CN1166987A - Magnetic resonance imaging contrast medium of paramagnetism metal compound containing D-galactose group - Google Patents
Magnetic resonance imaging contrast medium of paramagnetism metal compound containing D-galactose group Download PDFInfo
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- CN1166987A CN1166987A CN 97109142 CN97109142A CN1166987A CN 1166987 A CN1166987 A CN 1166987A CN 97109142 CN97109142 CN 97109142 CN 97109142 A CN97109142 A CN 97109142A CN 1166987 A CN1166987 A CN 1166987A
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- dtpa
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- edta
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Abstract
The invented radiopaque medium is obtained through the following process: the double N-hydroxy succimide ester of diethyl triamino pentacetic acid (DTPA) and ethyl diaminotetra acetic acid (eDTA) or double anhydride of DTPA and eDTA and a series of amino D-galactose derivants undergo the selective acylating reaction to obtain a series of diamide ligand of DTPA and EDTA containing D-galatose radical at two ends and with adjustable spacing radical of different kinds, length and flexibility. Said diamide ligand and the paramagnetic metal ion further undergo the cheletropic reaction to obtain the finished product. It possesses of the obvious target character of liver and relatively low acute toxicity.
Description
The invention discloses the paramagnetic metal complex magnetic resonance imaging contrast that a class contains the D-galactosyl, it belongs to medicine and pharmacology, technical field of chemistry.Magnetic resonance imaging contrast is to be used to strengthen radiography in the strongest present medical diagnostic method-nuclear magnetic resonance (MRI) technology, improve image contrast's a compounds, be applied to Gd-DTPA (the D.H.Carr et al of clinical diagnosis the earliest, Lancet, 1984,1,484), with the non-ionic contrast agent Gd (DTPA-BMA) (W.P.Cacheris ctal, the Magn.Reson.Imag. that came out successively afterwards, 1990,8,467), liver and gall selectivity contrast agent Gd (DTPA-EOB) (H.J.Weinmann et al, Magn.Reson.Med., 1991,22,233) be the representative of many ammonia of line style multi-carboxylic acid contrast agent.The above two and dynamic stability is good, synthetic more complicated many ammonia of macro ring multi-carboxylic acid contrast agent Gd-DOTA (M.Magerstade et al, Magn.Reson.Med., 1986,3,808), Gd (HP-DO3A) (M.F.Tweedle et al, Drugs Future, 1992,17,187) be applied to clinically, the central nervous system has been had radiography reinforced effects preferably, not ideal enough to the radiography of some other organ (as liver) in the body comparatively speaking.These hydrophilic contrast agent are by after intravenous injection is in the human body, at once by vascularity in extracellular fluid compartment, and after glomerular filtration and drain rapidly.These hydrophilic contrast agent are typical extracellular distribution contrast agent, do not have organ or tissue's selectivity.And the amphipathic characteristics of Gd (DTPA-EOB) cause it mainly to drain through liver and gall, thereby its distribution has certain selectivity to liver, but its toxicity will be higher than the contrast agent of nonionic, and drainage rate is also slower than Gd-DTPA.Recently, saccharide is because its unique character, as strongly hydrophilic and have the specificity of some cell-membrane receptor etc., begun to have caused people's attention in the design of MRI contrast agent, in synthetic.People such as W.A.Gibby are tied natural amino sugar and DTPA and analog thereof by amide or C-N key, obtain new many ammonia of the line style multi-carboxylic acid contrast agent (US Patent, 5,330,743, Jul, 19,1994) of a class.They have the structure of nonionic, and wherein the two galactose amide gadoliniums of DTPA have certain selectivity radiography potentiation to the liver of rabbit, but raw material such as 2-amino-2-deoxidation-D-galactosamine price is expensive; The synthesis step of the glycosyl DTPA derivant that connects with the C-N key is then more loaded down with trivial details.
