CN102274529A - Magnetic resonance imaging contrast agent and preparation method thereof - Google Patents
Magnetic resonance imaging contrast agent and preparation method thereof Download PDFInfo
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- CN102274529A CN102274529A CN2011101166744A CN201110116674A CN102274529A CN 102274529 A CN102274529 A CN 102274529A CN 2011101166744 A CN2011101166744 A CN 2011101166744A CN 201110116674 A CN201110116674 A CN 201110116674A CN 102274529 A CN102274529 A CN 102274529A
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Abstract
The invention provides a magnetic resonance imaging contrast agent and a preparation method thereof. The invention is characterized in that: the magnetic resonance imaging contrast agent is a metal complex with 3-hydroxy pyridin-4-one as a hexadentate ligand, which is formed by complexing the 3-hydroxy pyridin-4-one hexadentate ligand and paramagnetic metal ion according to a molar ratio of 1:1; and the preparation method comprises the following preparation steps: preparing the benzyl-protected 3-hydroxy pyridin-4-one hexadentate ligand; and removing benzyl by catalytic hydrogenation to obtain the 3-hydroxy pyridin-4-one hexadentate ligand, and finally complexing the obtained 3-hydroxy pyridin-4-one hexadentate ligand with paramagnetic metal ions according to a molar ratio of 1:1, and thus, obtaining the metal complex of the 3-hydroxy pyridin-4-one hexadentate ligand, namely the magnetic resonance imaging contrast agent. The method has the advantages of high stability, small toxic and side effect on human body tissues, high relaxation rate and high water solubility, and the preparation method is simple and easy to operate.
Description
Technical field
The present invention relates to be used for the magnetic resonance contrast agent of early diagnosis of tumor, especially relate to a kind of magnetic resonance imaging contrast and preparation method thereof.
Background technology
Mr imaging technique (magnetic resonance imaging, MRI) be widely used in the radiography of head, nervous system, abdominal part and the blood vessel of human body, effective especially to detecting tissue necrosis, ischemia and various malignant change, and can carry out early diagnosis, in order to improve the effect of nuclear magnetic resonance, need to use NMR contrast agent usually.Mri contrast agent is that a class can improve the sensitivity of MRI diagnosis and specificity, enhancing signal contrast, and improves the magnetisable material of soft-tissue signal's resolution.
The contrast agent that is used for clinical magnetic resonance imaging at present is mainly the coordination compound of micromolecule gadolinium or manganese: Gd-DTPA (Magnevist, magnevist), Gd-DOTA (Dotarem, many its spirits), Mn-DPDP (Teslascan, safe happy shadow) 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, can not satisfy tissue, organ is requirement optionally, and it is unstable, decompose in vivo easily and discharge virose metal ion, relaxation rate is low, poorly water-soluble.
Summary of the invention
It is high that technical problem to be solved by this invention provides a kind of stability, the relaxation rate height, and good water solubility is to little magnetic resonance contrast agent of the toxic and side effects of tissue and preparation method thereof.
The present invention solves the problems of the technologies described above the technical scheme that is adopted: a kind of magnetic resonance imaging contrast, this magnetic resonance imaging contrast is the metal complex of 3-pyridone-4-ketone sexadentate ligand of being obtained by mol ratio coordination in 1: 1 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 as follows:
R wherein
1=H, CH
3R
2=H, C
1-3Alkyl, (CH
2)
2-6OH, (CH
2)
2-6OCH
3, (CH
2CH
2O)
1-3H; N=1-3; Y is the trivalent group, and its structure is as follows:
M is paramagnetic metal ion Fe, La, Eu, Gd or Dy.
Described paramagnetic metal ion is gadolinium Gd.
