Preparation of metal complexes of 3-hydroxypyridin-4-one hexadentate ligands

The 3-hydroxypyridin-4-one hexadentate ligand obtained in step (2) is coordinated with the paramagnetic metal ion in a molar ratio of 1:1 to obtain the metal of the 3-hydroxypyridin-4-one hexadentate ligand The complex, that is, the MRI contrast agent, has the following structure:

Wherein R ₁ =H, CH ₃ ; R ₂ =H, C _1-3 hydrocarbon group, (CH ₂ ) _2-6 OH, (CH ₂ ) _2-6 OCH ₃ , (CH ₂ CH ₂ O) _1-3 H; n=1-3; Y is a trivalent group, its structure is as follows:

M=Fe, La, Eu, Gd, Dy.

The tricarboxylic acid is nitrilotriacetic acid, and the benzyl-protected 3-hydroxypyridin-4-one bidentate ligand containing free amino groups is 2-aminomethyl-3-benzyloxy-1, 6-lutidine-4-one, the nitrilotriacetic acid, the 2-aminomethyl-3-benzyloxy-1,6-lutidine-4-one, the The molar ratio of 1,3-dicyclohexylcarbodiimide to the 1-hydroxybenzotriazole mixed is 2:6.9:6.9:6.9; the nitrilotriacetic acid and the N,N - The molar volume ratio of dimethylformamide is 1 mmol: 10 mL; the mobile phase of the silica gel column is a mixture of methanol and dichloromethane in a volume ratio of 1.5: 8.5.

The tricarboxylic acid is 3,3',3"-nitrilotriacetic acid, and the benzyl-protected 3-hydroxypyridin-4-one bidentate ligand containing free amino groups is 2-aminomethyl -3-benzyloxy-1,6-dimethylpyridin-4-one, the 3,3',3"-nitrilotriacetic acid, the 2-aminomethyl-3-benzyloxy Base-1,6-dimethylpyridin-4-one, the 1,3-dicyclohexylcarbodiimide and the 1-hydroxybenzotriazole are mixed in a molar ratio of 2.66:9.57: 9.57: 9.57; the molar volume ratio of said nitrilotriacetic acid to said N,N-dimethylformamide is 2.66mmol: 25mL; the mobile phase of said silica gel column is methanol and dichloromethane by 1.5 : Mixed at a volume ratio of 8.5.

The mass volume ratio of the benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand to the methanol is 1.75g: 40mL; the benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand The mass ratio of the tooth ligand to the palladium carbon is 5:1; the volume ratio of the methanol to the concentrated hydrochloric acid is 80:3.

Dissolve the 3-hydroxypyridin-4-one hexadentate ligand obtained in step (2) in methanol and water, add GdCl ₃ 6H ₂ O and pyridine to obtain a third mixed solution, and reflux the third mixed solution for 4 hours , the solvent was evaporated to obtain a solid precipitate, and the solid precipitate was washed with cold ethanol to obtain a white solid gadolinium complex, which is a magnetic resonance imaging contrast agent, with the following structure:

where n=1,2.

Compared with the prior art, the present invention has the advantages that: 3-hydroxypyridin-4-ketone is a class of chelating agent with broad clinical application prospect, because its coordinating atom oxygen atom is a hard base, it is suitable for hard acid type The affinity of metal ions is higher, and its bidentate ligand (Deferiprone) has been used to treat diseases related to iron excess (such as thalassemia, etc.), and its hexadentate ligand has a higher affinity to metal ions than The bidentate ligands are much higher, so some trivalent metal complexes of 3-hydroxypyridin-4-one hexadentate ligands have high stability, and some metals, such as gadolinium, can form 8 coordination bonds, with After the coordination of the hexadentate ligand, there are still two positions that can coordinate with water molecules, which is beneficial to improve the relaxation rate of the complex. By changing the substituents (R ₁ and R ₂ ) on 3-hydroxypyridin-4-one, the hydrophilic property of the molecule can be changed, so the gadolinium complexes of 3-hydroxypyridin-4-one hexadentate ligands are a class of A magnetic resonance imaging contrast agent with development prospects can be used in magnetic resonance imaging analysis, X-ray imaging analysis and ultrasonic imaging analysis.

In summary, a magnetic resonance contrast agent 3-hydroxypyridin-4-one hexadentate ligand of the present invention has the advantages of high stability, less toxic and side effects on human tissues, high relaxation rate, and good water solubility, and The preparation method is simple and easy to operate.

Detailed ways

Below in conjunction with embodiment the present invention is described in further detail.