The objective of the invention is: intend having a kind of can optionally discern and in conjunction with the protein-asialoglycoprotein receptor of D-galactose end group according to the hepatocyte of mammal surface, contrast agent part DTPA (EDTA) is carried out structure of modification, introduce the D-galactose group that contains amino at its two ends by amido link and polytype interval base, generally there is not optionally shortcoming of organ-tissue in the hope of the hydrophilic contrast agent that overcomes present clinical use, expectation is with hepatic targeting, the molecular structure of nonionic, relaxation performance and strongly hydrophilic are united preferably, obtain the practical magnetic resonance imaging contrast of new class of low toxicity and tool hepatic targeting.
Be the technical measures that realize that purpose of the present invention is taked:
1. contain the synthetic of amino D-galactose derivative:
A. single lactose acylate lactobionic acid of diamine is in non-proton type polar solvent (as DMF, DMSO etc.); at N; N '-dicyclohexylcarbodiimide and organic base (as triethylamine, pyridine) exist down and the N-hydroxy-succinamide condensation gets lactobionic acid N-hydroxyl succinum imines active ester; it or δ-lactobionic acid lactone are used for and excessive 20 to 100 times of diamines (except the butanediamine) reaction, obtain single lactose acylate of diamine.
Single replacement-D-galactose (or lactose) amine of b 1-N-
React in low amounts of water or under the condition of no solvent by D-galactose (or lactose) and primary amine and to obtain.
C 1-N-β-D-galactosamine (or lactose amine)
By D-galactose (or lactose) and saturated NH
4HCO
3Reactant aqueous solution is after highly acid H
+The type ion exchange column with ammonia/formic acid solution drip washing, obtains target product.
D amine alkyl (or amine aryl)-β-D-galactoside (or lactoside)
2,3,4,6-O-tetrem acyl-alpha-brominated-D-galactose (or O-seven acetyl-alpha-brominated lactose) and N-TFA base amine alkylol (2-ethylaminoethanol, 3-aminopropanol, 6-amino-hexanol except), amine aryl alcohol or phenol are at catalyst A g
2CO
3Or Hg (CN)
2Exist and to carry out K nig-Knorr reaction down, deacetylated and N-takes off trifluoroacetylation and reacts through O-again, obtains amine alkyl (amine aryl)-β-D-galactoside (lactoside).
2 DTPA (or EDTA) bisgallic acid acid anhydride and N-hydroxy-succinamide (1: 2～3 mol ratio) in DMF (DMSO) 〉=60 to 90 ℃ of reactions obtain the two N-hydroxy-succinamide esters of DTPA (EDTA).
N=1, the two active ester of DTPA
N=0, the two active ester of EDTA
3 is that acylating agent, DMF-water are medium with the two N-hydroxy-succinamide esters of DTPA (EDTA), or is acylating agent with DTPA (EDTA) bisgallic acid acid anhydride, and DMSO is a medium, obtains the contrast agent part with containing amino D-galactose derivative reaction, and structural formula is as follows:
During n=1, the DTPA bisamide
During n=0, EDTA bisamide a X=
R is straight chained alkyl or substituted alkyl (no more than 10 carbon atoms), aromatic radical, substituted aromatic base ,-CH
2(CH
2OCH
2)
nCH
2-(n=1,2); H
2N-R-NH
2Can also be lysine Arrcostab (aryl ester), hydrazine etc.B X=
R
1=OH, R
2=H 1-α, β-D-galactosamine derivant R
1=H, R
2==β-D-galactoside 1-α, beta lactose amine derivative R
3Be alkyl, substituted alkyl, aromatic radical, substituted aromatic base, hydroxyalkyl, replacement hydroxyalkyl etc.C X=
R
1=OH, R
2=H 1-β-D-galactosamine derivant R
1=H, R
2=β-D-galactoside 1-beta lactose amine derivative d X=
R
1=OH, R
2=H β-D-galactosamine derivant R
1=H, R
2=β-D-galactoside beta lactose glycoside derivates R
3Be straight chained alkyl (CH
2)
n(n=2-10), substituted alkyl, aromatic radical, substituted aromatic base; HO-R
3-NH
2Can also be serine, threonine Arrcostab (aryl ester) etc.
