CN102727911B - Diamino polyethylene glycol modified paramagnetic metal complex magnetic resonance imaging contrast agent - Google Patents
Diamino polyethylene glycol modified paramagnetic metal complex magnetic resonance imaging contrast agent Download PDFInfo
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- CN102727911B CN102727911B CN 201210234612 CN201210234612A CN102727911B CN 102727911 B CN102727911 B CN 102727911B CN 201210234612 CN201210234612 CN 201210234612 CN 201210234612 A CN201210234612 A CN 201210234612A CN 102727911 B CN102727911 B CN 102727911B
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Abstract
The invention provides a diamino polyethylene glycol modified paramagnetic metal complex magnetic resonance imaging contrast agent, and aims at solving the problems of low relaxation rate, high toxicity and large dosage of a contrast agent in the prior art. The contrast agent is prepared by the following steps: reacting 1,4,7,10-tetrazacyclododecane-1,4,7,10-tetraacetic acid compound with diamino polyethylene glycol with different molecular weights; preparing a macromolecular ligand through an amidation reaction; and forming a paramagnetic metal complex with paramagnetic metal elements Sc, Ti, V, Mn, Cu, Mo, Ru, Fe or positive trivalent or divalent ion of lanthanide rare-earth elements. The contrast agent has the advantages of high stability, water solubility, relaxation rate and small dosage.
Description
Technical field
The present invention relates to magnetic resonance imaging contrast, more particularly, relate to a kind of two amino polyethyleneglycol modified paramagnetic metal complex magnetic resonance imaging contrast.
Background technology
(Magnetic Resonance Imaging is a kind ofly to have than high safety factor higher resolution, the medical diagnosis technology that can carry out the tomography surface sweeping from each orientation MRI) in nuclear magnetic resonance.Nowadays, this technology has been made bigger contribution on clinical medicine.In order to make some comparatively complicated diseases obtain definite diagnosis, about 30～40% magnetic resonant imaging examination need use contrast agent.Check that on clinical medicine the magnetic resonance contrast agent that uses can improve image contrast, imaging definition and soft tissue resolution, tissue sensitivity's degree.
At present, the magnetic resonance contrast agent that clinical medicine uses is less as the molecular dimension of many its spirits, magnevist etc., and it is very fast to see through the capillary tube speed ratio, and the speed of rotation of molecule is higher, and relaxation efficient is lower, and dosage is bigger, and the medicine frequency of injection is higher, and toxicity is bigger.With micromolecule contrast agent macromoleization is the important research direction of magnetic resonance imaging contrast in the world.In the last few years, magnetic resonance imaging contrast mainly is devoted to diethylenetriamine pentaacetic acid (Diethylenetriaminepentaacetic acid, hereinafter to be referred as DTPA) with 1,4,7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid is hereinafter to be referred as DOTA) carry out chemical modification, make various types of contrast agent, with micromolecule contrast agent Gd-DOTA, Gd-DTPA introduces the macromolecule of synthetic or natural macromole, as the macromolecular paramagnetic metal complex contrast agent that polysaccharide or Polyethylene Glycol and derivant thereof etc. form, relaxation efficient height, good water solubility, toxicity is low, and dosage is little.In recent years, because Polyethylene Glycol and derivant good water solubility thereof, immunogenicity is low, and toxicity is low, usually self advantage is imparted in the molecule after the modification, usually is widely used in doing pharmaceutical carrier in biological and the clinical medicine domain.According to existing bibliographical information (polylactic acid and the research of poly ethyldiol modified polylactic acid external degradation, Third Military Medical University's journal, 2002,24 (8): 995-996) Polyethylene Glycol is introduced in the polylactic acid, improved the hydrophilic of polylactic acid, improved drug compatibility, can become protein, aminoacid, nucleic acid, the bio-carrier that polypeptide etc. are good.
Summary of the invention
The objective of the invention is that prior art contrast agent relaxation rate is low in order to solve, high toxicity and the big problem of dosage, and provide a kind of two amino polyethyleneglycol modified paramagnetic metal complex magnetic resonance imaging contrast.