A kind of preparation method of magnetic resonance imaging contrast 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, filtrate is under reduced pressure boiled 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;
(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 precipitation more no longer separates out, the collecting precipitation thing, with the precipitate vacuum drying get the white powder product promptly-3-pyridone-4-ketone sexadentate ligand;
(3) preparation of the metal complex of 3-pyridone-4-ketone sexadentate ligand
3-pyridone-4-ketone sexadentate ligand that step (2) is obtained with the mol ratio coordination of paramagnetic metal ion by 1: 1, obtain the metal complex of 3-pyridone-4-ketone sexadentate ligand, i.e. magnetic resonance imaging contrast, structure is as follows:
R wherein
1=H, CH
3R
2=H, C
1-3Alkyl, (CH
2)
2-6OH, (CH
2)
2-6OCH
3, (CH
2CH
2O)
1-3H; N=1-3; Y is the trivalent group, and its structure is as follows:
M＝Fe、La、Eu、Gd、Dy。
Described 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 1.5: 8.5 volume ratio with dichloromethane.
Described tricarboxylic acids is 3,3 '; 3 "-nitrilotriacetic acid(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 "-and nitrilotriacetic acid(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 nitrilotriacetic acid 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 1.5: 8.5 volume ratio with dichloromethane.
3-pyridone-4-ketone the sexadentate ligand of described 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-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, and the processing of the 3rd mixed-liquor return after 4 hours, is boiled off solvent and obtains solid sediment, and it is magnetic resonance imaging contrast that solid sediment is obtained the white solid Gd coordination compound with cold washing with alcohol, and structure is as follows:
N=1,2 wherein.
Compared with prior art, the invention has the advantages that: 3-pyridone-4-ketone is the chelating agen that a class has wide application prospects clinically, because its coordination atom oxygen atom is a hard base, affinity to the metal ion of hard acid type is higher, its bidentate ligand (Deferiprone) has been used to treat the disease too much relevant with ferrum (as thalassemia etc.), its sexadentate ligand is more much higher than bidentate ligand to the affinity of metal ion, therefore some trivalent metal coordination compounds of 3-pyridone-4-ketone sexadentate ligand have very high stability, and some metal, can form 8 coordinate bonds as gadolinium, after the sexadentate ligand coordination, also have 2 positions can with the hydrone coordination, help improving the relaxation rate of coordination compound.By changing the substituent group (R on 3-pyridone-4-ketone
1And R
2), can change the hydrophilicity of molecule, so the Gd coordination compound of 3-pyridone-4-ketone sexadentate ligand is the magnetic resonance imaging contrast that a class has DEVELOPMENT PROSPECT, can be used for magnetic resonance imaging analysis, the analysis of X-radial imaging and ultrasonic imaging analysis.
In sum, it is high that a kind of magnetic resonance contrast agent 3-pyridone of the present invention-4-ketone sexadentate ligand has stability, little to the toxic and side effects of tissue, the relaxation rate height, and the advantage of good water solubility, and preparation method is simple, and easy to operate.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail.
Embodiment 1
A kind of magnetic resonance imaging contrast, the metal complex of 3-pyridone-4-ketone sexadentate ligand that this magnetic resonance imaging contrast obtains by mol ratio coordination in 1: 1 with 3-pyridone-4-ketone sexadentate ligand and paramagnetic metal ion, this metal complex has following general structure:
The structure of described 3-pyridone-4-ketone sexadentate ligand is as follows:
R wherein
1=H, CH
3R
2=H, C
1-3Alkyl, (CH
2)
2-6OH, (CH
2)
2-6OCH
3, (CH
2CH
2O)
1-3H; N=1-3; Y is the trivalent group, and its structure is as follows:
M is paramagnetic metal ion Fe, La, Eu, Gd or Dy.
The preparation method of this magnetic resonance imaging contrast specifically comprises 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, get upper strata filtrate, filtrate under reduced pressure concentrated 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;
(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 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 precipitation more no longer separates out, the collecting precipitation thing, with the precipitate vacuum drying get the white powder product promptly-3-pyridone-4-ketone sexadentate ligand;
(3) preparation of the metal complex of 3-pyridone-4-ketone sexadentate ligand
3-pyridone-4-ketone sexadentate ligand that step (2) is obtained and paramagnetic metal ion were by 1: 1 mol ratio coordination, and the metal complex that obtains 3-pyridone-4-ketone sexadentate ligand is a magnetic resonance imaging contrast.