4, part and mole paramagnetic metal ion (Gd such as contain
3+, Mn
2+, Cr
3+, Fe
3+, Cu
2+, Co
2+, Ni
2+, Tc
2+Deng) salt (acetate, hydrochlorate, carbonate etc.) or oxide reaction (generally being reaction medium) with water, can obtain DTPA (EDTA) the bisamide paramagnetic metal complex magnetic resonance imaging contrast (Gd wherein of a series of D-of containing galactosyls
3+The coordination compound toxicity that forms with the EDTA bisamide derivatives is bigger, should not be used as contrast agent).
The present invention compared with the prior art, the technique effect that has reached:
1 pair of liver has targeting preferably, can optionally strengthen making liver after injecting this class contrast agent
Shadow has improved this position image contrast (confirmation of rabbit imaging experiment).
Kind, flexibility and the length of the interval base of 2 targeting groups and DTPA (EDTA) covalent bond all can be regulated, be beneficial to the D-galactosyl by the surface of hepatocytes specific receptor discern, combination.
3 parts cooperate with suitable paramagnetic metal ion, can obtain non-ionic contrast agent, this class radiography
Agent toxicity is very little.Mouse experiment confirms, disposable vein injection fatal dose reaches 〉=and 12 arrives
14mmolkg
-1, be more than 120 times of contrast agent common dose.
The spin lattice relaxation performance and the Gd-DTPA of 4 these type of contrast agent are suitable.
The connection of D-galactose all presents its natural existence form in vivo in 5 contrast agent:
O-galactoside or N-acidylate galactoside, thereby certain biocompatibility is arranged.
6 these class contrast agent water solublity are fine, are convenient to the wiring solution-forming injection and use.
7 these class contrast agent aqueous solution Heat stability is goods are suitable for the pressure sintering sterilization.
8 synthetic routes are simpler and more direct relatively, the synthetic step productive rate average out to 95% of part, and the synthetic step productive rate of coordination compound reaches 100%.
9 DTPA (EDTA) active ester is successfully used to avoid hydrolysis, esterification side reaction with containing the amino reaction of carbohydrate derivative in nonelectrolyte mixed aqueous solution.This also can carry out the synthetic of contrast agent part in aqueous solution, expanded the range of choice of synthesis material.
The animal imaging experiment.Use An Ke company's whole body nuclear magnetic resonance imaging instrument (30cm Helmholtz coil, 50cm aperture, 0.16T magnetic field), adopt T
1Weighting spin-echo-wave imaging mode, TR=500ms, TE=30ms, 2kg male rabbit intravenous injection pentobarbital sodium (30mgkg
-1) after the anesthesia, intravenous injection contrast agent (dosage 0.1mmol.Gd.kg again
-1) imaging behind the aqueous solution.The result shows, uses this class novel type radiographic contrast to compare with using same dose Gd-DTPA, and the former obviously strengthens the radiography of liver, and contrast improves, and has demonstrated its hepatic targeting preferably.
Below in conjunction with embodiment the present invention is further described.
Embodiment 1:
The deutero-DTPA bisamide of ethylenediamine list lactose acylate gadolinium
A) 8.9gDTPA bisgallic acid acid anhydride, 5.8gN-N-Hydroxysuccinimide were reacted 4 hours in 70 ℃ in DMF or DMSO.Reacted postcooling, isopropanol precipitating, the washing of dehydrated alcohol, ether, dry white solid, i.e. two N-hydroxy-succinamide active ester of DTPA, productive rate 96%.
B) 20g lactobionic acid and 11.6gN, N '-dicyclohexylcarbodiimide is in DMF-NEt
3In-5 ℃ of reactions 30 minutes, add the 6.4g N-hydroxy-succinamide, room temperature reaction obtained white lactobionic acid N-hydroxy-succinamide ester, productive rate 90% in 12 hours.The 15mL DMF solution of the above-mentioned intermediate product of 2g (4.4mmol) is added drop-wise in the 60mL DMF solution of 12g ethylenediamine (200mmol) in stirring down, and 60 ℃ were reacted 2 hours, and crude product is dissolved in the low amounts of water, crosses strong-acid type ion exchange column (H
+Type), successively with distilled water, the drip washing of 0.5M ammonia, obtain pure ethylenediamine list lactose acylate, productive rate 94%.
