CN104436219B - A kind of water-soluble magnetic resonance imaging contrast of the base containing nitroimidazole and preparation method thereof - Google Patents

A kind of water-soluble magnetic resonance imaging contrast of the base containing nitroimidazole and preparation method thereof Download PDF

Info

Publication number
CN104436219B
CN104436219B CN201410616994.XA CN201410616994A CN104436219B CN 104436219 B CN104436219 B CN 104436219B CN 201410616994 A CN201410616994 A CN 201410616994A CN 104436219 B CN104436219 B CN 104436219B
Authority
CN
China
Prior art keywords
imidazoles
nitro
bis
acid
acetic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410616994.XA
Other languages
Chinese (zh)
Other versions
CN104436219A (en
Inventor
郝志峰
余灿煌
杨少兵
何俊添
黄淑贞
谭桂珍
黄建新
余坚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong University of Technology
Original Assignee
Guangdong University of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong University of Technology filed Critical Guangdong University of Technology
Priority to CN201410616994.XA priority Critical patent/CN104436219B/en
Publication of CN104436219A publication Critical patent/CN104436219A/en
Application granted granted Critical
Publication of CN104436219B publication Critical patent/CN104436219B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The present invention relates to new type water-solubility magnetic resonance imaging contrast of a kind of base containing nitroimidazole and preparation method thereof, belong to medicine and pharmacology, technical field of chemistry.The contrast agent of the present invention is that esterification occurs under microwave action by the compound of the polycarboxylic reactive derivative of polyamines and the base containing nitroimidazole, the novel organic ligand of the base containing nitroimidazole is prepared, such part chelates to obtain corresponding paramagnetic metal chelates contrast agent with paramagnetic metal ion.This kind of contrast agent relaxivity is high, good water solubility, particularly with kidney targeting, the mr imaging technique available for the Various Tissues or organ of human body or other mammals.

Description

A kind of water-soluble magnetic resonance imaging contrast of the base containing nitroimidazole and preparation method thereof
Technical field
The invention discloses water-soluble magnetic resonance imaging contrast of one kind base containing nitroimidazole and preparation method thereof, specifically Say to be exactly the polyamines multi-carboxylic acid chelating agents and paramagnetic metal ion reaction generation metallo-chelate conduct for containing nitroimidazole base Magnetic resonance imaging contrast and their preparation method, the invention belongs to technical field of chemistry, falls within medicine and pharmacology technology neck Domain.
Background technology
Cancer is seriously to jeopardize one of three big diseases of human health now.In current clinical medicine, tumour it is timely, The accurate treatment for finding and diagnosing to cancer is very important.Magnetic resonance imaging was realized first from Lauterbur in 1973 (Magnetic resonance imaging, MRI) over more than 40 years so far, MRI is in fields such as medical science, biology, material science Obtain fast-developing and extensive use.Especially attract people's attention, in clinical medicine diagnostic field, MRI is after CT scanner A kind of newest Tomographic Diagnosis Technology afterwards, there is high-resolution, any imaging, without radiation insult, provided for clinic A kind of new, not damaged video diagnostic technology.
MRI imagings are to form rambling small magnetic moment using partes corporis humani position Hydrogen Proton, under RF magnetic field, are occurred Difference vibration, after radio-frequency pulse is withdrawn, each Hydrogen Proton discharges the energy oneself just absorbed, then being discharged Radio signal is converted into the gray-scale pixels of each tomography, the space bit of locus and each Hydrogen Proton for different each tomographies Put, then by gradient magnetic GX, GY, GZTo complete.The MRI signal intensity of water proton relevant (spin with several factors in tissue Density NH, imaging volume parameter fV, longitudinal relaxation time T1, T2 T2And sweep time TE and TR), wherein most Two main imaging parameters are relaxation time T1And T2.The compound of some cores containing paramagnetism can be used for significantly changing week Enclose the T of proton1And T2, the contrast of imaging is improved, this kind of paramagnet is referred to as contrast agent.Its action principle is paramagnetism Local magnetic field caused by material, to neighbouring tested core such as water proton1H relaxation rate is (to by radio-frequency drive to upper state Tested dissipation strength energy return the speed of this process of lower state) there is acceleration effect so that depending on relaxation rate (1/T1Or 1/T2) the picture signal of magnetic resonance imaging strengthened, the contrast and definition for as a result causing image improve.According to According to this principle, when paramagnetic metal chelates are as contrast agent, what is worked is actually paramagnetic metal ion therein, The main function of chelating agent is paramagnetic metal ion is formed stable, water miscible chelate, reduces the poison of metal ion Property simultaneously makes it easier to use.