Example 1

A magnetic resonance imaging contrast agent, the magnetic resonance imaging contrast agent is 3-hydroxypyridin-4-one obtained by coordination of 3-hydroxypyridin-4-one hexadentate ligand and paramagnetic metal ion in a molar ratio of 1:1 A metal complex of a hexadentate ligand, the metal complex has the following general structural formula:

The structure of the 3-hydroxypyridin-4-one hexadentate ligand is as follows:

Wherein R ₁ =H, CH ₃ ; R ₂ =H, C _1-3 hydrocarbon group, (CH ₂ ) _2-6 OH, (CH ₂ ) _2-6 OCH ₃ , (CH ₂ CH ₂ O) _1-3 H; n=1-3; Y is a trivalent group, its structure is as follows:

M is a paramagnetic metal ion Fe, La, Eu, Gd or Dy.

The preparation method of the magnetic resonance imaging contrast agent specifically includes the following steps:

(1) Preparation of benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand

Mix tricarboxylic acid with benzyl-protected 3-hydroxypyridin-4-one bidentate ligand containing free amino group, 1,3-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and dissolve in In N,N-dimethylformamide, the obtained first mixed solution was stirred at room temperature for at least 2 days and then filtered, the upper layer filtrate was taken, the filtrate was concentrated under reduced pressure to remove the solvent, and the obtained concentrate was passed through a silica gel column Chromatographic separation and purification yielded a white solid, namely benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand;

(2) Preparation of 3-hydroxypyridin-4-one hexadentate ligand

After dissolving the benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand obtained in step (1) in methanol, add palladium carbon and concentrated hydrochloric acid to obtain a second mixed solution, and react in hydrogen at a pressure of 4.2mPa for 3 Hours later, filter and evaporate, remove the solvent in the second mixed solution to obtain a solid residue, add methanol to the solid residue until the solid residue is completely dissolved, then add acetone until the precipitate no longer separates out, and collect the precipitate , the precipitate was vacuum-dried to obtain a white powder product, namely -3-hydroxypyridin-4-one hexadentate ligand;

(3) Preparation of metal complexes of 3-hydroxypyridin-4-one hexadentate ligands

The 3-hydroxypyridin-4-one hexadentate ligand obtained in step (2) is coordinated with the paramagnetic metal ion in a molar ratio of 1:1 to obtain the metal coordination of the 3-hydroxypyridin-4-one hexadentate ligand The substance is the magnetic resonance imaging contrast agent.

Example 2

The preparation of the gadolinium complex of the 3-hydroxypyridin-4-one hexadentate ligand specifically comprises the following steps:

(1) Nitrilotriacetic acid (0.382g, 2mmol), 2-aminomethyl-3-benzyloxy-1,6-dimethylpyridin-4 (1 hydrogen)-one (1.78g, 6.9mmol) , 1,3-dicyclohexylcarbodiimide (1.42g, 6.9mmol), 1-hydroxybenzotriazole (0.93g, 6.9mmol) was dissolved in N,N-dimethylformamide (20mL) The first mixed solution was obtained, and the first mixed solution was stirred at room temperature for 2 days and then filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography using MeOH/CH ₂ Cl ₂ (volume ratio 1.5:8.5) as mobile phase Purified to obtain a white solid (1.8g), namely benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand (1a), the structure is as follows

The nuclear magnetic resonance spectra were measured on a Bruker Avance400 nuclear magnetic resonance instrument, using tetramethylsilane as an internal standard, and the unit of chemical shift (δ) was ppm. ESI mass spectra were determined on a Q4000 mass spectrometer. ¹ H NMR (DMSO-d ₆ , 400MHz) δ2.22(s, CH ₃ , 9H), 3.30(s, CH ₂ , 6H), 3.34(s, CH ₃ , 9H), 4.35(d, J=5.0 Hz, CH ₂ , 6H), 5.07(s, CH ₂ , 6H), 6.18(s, Pyridinone 5C-H, 3H), 7.29-7.35(m, Ph, 9H), 7.42(m, Ph, 6H), 8.39 (t, J=5.0Hz, NH, 3H); ¹³ C NMR (DMSO-d ₆ ) δ20.0 (CH ₃ ), 34.1 (NHCH ₂ -pyridone), 35.6 (NCH ₃ ), 57.4 (NCH ₂ CO), 72.1 (CH ₂ Ph), 117.4 (pyridone C-5H), 127.7 (CH in Ph), 128.1 (CH in Ph), 128.3 (CH in Ph), 1376 (C inPh), 140.0 (pyridone C-2), 145.6 (pyridone C-3), 147.7 (pyridone C-6), 170.5 (pyridone C-4), 171.9 (CONH). ESI-MS: m/z 912 ([M+H] ⁺ ).