δ-lactobionic acid lactone replaces lactobionic acid N-hydroxyl succinum imines ester, also can obtain equifinality, just the response time long (～4 hours).
C) product (2g) is dissolved in DMF-water (volume ratio 3: the 2) mixed solvent among the 5mmolb, adds product among the 1.47ga (2.5mmol) under-15 ℃ in batches ,-15 ℃～10 ℃ reactions 1 hour, and room temperature continues reaction 12 hours.The reactant mixture concentrating under reduced pressure, the dehydrated alcohol precipitation, through ethanol, ether washing, the dry product that gets.Or employing following steps: product is dissolved among the 15ml DMSO among the 5mmolb, stir add down in batches DTPA bisgallic acid acid anhydride (2.5mmol, 0.89g), room temperature reaction 12 hours, concentrating under reduced pressure, ether sedimentation.After the low amounts of water dissolving, dehydrated alcohol precipitation, dry product, the productive rate 96% of getting of ether washing.
D) product (1.74g) is dissolved in the 20ml redistilled water among the 1.50mmolc, adds Gd
2O
3Pressed powder 0.27g (0.75mmol), 80 ℃ of stirring reactions got clear solution in 8 hours.Evaporated under reduced pressure gets crystalline product.If use GdCl
36H
2(0.56g 1.5mmol) replaces Gd to O
2O
3(0.27g, 0.75mmol), reaction gets final product half an hour, and evaporated under reduced pressure adds dehydrated alcohol evaporated under reduced pressure again, repeatedly for several times, gets crystalline product, productive rate 99%.
Embodiment 2:
Two (N, N-normal-butyl lactose base) DTPA bisamide gadolinium
A) with a in the example 1.
B) 20g lactose-hydrate mixes rearmounted solid carbon dioxide and bathes and go up heating with the 9g n-butylamine, and 80 ℃ are reacted to lactose and dissolve fully, continue heating 10 minutes, cooling, ethanol, ether sedimentation, the ether washing, dioxane-recrystallizing methanol, crystalline product, productive rate 82%.
C) product participation reaction among product (1.99g) the typical example 1b among the above-mentioned b of c. 5mmol in the similar example 1, productive rate 92%.
D) product reaction among the routine 1c of product (1.73g) replacement among the d.1.5mmol above-mentioned c in the similar example 1, productive rate 100%.
Embodiment 3:
Two (1-N-β-D-galactoside) DTPA bisamide gadolinium
A) with a in the example 1.
B) the 2.0gD-galactose is dissolved in the 100ml water, adds NH
4HCO
3Make saturated, 30 ℃ of stirring reactions of constant temperature 6 days.In the reaction, constantly add NH
4HCO
3It is saturated to keep solution.Reactant mixture is with the dilution of 200mL water, and 30 ℃ concentrate down, so repeated multiple times.Concentrated solution is crossed the highly acid ion exchange column, successively with distilled water, 0.5M ammonia-methanol solution drip washing, collects the product component, and lyophilization gets 1-β-D-galactosamine, productive rate 72%.
C) c in the similar example 1, product (0.90g) replaces product reaction among the routine 1b, productive rate 96% among the above-mentioned b of 5mmol.
D) d in the similar example 1, product (1.07g) replaces product reaction among the routine 1c, productive rate 100% among the above-mentioned c of 1.5mmol.
Embodiment 4:
Two (2-N-ethyl-beta lactose glycosides) DTPA bisamide gadolinium
A) with a in the example 1.