With the gadolinium ion Gd with 7 unpaired electrons3+Exemplified by illustrate, Gd3+Electron configuration be f7, due in the presence of 7 Individual unpaired electron thus produces a big magnetic moment, and dissociate Gd3+It can be combined, be confronted with 9 water molecule coordinations in aqueous The relaxation process of son has good acceleration effect.But due to the Gd that dissociates3+Very big toxicity is produced in human body and is limited It is applied, in order to reduce Gd3+Toxicity, it is effective to make it carry out with the multiple tooth chelating agent with strong coordination ability being coordinated chelating One of method.Weinmann of Schering AG companies in 1984 et al. successfully have developed Gd-DTPA first, and (DTPA is diethyl Pentaacetic acid) contrast agent, and extensive use is obtained in clinic with the advantages of its small toxicity, but Gd-DTPA only brain, Preferable effect is shown in backbone radiography, and other positions are by a definite limitation.The non-ionic contrast medium Gd to come out successively later (DTPA-BMA) (W.P.Cacheris et al, Magn.Reson.Imag., 1990,8,467) and liver and gall selectivity contrast agent Gd (DTPA-EOB) (H.J.Weinmann et al, Magn.Reson.Med., 1991,22,233) is the more ammonia polycarboxylic acids of line style The representative of class contrast agent.More ammonia multi-carboxylic acid contrast agent Gd-DOTA (the M.Magerstade et of more complicated big ring of synthesis Al, Magn.Reson.Med., 1986,3,808), Gd (HP-DO3A) (M.F.Tweedle et al, Drugs Future, 1992,17,187) it is applied to clinic, Central nervous system has preferable contrast enhancing effects, but to other in vivo The radiography of some organs is not ideal enough.
Another effect of chelating agent is to make the paramagnetic metal chelates as contrast agent to some specific in human body Tissue or organ have targeting, in other words can selective enrichment in some specific tissues in human body or organ.In recent years Come, in order to reach internal Targeting Effect, researcher's selection is to the more ammonia polycarboxylic acid diethylenetriamine pentaacetic acids of line style (DTPA) and greatly More ammonia polycarboxylic acid l, 4,7,10- tetraazacyclododecanand-l, the 4,7,10- tetraacethyls (DOTA) of ring and the skeleton of their derivatives Chemical modification is done, according to the difference of tissue, organ and cell receptor species, different targeting groups can be selected to prepare targeting Contrast agent, this is one of most important progress of magnetic resonance imaging contrast, and represent magnetic resonance imaging contrast the present in recent years Afterwards developing direction (Chem.Rev., 1999,99:2293,Coord.Chem.Rev.,2007,251:2428).
The content of the invention
Modern medicine study shows, in entity tumor, most tumour cells have the characteristics of unrestricted division, are in The feature of Clonal growth, the malignant cell of its mostly single mutation that originates from.However, the tumour growth occurred from individual cells is Limited, due to consumption of the eubolism to oxygen, a partial pressure of oxygen gradient in tumour cell spheroid be present.Away from blood vessel week Enclose more than 150mm tumour cell and anoxia state be in due to oxygen that cannot be sufficient, then outer layer cell due to absorption Less than oxygen, tumour cell is in dead state, i.e. anaerobic cell.When malignant cell all living creatures is up to diameter 1mm-2mm, The effective Spread scope of oxygen of tumor cell group surrounding capillaries can not reach the needs for meeting tumour fast-growth propagation, so Massive tumor cell is constantly elapsed outside the effective Spread scope of capillary oxygen, and cause the hypoxemia in tumor tissues Microenvironment further deteriorates, and then produces more anoxic cells, therefore the microenvironment of malignant tumour hypoxemia is in its evolution The special biological characteristics occurred.The weary oxygen degree of tumour cell is higher, and the possibility of tumor progression is bigger, therefore, clinically Research and develop a variety of methods to be used to detect Tumor cell hypoxia degree, wherein nitro glyoxaline (MISO) compound is a kind of normal Hypoxic tissue imaging medicament.Its main mechanism be (Nuclear Medicine and Biology, 2010,37, 125)：Nitro glyoxaline compound has suitable oxidation-reduction potential, and it can be entered intracellular by disperse.Nitro is in cell One-electron reduction occurs in the presence of interior enzyme (mainly xanthine oxidase), produces free radical anion.In normal cell, Because oxidation nitro has a higher electron affinity, free radical anion and can is reoxidized as former compound by rapid, is diffused into It is extracellular；In anoxic cell, free radical anion is further reduced untill becoming amido, due to amido energy and cell In macromolecular covalent bond so that medicine be detained in anoxic cell with accumulation.