(2) Dissolve the 3-hydroxypyridin-4-one hexadentate ligand 1a (1.75g) of benzyl protection in methanol (40mL), add 5% palladium on carbon (0.35g) and 1.5mL of concentrated hydrochloric acid, under pressure React in a hydrogen atmosphere of 4.2mPa for 3 hours, filter and evaporate, remove the solvent in the second mixed solution to obtain a solid residue, add methanol to the solid residue until the solid residue is completely dissolved, then add acetone until the precipitate no longer separates out , collect the precipitate, and vacuum-dry the precipitate to obtain a white powder product, namely -3-hydroxypyridin-4-one hexadentate ligand, with the following structure;

The nuclear magnetic resonance spectra were measured on a Bruker Avance400 nuclear magnetic resonance instrument, using tetramethylsilane as an internal standard, and the unit of chemical shift (δ) was ppm. ESI mass spectra were determined on a Q4000 mass spectrometer. ¹ H NMR (DMSO-d ₆ ) 2.55 (s, CH ₃ , 9H), 3.55 (br, CH ₂ , 6H), 3.85 (s, CH ₃ , 9H), 4.62 (d, J=4.5Hz, CH ₂ , 6H), 7.33(s, Pyridinone 5C-H, 3H), 9.29(br, NH, 3H); 10.70(br, 1H, HN ⁺ ); ¹³ CNMR(DMSO-d ₆ )δ20.6(CH ₃ ) , 34.6 (NHCH ₂ -pyridinone), 39.3 (NCH ₃ ), 56.8 (NCH ₂ CO), 112.6 (pyridinone C-5H), 139.4 (pyridinone C-2), 142.6 (pyridinone C-3), 148.3 (Pyridone C-6), 159.3 (Pyridone C-4), 211.0 (CONH).ESI-MS: m/z 642 ([M+H] ⁺ ); HRMS: C ₃₀ H ₄₀ N ₇ O ₉ ( [M+H] ⁺ ) Calculated 642.2886, found 642.2883.

(3) Dissolve 3-hydroxypyridin-4-one hexadentate ligand 1b (0.201g, 0.254mmol) in methanol (5mL) and water (5mL), add GdCl ₃ ·6H ₂ O (0.094g, 0.254mmol) , then added pyridine (0.281g, 3.556mmol) to obtain the third mixed solution, the third mixed solution was refluxed for 4 hours, the solvent was evaporated to obtain a solid precipitate, the solid precipitate was washed with cold ethanol to obtain a white solid gadolinium complex magnetic The metal complex 1 (0.182g, 90.1%) of the resonance contrast agent 3-hydroxypyridin-4-one hexadentate ligand has the following structure:

ESI mass spectra were determined on a Q4000 mass spectrometer. ESI-MS: m/z 797 ([M+H] ⁺ ). The solubility in water is greater than 100 mg/mL, and the longitudinal relaxation rate r1 is 7.3 (mM·s) ^-1 , which is 3.8 (mM·s) ^-1 compared with the existing magnetic resonance imaging contrast agent Gd-DTPA (Magnevist, Magnevist) 1.9 times higher than that.

Example 3

The preparation of the gadolinium complex of the 3-hydroxypyridin-4-ketone hexadentate ligand specifically comprises the following steps:

(1) 3,3',3"-nitrilotripropionic acid (0.62g, 2.66mmol), 2-aminomethyl-3-benzyloxy-1,6-lutidine-4(1H )-ketone (2.47g, 9.57mmol), 1,3-dicyclohexylcarbodiimide (1.97g, 9.57mmol), 1-hydroxybenzotriazole (1.46g, 9.57mmol) dissolved in N, N - Dimethylformamide (25mL) to obtain the first mixed solution, the first mixed solution was stirred at room temperature for 2 days and then filtered, the filtrate was concentrated under reduced pressure, and the residue was prepared with MeOH/CH ₂ Cl ₂ (1.5:8.5) The mobile phase was separated and purified by silica gel column chromatography to obtain a white solid-benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand 2a (1.9g), the structure of which is as follows:

The nuclear magnetic resonance spectra were measured on a Bruker Avance400 nuclear magnetic resonance instrument, using tetramethylsilane as an internal standard, and the unit of chemical shift (δ) was ppm. ESI mass spectra were determined on a Q4000 mass spectrometer. ¹ HNMR (DMSO-d ₆ ) 2.18 (m, CH ₂ , 6H), 2.25 (s, CH ₃ , 9H), 2.60 (m, CH ₂ , 6H), 3.37 (s, CH ₃ , 9H), 4.33 ( d, J=4.9Hz, CH ₂ , 6H), 5.07(s, CH ₂ , 6H), 6.17(s, pyridone 5C-H, 3H), 7.28-7.36(m, Ph, 9H), 7.42(m , Ph, 6H), 8.13 (t, J=4.9Hz, NH, 3H); ¹³ C NMR (DMSO-d ₆ ) δ20.0 (CH ₃ ), 32.8 (NCH ₂ CH ₂ ), 34.3 (NHCH ₂ - pyridone), 35.6 (NCH ₃ ), 48.9 (NCH ₂ CH ₂ ), 72.2 (CH ₂ Ph), 117.4 (pyridone C-5H), 127.8 (CH in Ph), 128.2 (CH in Ph), 128.3 ( CH in Ph), 137.6 (Cin Ph), 140.3 (C-2 in pyridinone), 145.6 (pyridinone C-3), 147.8 (pyridinone C-6), 171.2 (pyridinone C-4), 172.0 (CONH) .ESI-MS: m/z 954 ([M+H] ⁺ ).

(2) Dissolve the benzyl-protected 3-hydroxypyridin-4-one hexadentate ligand 2a (1.75g) in methanol (40mL), add 5% palladium carbon (0.35g) and 1.5mL of concentrated hydrochloric acid, in The pressure is 4.2mPa, react in hydrogen for 3 hours, filter and evaporate, remove the solvent in the second mixed solution to obtain a solid residue, add methanol to the solid residue until the solid residue is completely dissolved, then add acetone until the precipitate no longer separates out , collect the precipitate, and vacuum-dry the precipitate to obtain a white powder product, namely -3-hydroxypyridin-4-one hexadentate ligand, with the following structure;

The nuclear magnetic resonance spectra were measured on a Bruker Avance400 nuclear magnetic resonance instrument, using tetramethylsilane as an internal standard, and the unit of chemical shift (δ) was ppm. ESI mass spectra were determined on a Q4000 mass spectrometer. ¹ H NMR (DMSO-d ₆ ) 2.58 (s, CH ₃ , 9H), 2.75 (t, J=7.0 Hz, CH ₂ , 6H), 3.28 (m, CH ₂ , 6H), 3.90 (s, CH ₃ , 9H), 4.62(d, J=4.8Hz, CH ₂ , 6H), 7.35(s, pyridone 5C-H, 3H), 9.01(t, J=4.7Hz, NH, 3H), 11.00(br, HN ⁺ , 1H); ¹³ C NMR (DMSO-d ₆ ) δ20.5 (CH ₃ ), 28.8 (NCH ₂ CH ₂ ), 34.5 (NHCH2-pyridone), 39.2 (NCH ₃ ), 48.2 (NCH ₂ CH ₂ ), 112.5 (pyridone C-5H), 139.4 (pyridone C-2), 142.6 (pyridone C-3 pyridone), 148.3 (pyridone C-6), 159.3 (pyridone C-4), 169.3 (CONH). ESI-MS: 684.3 ([M+H] ⁺ ), 342.7 ([M+2H] ²⁺ ); HRMS: Calcd. for C ₃₃ H ₄₆ N ₇ O ₉ ([M+H] ⁺ ) 684.3356, found 684.3320.

(3) Dissolve 3-hydroxypyridin-4-one hexadentate ligand 2b (0.201g, 0.254mmol) in methanol (5mL) and water (5mL), add GdCl ₃ ·6H ₂ O (0.094g, 0.254mmol) , then added pyridine (0.281g, 3.556mmol) to obtain the third mixed solution, the third mixed solution was refluxed for 4 hours, the solvent was evaporated to obtain a solid precipitate, the solid precipitate was washed with cold ethanol to obtain a white solid gadolinium complex magnetic The metal complex 1 (0.182g, 90.1%) of the resonance contrast agent 3-hydroxypyridin-4-one hexadentate ligand has the following structure:

ESI mass spectra were determined on a Q4000 mass spectrometer. ESI-MS: m/z 839 ([M+H] ⁺ ). The solubility in water is greater than 100mg/mL, and the longitudinal relaxation rate r1 is 5.8(mM·s) ^-1 , compared with the existing magnetic resonance imaging contrast agent Gd-DTPA (Magnevist, Magnevist) 3.8(mM·s) ^-1 1.5 times higher than that.