Embodiment 2
The preparation of the Gd coordination compound of 3-pyridone-4-ketone sexadentate ligand specifically may further comprise the steps:
(1) with nitrilotriacetic acid (0.382g, 2mmol), 2-aminomethyl-3-benzyloxy-1,6-lutidines-4 (1 hydrogen)-ketone (1.78g, 6.9mmol), 1,3-dicyclohexyl carbon imidodicarbonic diamide (1.42g, 6.9mmol), (0.93g 6.9mmol) is dissolved in N to I-hydroxybenzotriazole, obtain first mixed solution in the dinethylformamide (20mL), at 2 days after-filtration of stirring at room, filtrate under reduced pressure concentrates, residue MeOH/CH with first mixed solution
2Cl
2(volume ratio 1.5: 8.5) made mobile phase and got white solid (1.8g) through silica gel column chromatography separating purification, i.e. the 3-of benzyl protection pyridone-4-ketone sexadentate ligand (1a), and structure is as follows
Nuclear magnetic resonance map records on Bruker Avance400 nuclear magnetic resonance analyser, and as interior mark, the unit of chemical shift (δ) is ppm with tetramethylsilane.The ESI mass spectrum is measured on the Q4000 mass spectrograph.
1H NMR (DMSO-d
6, 400MHz) δ 2.22 (s, CH
3, 9H), 3.30 (s, CH
2, 6H), 3.34 (s, CH
3, 9H), 4.35 (d, J=5.0Hz, 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);
13C NMR (DMSO-d
6) δ 20.0 (CH
3), 34.1 (NHCH
2-pyridone), 35.6 (NCH
3), 57.4 (NCH
2CO), 72.1 (CH
2Ph), 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) the 3-pyridone-4-ketone sexadentate ligand 1a (1.75g) with benzyl protection is dissolved in methanol (40mL), the concentrated hydrochloric acid that adds 5% palladium carbon (0.35g) and 1.5mL, at pressure is to react 3 hours in the 4.2mPa hydrogen atmosphere, filter and evaporation, the solvent of removing in second mixed solution obtains solid residue, after adding methanol to solid residue dissolves fully in solid residue, adding acetone to precipitation more no longer separates out, the collecting precipitation thing, it is-3-pyridone-4-ketone sexadentate ligand that structure is as follows that the precipitate vacuum drying is got the white powder product;
Nuclear magnetic resonance map records on Bruker Avance400 nuclear magnetic resonance analyser, and as interior mark, the unit of chemical shift (δ) is ppm with tetramethylsilane.The ESI mass spectrum is measured on the Q4000 mass spectrograph.
1H 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
+);
13CNMR (DMSO-d
6) δ 20.6 (CH
3), 34.6 (NHCH
2-pyridinone), 39.3 (NCH
3), 56.8 (NCH
2CO), 112.6 (pyridone C-5H), 139.4 (pyridone C-2), 142.6 (pyridone C-3), 148.3 (pyridone C-6), 159.3 (pyridone C-4), 211.0 (CONH) .ESI-MS:m/z, 642 ([M+H]
+); HRMS:C
30H
40N
7O
9([M+H]
+) value of calculation 642.2886, measured value 642.2883.
(3) (0.201g 0.254mmol) is dissolved in methanol (5mL) and water (5mL), adds GdCl with 3-pyridone-4-ketone sexadentate ligand 1b
36H
2O (0.094g, 0.254mmol), add pyridine (0.281g again, 3.556mmol) obtain the 3rd mixed solution, with the 3rd mixed solution reflow treatment 4 hours, boil off solvent and obtain solid sediment, solid sediment is obtained the metal complex 1 (0.182g of white solid Gd coordination compound magnetic resonance contrast agent 3-pyridone-4-ketone sexadentate ligand with cold washing with alcohol, 90.1%), structure is as follows:
The ESI mass spectrum is measured on the Q4000 mass spectrograph.ESI-MS：m/z?797([M+H]
+)。Dissolubility in water is greater than 100mg/mL, and longitudinal relaxation rate r1 is 7.3 (mMs)
-1, with existing magnetic resonance imaging contrast Gd-DTPA (Magnevist, magnevist) 3.8 (mMs)
-1Compare and improved 1.9 times.