B) O-seven acetyl-alpha-lactose bromide (8mmol) is dissolved in the 10mL chloroform, joins 2-trifluoroacetyl amido ethanol (9mmol), Disilver carbonate (11mmol), micro iodine (80mg), anhydrous CaSO under stirring
4(3g) and in the 40mL chloroform, lucifuge reaction 36h.Crude product silicagel column purification gets 2-trifluoroacetamido ethyl seven-O-acetyl-beta lactose glycosides, productive rate 28%.This intermediate product strong basic type anion-exchange resin (OH
-Type) sloughs trifluoroacetyl group and acetyl group, reuse H
+Ion-exchange resin purification (0.5M ammonia is made eluent) is collected the product component, and lyophilization gets 2-aminoethyl beta lactose glycosides, productive rate 40%.
C) c in the similar example 1, product (1.93g) replaces product reaction among the routine 1b, productive rate 94% among the above-mentioned b of 5mmol.
D) d in the similar example 1, product (1.69g) replaces product reaction among the routine 1c, productive rate 100% among the above-mentioned c of 1.5mmol.
Embodiment 5:
Two (2-N-ethyl-beta lactose glycosides) EDTA bisamide manganese
A) 6.4gEDTA bisgallic acid acid anhydride, 5.8gN-N-Hydroxysuccinimide in DMSO 70 ℃ the reaction 4 hours.Reaction is finished, cooling, isopropanol precipitating, dehydrated alcohol, ether washing, dry white solid, i.e. two N-hydroxy-succinamide active ester of EDTA, productive rate 95%.
B) with b in the example 4.
C) c in the similar example 1, product (1.93g) replaces product reaction among the routine 1b among the above-mentioned b of 5mmol, and product (1.22g) replaces product reaction among the routine 1a, productive rate 92% among the above-mentioned a of 1.5mmol.
D) d in the similar example 1 is with the hydrochlorate reaction of Mn (II).With MnCl
24H
2(0.30g 1.5mmol) replaces GdCl to O
36H
2O, product (1.54g) replaces product reaction among the routine 1c, productive rate 100% among the above-mentioned c of 1.5mmol.
Claims (9)
1 contains the paramagnetic metal complex magnetic resonance imaging contrast of D-galactosyl; it is characterized in that: contrast agent of the present invention is that (or DTPA, EDTA bisgallic acid acid anhydride and a series of D-galactose derivative that contains amino carry out the selectively acylating reaction by the two N-hydroxy-succinamide esters of DTPA, EDTA; obtain DTPA, EDTA bisamide part that a series of two ends contain the basic kind of D-galactosyl and interval, length and flexible adjustable; further cooperate with paramagnetic metal ion to obtain, they have tangible hepatic targeting and quite low acute toxicity.
2 contain the paramagnetic metal complex magnetic resonance imaging contrast of D-galactosyl, it is characterized in that: two N-hydroxy-succinamide active ester of synthetic intermediate DTPA or EDTA be by DTPA or EDTA and N-hydroxy-succinamide with 1: in 〉=60 to the 90 ℃ of reactions in DMF or DMSO of 〉=2 to 3 mol ratio obtained in 〉=3 to 6 hours, and structure is as follows:
3 contain the paramagnetic metal complex magnetic resonance imaging contrast of D-galactosyl, it is characterized in that: the D-galactose derivative of amino-contained is synthetic as follows in the reaction intermediate
Lactobionic acid is in DMF-NEt
3In with N-hydroxy-succinamide, N, N '-dicyclohexylcarbodiimide reaction obtains lactobionic acid N-hydroxy-succinamide ester; Lactobionic acid active ester or δ-lactobionic acid lactone and excessive 20-100 diamine doubly is in DMF or DMSO, and 〉=50 to 90 ℃ were reacted 〉=2 to 6 hours, and obtained diamine list lactose acylate, through ion exchange column or silicagel column purification; The D-galactose with keep saturated NH
4HCO
330 ℃ of reactions of aqueous solution are after strong acid ion exchange resin (H
+), ammonia/methanol drip washing obtains 1-β-D-galactosamine;
Seven-O-acetyl-alpha-brominated lactoside and N-TFA base amine alkylol (amine aryl alcohol or phenol) are at Disilver carbonate or Hg (CN)
2Carry out K nig-Knorr reaction under the catalysis, deacetylate and trifluoroacetyl group obtain amine alkyl (amine aryl)-beta lactose glycosides again; 2,3,4,6-O-tetrem acyl-alpha-brominated-D-galactose and N-TFA base amine alkylol or amine aryl alcohol, phenol are at Disilver carbonate or Hg (CN)
2Carry out the Konig-Knorr reaction under the catalysis, slough trifluoroacetyl group and acetyl group, obtain amine alkyl or amine aryl-β-D-galactoside.