The purpose of the present invention is former using targeting of the nitro glyoxaline compound to the selective binding of tumor hypoxia cell Reason, development one kind is new, has good relaxed performance, to some particular organizations of human body or organ (liver, kidney, spleen, courage Pipe, cardiac muscle etc.) there is the stabilization of certain targeting, less toxic magnetic resonance imaging contrast.
The targeting principle " grafting " that the present invention combines nitro glyoxaline compound to tumor hypoxia cell selective is applied To magnetic resonance imaging contrast, that is, to the basic framework of polyamines polycarboxylic acid part chemistry is carried out with nitro glyoxaline compound Modification, part of the design synthesis with bifunctional group, using wherein Hypoxic imaging agent functional group nitroimidazole in weary oxygen Delay and characteristic of accumulation in tumour cell, by paramagnetic Gd (III) ions by combining choosing with the polycarboxylic coordination of polyamines Tumor by local and tumour cell are transported to selecting property, tumor tissues longitudinal relaxation time can be shortened, tumor tissues paramagnetic is improved and is total to The signal contrast for the signal intensity, increase tumour and surrounding tissue of shaking, it is expected to improve the Sensitivity and Specificity of some tumours detections, So as to improve the selectivity of contrast agent and targeting.In addition, there is good coordination on the part of the bifunctional group of design synthesis The N and O atom of characteristic, these parts be also possible to be99mTc or62The excellent chelating agent of the radioactive metal ions such as Cu, these chelatings Agent can provide many valuable information for research and development hypoxic tumor selectivity developer, successfully explorative so as to be advantageous to The excellent anoxia developing agent of energy.
In order to achieve the above object, the technical solution adopted in the present invention is as follows：
A kind of new type water-solubility magnetic resonance imaging contrast of base containing nitroimidazole, the contrast agent is by the polycarboxylic work of polyamines Property derivative and the base containing nitroimidazole compound esterification occurs under microwave action, the base containing nitroimidazole is prepared Novel organic ligand, such part obtain corresponding paramagnetic metal chelates with paramagnetic metal ion generation chelatropic reaction and made Shadow agent, this kind of contrast agent relaxivity is high, good water solubility, has kidney targeting；The new of the described base containing nitroimidazole has Machine part is by the bicyclic acid anhydrides of ethylenediamine tetra-acetic acid (EDTA) or diethylenetriamine pentaacetic acid (DTPA) and the base containing nitroimidazole Compound carries out what esterification was prepared, and the crude product of esterification by obtaining ylidene ligands containing nitroimidazole after purification；
Described esterification using DMAP (DMAP) be catalyst, pyridine as solvent, under microwave radiation, Reaction temperature is 100~110 DEG C, and the reaction time is 20~30min, and the power of described microwave radiation is 300W；
The ratio between described amount of material of bicyclic acid anhydrides and nitroimidazole compound of progress esterification reaction is 1:2~1: 2.5；
The purge process of the described crude product of ylidene ligands containing nitroimidazole is：Semi-solid mixtures add ether, grind, so Afterwards plus appropriate frozen water is dissolved, then with cold 0.5molL in right amount-1Between citric acid solution adjusts pH to 4.5~5.5, in 4 DEG C of ice 36~60h is placed in case, filtering, washs precipitation with appropriate absolute ether, acetone, then recrystallized with absolute ethyl alcohol；
The part of the base containing nitroimidazole and the chelatropic reaction of paramagnetic metal ion are：Part and Gd2O3By material The ratio between amount 1:1 carries out heating stirring in water, 50~60 DEG C of reaction temperature, 20~30min of reaction time, is filtered to remove while hot not The Gd of reaction2O3Solid, pH value then is adjusted between 6.5~8.0 with the alkali of physiological compatibility, with without water beetle after being concentrated under reduced pressure Alcohol-Diethyl ether recrystallization；The alkali of described physiological compatibility is N- methyl glucoses osamine, triethanolamine, ammoniacal liquor, NaOH, Na2CO3Or NaHCO3；