The paramagnetic metal complex magnetic resonance imaging contrast that two amino are polyethyleneglycol modified, be two molecule 1s, 4,7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl chemical compound is connected to form two amino polyethyleneglycol modified DOTA macromolecular ligands by amido link and the two amino Polyethylene Glycol macromole of a part; Then with this macromolecular ligand and paramagnetic metal element S c, Ti, V, Mn, Cu, Mo, Ru, Fe or lanthanide series rare-earth elements+2 or+3 valency ions cooperate by the 1:2 mol ratio and obtain, its structural formula is as follows:
Wherein the mean molecule quantity of two amino Polyethylene Glycol is 2000,4000,5000,6000,8000,10000,20000,50000 or 100000, i.e. n=44,89,112,135,180,226,453,1135 or 2271;
M
M+Be paramagnetic metal ion, be paramagnetic metal element S c, Ti, V, Mn, Cu, Mo, Ru, Fe and lanthanide series rare-earth elements+2 or+3 valency ions; Be preferably lanthanide series rare-earth elements+2 or+3 valency ions; More preferably paramagnetic metal ion is Gd
3+, Tb
3+, Dy
3+, Nd
3+Most preferably being paramagnetic metal ion is Gd
3+
M is the quantivalence of paramagnetic metal ion, m=2 or 3;
During m=2, R
1For-COOH; During m=3, R
1For-COO
-
Contained two amino polyethyleneglycol modified DOTA macromolecular ligand in described two amino polyethyleneglycol modified paramagnetic metal complex magnetic resonance imaging contrast, its structural formula is as follows:
Wherein the mean molecule quantity of two amino Polyethylene Glycol is 2000,4000,5000,6000,8000,10000,20000,50000 or 100000, i.e. n=44,89,112,135,180,226,453,1135 or 2271.
The synthetic method and the step of the paramagnetic metal complex magnetic resonance imaging contrast that two amino are polyethyleneglycol modified are as follows:
(1) with 1,4,7,10-tetraazacyclododecanand-1,4,7, after 10-tetraacethyl (DOTA) is dissolved in deionized water, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) and the inferior amide (S-NHS) of N-hydroxyl sulfo-succinum, EDCHCl, S-NHS respectively at 5 ℃, the mass ratio of DOTA is 2:3:3, regulate pH=6.0, stir 50min, obtain the active ester of DOTA.
(2) under 5 ℃ of conditions, two amino Polyethylene Glycol are dissolved in water, regulating pH with NaOH is 7.5 ~ 8.5, slowly is added drop-wise in the active ester of DOTA, and the active ester of DOTA is 8:1 with the mass ratio of two amino Polyethylene Glycol, stirred 30 hours down at 20 ℃, dialysis concentrates lyophilizing, obtain two amino polyethyleneglycol modified DOTA macromolecular ligands, structural formula is as follows:
Wherein the mean molecule quantity of two amino Polyethylene Glycol is 2000,4000,5000,6000,8000,10000,20000,50000 or 100000, i.e. n=44,89,112,135,180,226,453,1135 or 2271.
(3) 20 ℃ down will on synthetic macromolecular ligand of step and metallic element Sc, Ti, V, Mn, Cu, Mo, Ru, Fe or lanthanide series rare-earth elements+2 or+3 valency ions are dissolved in the water respectively, regulating pH with NaOH is 6.0, the amount of substance of DOTA is than being 1.3:1 in above-mentioned metal ion and the polyethyleneglycol modified DOTA macromolecular ligand of two amino, stirred 30 hours down at 20 ℃, dialysis, concentrate, lyophilizing obtains two amino polyethyleneglycol modified paramagnetic metal complexes.