The described paramagnetic metal complex magnetic resonance imaging contrast that contains the D-galactosyl of 4 claim 1 is characterized in that: three classes contain the structural formula of amino D-galactose derivative and are in the synthetic intermediate
R be the straight chained alkyl of no more than 10 carbon atoms or substituted alkyl, aromatic radical, substituted aromatic base ,-CH
2(CH
2OCH
2)
nCH
2-, n=1,2; NH
2-R-NH
2Can also be lysine Arrcostab (aryl ester), hydrazine;
R
1=OH, R
2During=H, R
3Can be straight chained alkyl (CH
2)
n, n 〉=2 to 10, substituted alkyl, aromatic radical,
Substituted aromatic base;
R
1=H, R
2During=β-D-galactoside, R
3Be straight chained alkyl (CH
2)
n, n=4,5, 〉=7 to 10, replace alkane
Base, aromatic radical, substituted aromatic base;
HO-R
3-NH
2Can also be serine, threonine Arrcostab (aryl ester)
The described paramagnetic metal complex magnetic resonance imaging contrast that contains the D-galactosyl of 5 claim 1 is characterized in that: contrast agent part of the present invention is to obtain with the D-galactose derivative reaction that contains amino in 〉=1 to the 1.7:1 DMF-water mixed solvent by the two N-hydroxy-succinamide active ester of DTPA, EDTA in volume ratio; DTPA or EDTA bisgallic acid acid anhydride react in DMSO with under the D-galactose derivative room temperature that contains amino, can obtain DTPA or EDTA bisamide contrast agent part.
6. the described paramagnetic metal complex magnetic resonance imaging contrast that contains the D-galactosyl of claim 1, it is characterized in that: the structural formula of contrast agent part is
In the said structure formula, substituent X is
R is the straight chained alkyl or the substituted alkyl of no more than 10 carbon atoms, aromatic radical, substituted aromatic base ,-CH
2-(CH
2OCH
2)
nCH
2-, n=1,2; NH
2-R-NH
2Can also be lysine Arrcostab (aryl ester), hydrazine; Substituent X is
R
1=OH, R
2=H 1-α, β-D-galactosamine derivant R
1=H, R
2=β-D-galactoside 1-α, beta lactose amine derivative R
3Be alkyl, substituted alkyl, aromatic radical, substituted aromatic base, hydroxyalkyl, replacement hydroxyalkyl; Substituent X is
R
1=OH, R
2=H 1-β-D-galactosamine derivant R
1=H, R
2=β-D-galactoside 1-beta lactose amine derivative; Substituent X is
R
1=OH, R
2=H β-D-galactoside derivant R
1=H, R
2=β-D-galactoside beta lactose glycoside derivates R
3Can be following groups: straight chained alkyl (CH
2)
n, n 〉=2 are to 10; Substituted alkyl, aromatic radical, substituted aromatic base HO-R
3-NH
2Can also be serine, threonine Arrcostab (aryl ester).
The described paramagnetic metal complex magnetic resonance imaging contrast that contains the D-galactosyl of 7 claim 1 is characterized in that: it is contrast agent that contrast agent part of the present invention and paramagnetic metal ion form coordination compound by 1: 1 mol ratio, and these metal ions comprise Gd
3+, Mn
2+, Cr
3+, Fe
3+, Co
2+, Ni
2+, Tc
2+And Cu
2+
The described paramagnetic metal complex magnetic resonance imaging contrast that contains the D-galactosyl of 8 claim 1 is characterized in that: contrast Material Injection Protocols of the present invention ... above-mentioned contrast agent intravenous injection in the diagnosed object body, is carried out MRI scan then; Diagnosed object is behaved and other mammal, and the consumption of contrast agent is that per kilogram of body weight 〉=0.05 is to 5mmol.