Embodiment 3
The preparation of the Gd coordination compound of 3-pyridone-4-ketone sexadentate ligand specifically comprises the steps:
(1) with 3,3 ', 3 "-nitrilo-three propanoic acid (0.62g; 2.66mmol), 2-aminomethyl-3-benzyloxy-1,6-lutidines-4 (1H)-ketone (2.47g; 9.57mmol), 1, (1.97g; 9.57mmol), (1.46g 9.57mmol) is dissolved in N to I-hydroxybenzotriazole to 3-dicyclohexyl carbon imidodicarbonic diamide; obtain first mixed solution in the dinethylformamide (25mL); at 2 days after-filtration of stirring at room, filtrate under reduced pressure concentrates, residue MeOH/CH with first mixed solution
2Cl
2(1.5: 8.5) are made mobile phase and are got the 3-pyridone-4-ketone sexadentate ligand 2a (1.9g) of white solid-benzyl protection through silica gel column chromatography separating purification, and structure is as follows:
Nuclear magnetic resonance map records on Bruker Avance400 nuclear magnetic resonance analyser, and as interior mark, the unit of chemical shift (δ) is ppm with tetramethylsilane.The ESI mass spectrum is measured on the Q4000 mass spectrograph.
1HNMR (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);
13C NMR (DMSO-d
6) δ 20.0 (CH
3), 32.8 (NCH
2CH
2), 34.3 (NHCH
2-pyridone), 35.6 (NCH
3), 48.9 (NCH
2CH
2), 72.2 (CH
2Ph), (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-2in pyridinone), 145.6 (pyridone C-3), 147.8 (pyridone C-6), (171.2 pyridone C-4), 172.0 (CONH) .ESI-MS:m/z, 954 ([M+H]
+).
(2) the 3-pyridone-4-ketone sexadentate ligand 2a (1.75g) with benzyl protection is dissolved in methanol (40mL), the concentrated hydrochloric acid that adds 5% palladium carbon (0.35g) and 1.5mL, be to react 3 hours in the 4.2mPa hydrogen at pressure, filter and evaporation, the solvent of removing in second mixed solution obtains solid residue, after adding methanol to solid residue dissolves fully in solid residue, adding acetone to precipitation more no longer separates out, the collecting precipitation thing, it is-3-pyridone-4-ketone sexadentate ligand that structure is as follows that the precipitate vacuum drying is got the white powder product;
Nuclear magnetic resonance map records on Bruker Avance400 nuclear magnetic resonance analyser, and as interior mark, the unit of chemical shift (δ) is ppm with tetramethylsilane.The ESI mass spectrum is measured on the Q4000 mass spectrograph.
1H NMR (DMSO-d
6) 2.58 (s, CH
3, 9H), 2.75 (t, J=7.0Hz, 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);
13C NMR (DMSO-d
6) δ 20.5 (CH
3), 28.8 (NCH
2CH
2), 34.5 (NHCH2-pyridones), 39.2 (NCH
3), 48.2 (NCH
2CH
2), 112.5 (pyridone C-5H), 139.4 (pyridone C-2), 142.6 (pyridone C-3 pyridones), 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:C
33H
46N
7O
9([M+H]
+) value of calculation 684.3356, measured value 684.3320.
(3) (0.201g 0.254mmol) is dissolved in methanol (5mL) and water (5mL), adds GdCl with 3-pyridone-4-ketone sexadentate ligand 2b
36H
2O (0.094g, 0.254mmol), add pyridine (0.281g again, 3.556mmol) obtain the 3rd mixed solution, with the 3rd mixed solution reflow treatment 4 hours, boil off solvent and obtain solid sediment, solid sediment is obtained the metal complex 1 (0.182g of white solid Gd coordination compound magnetic resonance contrast agent 3-pyridone-4-ketone sexadentate ligand with cold washing with alcohol, 90.1%), structure is as follows:
The ESI mass spectrum is measured on the Q4000 mass spectrograph.ESI-MS：m/z?839([M+H]
+)。Dissolubility in water is greater than 100mg/mL, and longitudinal relaxation rate r1 is 5.8 (mMs)
-1, with existing magnetic resonance imaging contrast Gd-DTPA (Magnevist, magnevist) 3.8 (mMs)
-1Compare and improved 1.5 times.