Two amino polyethyleneglycol modified paramagnetic metal complex magnetic resonance imaging contrast among the present invention can be prepared into injection.According to the carrier of stipulating on the Pharmacopoeia of the People's Republic of China as: paramagnetic metal complex or the salt that two amino are polyethyleneglycol modified such as glucose injection, sodium chloride injection, distilled water are prepared into the solution that concentration is 0.5mol/L.Electrically charged with its institute of paramagnetic metal complex balance that lithotroph alkali aminoacid or ammonia, sodium hydroxide, sodium carbonate, sodium bicarbonate, slow blood amine, N-first class dextran amine etc. are non-vanishing with total electrical charge, and with pH regulator to 7.5.In general, in pharmaceutical preparation, add the salt of the macromolecule complex physiological compatibility that the arabinogalactan of the two amino polyethyleneglycol modified macromolecule complex of the salt of the polyethyleneglycol modified macromolecule complex physiological compatibility of the two amino polyethyleneglycol modified macromolecular ligand of the 0.1-15% be equivalent to two amino polyethyleneglycol modified paramagnetic metal complex quality or two amino or calcium, magnesium, copper, zinc or calcium, magnesium, copper, zinc modifies, guarantee paramagnetic metal ion such as Gd
3+Coordination fully with it.
Another kind of way with paramagnetic metal element S c, Ti, V, Mn, Cu, Mo, Ru, Fe or lanthanide series rare-earth elements+2 or+other required compositions such as the salt of the coordination compound of the macromolecular ligand of 3 valency ions and the 0.1-15% that is equivalent to paramagnetic metal complex weight or its salt or calcium, magnesium, copper, zinc or the physiological compatibility of these coordination compounds, pH regulator agent, antioxidant are mixed with dried solid preparation, just powder pin or injectable powder are diluted to desired concn with carriers such as sodium chloride injection or distilled water before using.
Contrast agent of the present invention can use according to conventional method, and this method comprises bestows diagnosis object such as human body or other mammalian body paramagnetic metal complex, carries out magnetic resonance imaging analysis then, draws enhanced nuclear magnetic resonance figure.The dosage of contrast agent 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 diagnostic device type different, generally, the injection consumption is the people of diagnosis main body or every kg body weight 0.001 to 5.0mmol of other mammalian body, and the selection of best concentration range is 0.05 to 0.5mmol.
Two amino polyethyleneglycol modified paramagnetic metal complex magnetic resonance imaging contrast among the present invention can also form heavy metal complex with heavy metal ion such as bismuth, lead, gold etc., is used for ultrasonic imaging or X-ray CT, PET or forms the contrast agent of radiometal complex as radiotherapy medicine or scintillography with radioactive metal ion.
Two amino polyethyleneglycol modified paramagnetic metal complex magnetic resonance imaging contrast of the present invention is compared with many its spirits of wide clinical application, and this class contrast agent has following advantage:
(1) this type of contrast agent molecule amount increases, and body internal rotation speed is low, relaxation rate height (7.4 ~ 7.8mmol
-1Ls
-1), with the relaxation rate (4.2mmol that is widely used in clinical many its spirits
-1Ls
-1) compare, be about 1.9 times of many its spirits;
(2) have good water solublity, be easy to be mixed with the intravenous injection of desired concn solution;
(3) aqueous stability is suitable for the pressure sintering sterilization;
(4) toxicity is low, because Polyethylene Glycol and derivant good water solubility thereof, immunogenicity is low, the characteristics that toxicity is low, and usually self advantage is imparted in the molecule after the modification, so the present invention has good water solubility with the contrast agent that two amino polyethyleneglycol modified paramagnetic metal complexes obtain, immunogenicity is low, the characteristics that toxicity is low;
(5) this contrast agent is a macromolecular contrast agent, and molecular dimension is bigger, and retention time is long in vivo, and the speed of rotation of molecule is lower, and relaxation rate is higher, and dosage is less.