9 claim 1 or the 7 described paramagnetic metal complex magnetic resonance imaging contrasts that contain the D-galactosyl is characterized in that: contrast Material Injection Protocols scope of the present invention comprises magnetic resonance imaging analysis, nuclear magnetic resonance spectroscopy and γ scintigraphy analysis; They also can be made injection with pharmaceutic adjuvant Polyethylene Glycol or serum albumin, dextran, N-methyl glucoside etc. and use except that can using separately.
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|---|---|---|---|
| CN 97109142 CN1166987A (en) | 1997-06-18 | 1997-06-18 | Magnetic resonance imaging contrast medium of paramagnetism metal compound containing D-galactose group |
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|---|---|---|---|
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Family
ID=5170956
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100382847C (en) * | 2005-02-05 | 2008-04-23 | 四川大学 | Ligand compound for image diagnosis and its preparing method and compound for image diagnosis and its intermediate preparation |
| CN100382846C (en) * | 1998-11-02 | 2008-04-23 | 福托金公司 | Method for improved imaging and photodynamic therapy |
| CN100431614C (en) * | 2006-06-16 | 2008-11-12 | 中国科学院长春应用化学研究所 | Paramagnetic metal coordination compound magnetic resonance imaging contrast medium with narrow-leaved oleaster polyose modification |
| US7609362B2 (en) | 2004-11-08 | 2009-10-27 | Asml Netherlands B.V. | Scanning lithographic apparatus and device manufacturing 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 |
| CN101307018B (en) * | 2007-05-17 | 2010-08-18 | 中国科学院化学研究所 | Diethylene triaminepentaacetic acid carboxyl active ester or analogues, method for synthesizing same and use |
| CN1966088B (en) * | 2006-11-16 | 2010-09-29 | 中国科学院长春应用化学研究所 | Magnetic resonance imaging contrast using arabinogalactan as carrier |
| CN102336838A (en) * | 2011-06-27 | 2012-02-01 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex and synthetic method and application thereof |
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1997
- 1997-06-18 CN CN 97109142 patent/CN1166987A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100382846C (en) * | 1998-11-02 | 2008-04-23 | 福托金公司 | Method for improved imaging and photodynamic therapy |
| US7609362B2 (en) | 2004-11-08 | 2009-10-27 | Asml Netherlands B.V. | Scanning lithographic apparatus and device manufacturing method |
| CN100382847C (en) * | 2005-02-05 | 2008-04-23 | 四川大学 | Ligand compound for image diagnosis and its preparing method and compound for image diagnosis and its intermediate preparation |
| CN100431614C (en) * | 2006-06-16 | 2008-11-12 | 中国科学院长春应用化学研究所 | Paramagnetic metal coordination compound magnetic resonance imaging contrast medium with narrow-leaved oleaster polyose modification |
| CN1966088B (en) * | 2006-11-16 | 2010-09-29 | 中国科学院长春应用化学研究所 | Magnetic resonance imaging contrast using arabinogalactan as carrier |
| CN101307018B (en) * | 2007-05-17 | 2010-08-18 | 中国科学院化学研究所 | Diethylene triaminepentaacetic acid carboxyl active ester or analogues, method for synthesizing same and use |
| CN101642579A (en) * | 2009-08-14 | 2010-02-10 | 江苏大学 | Chitosan modified paramagnetic metal ion magnetic resonance imaging contrast agent preparation method |
| CN101642579B (en) * | 2009-08-14 | 2013-10-23 | 江苏大学 | Chitosan modified paramagnetic metal ion magnetic resonance imaging contrast agent preparation method |
| CN102336838A (en) * | 2011-06-27 | 2012-02-01 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex and synthetic method and application thereof |
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