Claims (2)

1. magnetic resonance imaging contrast; It is characterized in that: this magnetic resonance imaging contrast is the metal complex of 3-pyridone-4-ketone sexadentate ligand of being obtained by the coordination of 1:1 mol ratio by 3-pyridone-4-ketone sexadentate ligand and paramagnetic metal ion, and this metal complex has following general structure:

The structure of described 3-pyridone-4-ketone sexadentate ligand is following:

R wherein ₁=CH ₃R ₂=CH ₃N=1-2;

M is paramagnetic metal ion gadolinium Gd.

2. the method for preparing of a magnetic resonance imaging contrast according to claim 1 is characterized in that may further comprise the steps:

(1) preparation of the 3-of benzyl protection pyridone-4-ketone sexadentate ligand

With tricarboxylic acids and the 3-pyridone-4-ketone bidentate ligand, 1 that contains the benzyl protection of free amine group; 3-dicyclohexyl carbon imidodicarbonic diamide, I-hydroxybenzotriazole are dissolved in N after mixing; In the dinethylformamide; First mixed solution that obtains is at room temperature stirred at least 2 days after-filtration, will filtrate and under reduced pressure boil off solvent, the concentrate that obtains is got the 3-pyridone that white solid is a benzyl protection-4-ketone sexadentate ligand through silica gel column chromatography separating purification;

Wherein said tricarboxylic acids is that nitrilotriacetic acid, the described 3-pyridone-4-ketone bidentate ligand that contains the benzyl protection of free amine group are 2-aminomethyl-3-benzyloxy-1; 6-lutidines-4-ketone; Described nitrilotriacetic acid, described 2-aminomethyl-3-benzyloxy-1; 6-lutidines-4-ketone, described 1,3-dicyclohexyl carbon imidodicarbonic diamide and the blended mol ratio of described I-hydroxybenzotriazole are 2:6.9:6.9:6.9; Described nitrilotriacetic acid and described N, the molal volume of dinethylformamide is than being 1mmol: 10mL; The mobile phase of described silicagel column is that methanol mixes by the volume ratio of 1.5:8.5 with dichloromethane; Perhaps described tricarboxylic acids is 3,3 ', 3 "-NTA, the described 3-pyridone-4-ketone bidentate ligand that contains the benzyl protection of free amine group are 2-aminomethyl-3-benzyloxy-1; 6-lutidines-4-ketone; described 3,3 ', 3 "-NTA, described 2-aminomethyl-3-benzyloxy-1; 6-lutidines-4-ketone, described 1,3-dicyclohexyl carbon imidodicarbonic diamide and the blended mol ratio of described I-hydroxybenzotriazole are 2.66:9.57:9.57:9.57; Described 3,3 ', 3 "-and NTA and described N, the molal volume of dinethylformamide is than being 2.66mmol: 25mL; The mobile phase of described silicagel column is that methanol mixes by the volume ratio of 1.5:8.5 with dichloromethane;

(2) preparation of 3-pyridone-4-ketone sexadentate ligand

After the 3-pyridone-4-ketone sexadentate ligand is dissolved in methanol of the benzyl protection that step (1) is obtained; Add palladium carbon and concentrated hydrochloric acid and obtain second mixed solution; At pressure is reaction after 3 hours in the hydrogen atmosphere of 4.2MPa; Filter and evaporation, the solvent of removing in second mixed solution obtains solid residue, after adding methanol to solid residue dissolves fully in described solid residue; Adding acetone to deposition more no longer separates out; The collecting precipitation thing, it is 3-pyridone-4-ketone sexadentate ligand that the precipitate vacuum drying is got the white powder product, the 3-pyridone-4-ketone sexadentate ligand of wherein said benzyl protection and the mass volume ratio of described methanol are 1.75g:40mL; 3-pyridone-4-ketone the sexadentate ligand of described benzyl protection and described palladium carbon mass ratio are 5:1; The volume ratio of described methanol and described concentrated hydrochloric acid is 80:3;

(3) preparation of the metal complex of 3-pyridone-4-ketone sexadentate ligand

3-pyridone-4-ketone sexadentate ligand that step (2) is obtained is dissolved in the first alcohol and water, adds GdCl ₃6H ₂O and pyridine obtain the 3rd mixed liquor; The processing of the 3rd mixed-liquor return after 4 hours, is boiled off solvent and obtains solid sediment, solid sediment is obtained white solid Gd coordination compound 3-pyridone-4-ketone sexadentate ligand with cold washing with alcohol; Be magnetic resonance imaging contrast, structure is following:

R wherein ₁=CH ₃R ₂=CH ₃N=1-2; M is paramagnetic metal ion gadolinium Gd, the mol ratio coordination that described 3-pyridone-4-ketone sexadentate ligand and described paramagnetic metal ion are pressed 1:1.