The specific embodiment
Embodiment 1
The preparation of (Gd-DOTA) gadolinium paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 2000 molecular weight (2KDa) are polyethyleneglycol modified
(1) 3g DOTA is dissolved in the 25mL deionized water, under 5 ° of C conditions, add the inferior amide of 2g1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and 3g N-hydroxyl sulfo-succinum, regulate pH=6.0 with NaOH, mixture is stirred 50min, obtain DOTA active ester solution;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3g2000 molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=7.5 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L GdCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned GdCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the amount of substance of middle metal gadolinium ion is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Gd-DOTA) gadolinium paramagnetic metal complexes.On nuclear magnetic resonance analyser, measure its relaxation time T with the inversion recovery method
1, can obtain couple relaxation rate r of amino polyethyleneglycol modified (Gd-DOTA) gadolinium paramagnetic metal complex
1Be 7.8mmol
-1Ls
-1
Embodiment 2
The preparation of (Cu-DOTA) copper paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 2000 molecular weight (2KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3g2000 molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.0 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L CuCl that obtain in 3g(2)
2Solution is dissolved in respectively in the water, amount of substance and the above-mentioned CuCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
2The ratio of the amount of substance of middle metal copper ion is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, aqueous solution is up to its longitudinal relaxation time T outside the exchange bag filter
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Cu-DOTA) copper paramagnetic metal complexes, relaxation rate r
1Be 7.6mmol
-1Ls
-1
Embodiment 3
The preparation of (Mn-DOTA) manganese paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 5000 molecular weight (5KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3g5000 molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.5 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 5 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L MnCl that obtain in 3g(2)
2Solution is dissolved in respectively in the water, amount of substance and the above-mentioned MnCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
2The ratio of the middle ionic amount of substance of manganese metal is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Mn-DOTA) manganese paramagnetic metal complexes, relaxation rate r
1Be 7.5mmol
-1Ls
-1
Embodiment 4
The preparation of (Gd-DOTA) gadolinium paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 50,000 molecular weight (50KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3g5 ten thousand molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=7.5 with NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L GdCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned GdCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the amount of substance of middle metal gadolinium ion is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate lyophilizing, two amino polyethyleneglycol modified (Gd-DOTA) gadolinium paramagnetic metal complex that makes, relaxation rate r
1Be 7.8mmol
-1Ls
-1
Embodiment 5
The preparation of (Cu-DOTA) copper paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 100,000 molecular weight (100KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3,g10 ten thousand molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.0 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L CuCl that obtain in 3g(2)
2Solution is dissolved in respectively in the water, amount of substance and the above-mentioned CuCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
2The ratio of the amount of substance of middle metal copper ion is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, aqueous solution is up to its longitudinal relaxation time T outside the exchange bag filter
1Greater than 3000ms, concentrate lyophilizing, two amino polyethyleneglycol modified (Cu-DOTA) copper paramagnetic metal complex that makes, relaxation rate r
1Be 7.7mmol
-1Ls
-1
Embodiment 6
The preparation of (Mn-DOTA) manganese paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 100,000 molecular weight (100KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3,g10 ten thousand molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.5 with 0.5mol/LNaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L MnCl that obtain in 3g(2)
2Solution is dissolved in respectively in the water, amount of substance and the above-mentioned MnCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
2The ratio of the middle ionic amount of substance of manganese metal is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate lyophilizing, two amino polyethyleneglycol modified (Mn-DOTA) manganese paramagnetic metal complex that makes, relaxation rate r
1Be 7.7mmol
-1Ls
-1
Embodiment 7
The preparation of (Fe-DOTA) ferrum paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 100,000 molecular weight (100KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3,g10 ten thousand molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.5 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, is stirring 30 hours below 20 ℃, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L FeCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned FeCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the middle ionic amount of substance of metallic iron is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Fe-DOTA) ferrum paramagnetic metal complexes, relaxation rate r
1Be 7.7mmol
-1Ls
-1
Embodiment 8
The preparation of (Tb-DOTA) terbium paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 100,000 molecular weight (100KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3,g10 ten thousand molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.5 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L TbCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned TbCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the middle ionic amount of substance of terbium metal is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Tb-DOTA) terbium paramagnetic metal complexes, relaxation rate r