Claims (7)
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 mol ratio coordination in 1: 1 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 as follows:
R wherein
1=H, CH
3R
2=H, C
1-3Alkyl, (CH
2)
2-6OH, (CH
2)
2-6OCH
3, (CH
2CH
2O)
1-3H; N=1-3; Y is the trivalent group, and its structure is as follows:
M is paramagnetic metal ion Fe, La, Eu, Gd or Dy.
2. a kind of magnetic resonance imaging contrast according to claim 1 is characterized in that: described paramagnetic metal ion is gadolinium Gd.
3. the preparation method 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, filtrate is under reduced pressure boiled 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;
(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 precipitation more no longer separates out, the collecting precipitation thing, with the precipitate vacuum drying get the white powder product promptly-3-pyridone-4-ketone sexadentate ligand;
(3) preparation of the metal complex of 3-pyridone-4-ketone sexadentate ligand
3-pyridone-4-ketone sexadentate ligand that step (2) is obtained with the mol ratio coordination of paramagnetic metal ion by 1: 1, obtain the metal complex of 3-pyridone-4-ketone sexadentate ligand, i.e. magnetic resonance imaging contrast, structure is as follows:
R wherein
1=H, CH
3R
2=H, C
1-3Alkyl, (CH
2)
2-6OH, (CH
2)
2-6OCH
3, (CH
2CH
2O)
1-3H; N=1-3; Y is the trivalent group, and its structure is as follows:
M＝Fe、La、Eu、Gd、Dy。
4. the preparation method of a kind of magnetic resonance imaging contrast according to claim 3, it is characterized in that: described 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 1.5: 8.5 volume ratio with dichloromethane.
5. the preparation method of a kind of magnetic resonance imaging contrast according to claim 3, it is characterized in that: described tricarboxylic acids is 3,3 '; 3 "-nitrilotriacetic acid(NTA), the described 3-pyridone-4-ketone bidentate ligand that contains the benzyl protection of free amine group is 2-aminomethyl-3-benzyloxy-1,6-lutidines-4-ketone, described 3,3 '; 3 "-nitrilotriacetic acid(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 nitrilotriacetic acid 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 1.5: 8.5 volume ratio with dichloromethane.
6. the preparation method of a kind of magnetic resonance imaging contrast according to claim 3, it is characterized in that: the 3-pyridone-4-ketone sexadentate ligand of described 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.
7. according to the preparation method of each described a kind of magnetic resonance imaging contrast in the claim 3 to 6, it is characterized in that: 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, and the processing of the 3rd mixed-liquor return after 4 hours, is boiled off solvent and obtains solid sediment, and it is magnetic resonance imaging contrast that solid sediment is obtained the white solid Gd coordination compound with cold washing with alcohol, and structure is as follows:
N=1,2 wherein.
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| CN101433726A (en) * | 2008-12-18 | 2009-05-20 | 复旦大学 | Magnetic resonance contrast agent based on carbon nano-tube and preparation method |
| CN101642579A (en) * | 2009-08-14 | 2010-02-10 | 江苏大学 | Chitosan modified paramagnetic metal ion magnetic resonance imaging contrast agent preparation method |
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| CN101433726A (en) * | 2008-12-18 | 2009-05-20 | 复旦大学 | Magnetic resonance contrast agent based on carbon nano-tube and preparation method |
| CN101642579A (en) * | 2009-08-14 | 2010-02-10 | 江苏大学 | Chitosan modified paramagnetic metal ion magnetic resonance imaging contrast agent preparation method |
Non-Patent Citations (1)
| Title |
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| 谢晨 等: "高分子钆配合物磁共振造影剂的研究进展", 《离子交换与吸附》, vol. 26, no. 2, 30 April 2010 (2010-04-30), pages 280 - 288 * |
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