1Be 7.6mmol
-1Ls
-1
Embodiment 9
The preparation of (Dy-DOTA) dysprosium paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 100,000 molecular weight (100KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3,g10 ten thousand molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.5 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L DyCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned DyCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the middle ionic amount of substance of metal dysprosium is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Dy-DOTA) dysprosium paramagnetic metal complexes, relaxation rate r
1Be 7.7mmol
-1Ls
-1
Embodiment 10
The preparation of (Nd-DOTA) neodymium paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 100,000 molecular weight (100KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3,g10 ten thousand molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.5 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L NdCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned NdCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the middle ionic amount of substance of neodymium metal is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Nd-DOTA) neodymium paramagnetic metal complexes, relaxation rate r
1Be 7.6mmol
-1Ls
-1
Embodiment 11
The preparation of (Sc-DOTA) scandium paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 10,000 molecular weight (10KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3g1 ten thousand molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.0 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L ScCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned ScCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the middle ionic amount of substance of metal scandium is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Sc-DOTA) scandium paramagnetic metal complexes, relaxation rate r
1Be 7.4mmol
-1Ls
-1
Embodiment 12
The preparation of (Ti-DOTA) titanium paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 6000 molecular weight (6KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3g6000 molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=7.5 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L TiCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned TiCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the middle ionic amount of substance of Titanium is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Ti-DOTA) titanium paramagnetic metal complexes, relaxation rate r
1Be 7.5mmol
-1Ls
-1
Embodiment 13
The preparation of (V-DOTA) vanadium paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 8000 molecular weight (8KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3g8000 molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.0 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L VCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned VCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the middle ionic amount of substance of vanadium metal is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (V-DOTA) vanadium paramagnetic metal complexes, relaxation rate r
1Be 7.6mmol
-1Ls
-1
Embodiment 14
The preparation of (Mo-DOTA) molybdenum paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 10,000 molecular weight (10KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3g1 ten thousand molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.5 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L MoCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned MoCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the middle ionic amount of substance of metal molybdenum is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Mo-DOTA) molybdenum paramagnetic metal complexes, relaxation rate r
1Be 7.5mmol
-1Ls
-1
Embodiment 15
The preparation of (Ru-DOTA) ruthenium paramagnetic metal complex magnetic resonance imaging contrast that the two amino of 8000 molecular weight (8KDa) are polyethyleneglycol modified
(1) with step (1) in the example 1;
(2) under 5 ° of C conditions, the two amino Polyethylene Glycol of 3g8000 molecular weight is added the 20mL deionized water, being made into mass concentration is 50mg/mL, regulate pH=8.0 with 0.5mol/L NaOH, slowly join in the DOTA active ester, the DOTA active ester is 8:1 with two amino Polyethylene Glycol mass ratioes, stirs 30 hours below the C at 20 °, dialysis is four days in the deionized water, and lyophilizing obtains two amino polyethyleneglycol modified DOTA macromolecular ligands;
(3) under 20 ° of C, two amino polyethyleneglycol modified DOTA macromolecular ligand and the 0.4mol/L RuCl that obtain in 3g(2)
3Solution is dissolved in respectively in the water, amount of substance and the above-mentioned RuCl of DOTA in the polyethyleneglycol modified DOTA macromolecular ligand of two amino
3The ratio of the middle ionic amount of substance of metal Ru is 1:1.3, and regulating pH with 0.5mol/L NaOH is 6.0, under 20 ° of C, stirred 30 hours, and dialysis, the outer aqueous solution of exchange bag filter is up to its longitudinal relaxation time T
1Greater than 3000ms, concentrate, lyophilizing obtains two amino polyethyleneglycol modified (Ru-DOTA) ruthenium paramagnetic metal complexes, relaxation rate r
1Be 7.4mmol
-1Ls
-1
The usage of the magnetic resonance imaging contrast of the paramagnetic metal complex that two amino are polyethyleneglycol modified is as follows:
Embodiment 16
Take by weighing two amino polyethyleneglycol modified (Gd-DOTA) gadolinium paramagnetic metal complex of the embodiment 1 of 0.2g, be dissolved in the conventional glucose injection, regulating pH value with slow blood amine is 6.5, is made into the magnetic resonance imaging contrast that concentration is 100mmol/L.
Embodiment 17
Take by weighing two amino polyethyleneglycol modified (Cu-DOTA) copper paramagnetic metal complex of the embodiment 2 of 0.2g, be dissolved in the conventional sodium chloride injection, regulating pH value with slow blood amine is 6.5, is made into the magnetic resonance imaging contrast that concentration is 100mmol/L.
Embodiment 18
Take by weighing two amino polyethyleneglycol modified (Mn-DOTA) manganese paramagnetic metal complex of the embodiment 3 of 0.2g, be dissolved in conventional sodium chloride-glucose injection, regulating pH value with slow blood amine is 6.5, is made into the magnetic resonance imaging contrast that concentration is 100mmol/L.
Embodiment 19
Take by weighing two amino polyethyleneglycol modified (Gd-DOTA) gadolinium paramagnetic metal complex of the embodiment 4 of 0.2g, be dissolved in the distilled water, regulating pH value with slow blood amine is 6.5, is made into the magnetic resonance imaging contrast that concentration is 100mmol/L.
Embodiment 20
Take by weighing two amino polyethyleneglycol modified (Cu-DOTA) copper paramagnetic metal complex of the embodiment 5 of 0.2g, be dissolved in the conventional sodium chloride injection, regulating pH value with slow blood amine is 6.5, is made into the magnetic resonance imaging contrast that concentration is 100mmol/L.
Embodiment 21
Take by weighing two amino polyethyleneglycol modified (Mn-DOTA) manganese paramagnetic metal complex of the embodiment 6 of 0.2g, be dissolved in the conventional glucose injection, regulating pH value with slow blood amine is 6.5, is made into the magnetic resonance imaging contrast that concentration is 100mmol/L.
Embodiment 22
Take by weighing two amino polyethyleneglycol modified (Gd-DOTA) gadolinium paramagnetic metal complex of the embodiment 1 of 0.2g, be dissolved in conventional sodium chloride-glucose injection, regulating pH value with slow blood amine is 6.5, is made into the magnetic resonance imaging contrast that concentration is 100mmol/L.
Claims (4)
1. the paramagnetic metal complex magnetic resonance imaging contrast that two amino are polyethyleneglycol modified, it is characterized in that, this contrast agent be with two amino polyethyleneglycol modified 1,4,7,10-tetraazacyclododecanand-1,4,7, the coordination compound that 10-tetraacethyl (DOTA) obtains with the paramagnetic metal ion coordination has following structure:
Wherein the mean molecule quantity of two amino Polyethylene Glycol is 2000,4000,5000,6000,8000,10000,20000,50000 or 100000, i.e. n=44,89,112,135,180,226,453,1135 or 2271;
M
M+Be paramagnetic metal ion, be paramagnetic metal element S c, Ti, V, Mn, Cu, Mo, Ru, Fe or lanthanide series rare-earth elements+2 or+3 valency ions;
M is the quantivalence of paramagnetic metal ion, m=2 or 3;
During m=2, R
1For-COOH; During m=3, R
1For-COO-.
2. two amino polyethyleneglycol modified paramagnetic metal complex magnetic resonance imaging contrast according to claim 1 is characterized in that, described two amino polyethyleneglycol modified 1,4,7,10-tetraazacyclododecanand-1,4,7, the structural formula of 10-tetraacethyl (DOTA) is as follows:
Wherein the mean molecule quantity of two amino Polyethylene Glycol is 2000,4000,5000,6000,8000,10000,20000,50000 or 100000, i.e. n=44,89,112,135,180,226,453,1135 or 2271.
3. two amino polyethyleneglycol modified paramagnetic metal complex magnetic resonance imaging contrast according to claim 1 is characterized in that described paramagnetic metal ion is Gd
3+, Tb
3+, Dy
3+, Nd
3+
4. two amino polyethyleneglycol modified paramagnetic metal complex magnetic resonance imaging contrast according to claim 1 is characterized in that described paramagnetic metal ion is Gd
3+
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Effective date of registration: 20161118 Address after: Changzhou City, Jiangsu province Hehai road 213000 No. 9 Patentee after: Changzhou Institute of Energy Storage Materials & Devices Address before: 130022 Changchun City, Chaoyang District province people's street, No. 5625, No. Patentee before: Changchun Institue of Applied Chemistry, Chinese Academy of Sciences |