It is part with the more ammonia polycarboxylic acids of the line style containing nitroimidazole or derivatives thereof, chelates and prepare with paramagnetic metal ion Paramagnetic metal chelates are magnetic resonance imaging contrast.Present invention magnetic resonance imaging contrast disclosed herein and its part or Chelating agent has the structure that formula 1 represents：
Wherein：N is 0 or 1；
R1,R2,R3It each can represent hydrogen atom, methyl or nitro, but R1,R2,R3It is at least one to represent nitro；According to this The technical scheme of invention, in the part that formula 1 represents, preferable part has the structure that formula 2 represents：
Technique according to the invention scheme, in the part that formula 1 represents, preferable part has the structure that formula 3 represents：
Technique according to the invention scheme, in the part that formula 1 represents, preferable part has the structure that formula 4 represents：
Technique according to the invention scheme, in the part that formula 1 represents, preferable part has the structure that formula 5 represents：
More ammonia multi-carboxylic acid compounds containing nitroimidazole that Chinese style 2-5 of the present invention is represented can be by corresponding more polycarboxylic work of ammonia Property derivative and the functional group containing nitroimidazole compound using microwave method it is quick, efficiently synthesize.Here " more more carboxylics of ammonia The reactive derivative of acid " can be understood as the polycarboxylic bicyclic acid anhydrides of more ammonia.It is anti-that although esterification can directly occur with alcohol for carboxylic acid Should, but be reversible reaction, General reactions speed compared with slowly, yield it is relatively low, thus first by more ammonia polycarboxylic acid EDTA in the present invention Or the Viability preferably bicyclic acid anhydrides of DTPA cyclisation." compound of the functional group containing nitroimidazole " refers to several classes containing nitroimidazole Alcohol.Although the esterification of bicyclic acid anhydrides and alcohol is fast compared with the esterification of carboxylic acid and alcohol, using normal heating backflow Method, generally requires 20~24h of reaction, and in product existing homonymy asymmetric diester compound, also have symmetrical double For ester compounds, it is necessary to which column chromatography is separated, yield is generally 60%~70%.In the present invention, inventor employs microwave Method carries out esterification, can by preferably synthetic condition (reactant ratio, reaction temperature, reaction time, solvent, catalyst etc.) With it is quick, efficiently synthesize the organic ligand containing nitroimidazole, the reaction time shortens to 20~30min, due to by-product in crude product Thing is less, can be purified by recrystallization method, yield is more than 80%.
General esterification or acylated common solvent are aprotic polar solvent, such as DMF (DMF), N, N- bis- Methylacetamide (DMAC), dimethyl sulfoxide (DMSO) or 1-METHYLPYRROLIDONE (NMP) etc..However, experimentation have shown that in formula During more ammonia multi-carboxylic acid compounds containing nitroimidazole that 2-5 is represented, solubility of the raw material containing nitroimidazole in these solvents It is not very big, reaction in addition terminates rear solvent and is not easy to remove, thus these solvents are not suitable for these reaction systems.In view of ester Change or acylated conventional pyridine is used as catalyst, the present invention selects solvent of the pyridine as esterification, and the N atoms on pyridine ring can Into salt, to be advantageous to improve the solubility of reactant or intermediate with active hydrogen, and then accelerate reaction rate, can also play and urge The effect of agent.In order to further speed up reaction, it is possible to additionally incorporate a small amount of 4- dimethylamino pyridines (DMAP) and be used as catalyst, In DMAP, because two methyl connected on the N of pyridine ring have reprimand electronic effect, so as to cause the cloud density of nitrogen-atoms Increase, DMAP dipole moment (4.40D) is set to increase much than pyridine (2.23D), nucleophilicity also substantially strengthens therewith.DMAP and acyl Stable N- acylation pyridiniujms can be formed by changing reagent, and the center charge of the molecules of salt is more dispersed, can form a connection Untight but stable N- acyl pyridine ion pairs, the ion pair are critically important intermediate during acylation reaction, it Rapidly and alcohol reacts to form ester, while DMAP can also be discharged again.
Microwave of the present invention synthesis in, the process conditions such as reactant ratio, reaction temperature, reaction time be also to Close important.Obtain the theoretical reaction of symmetrical diester compound, EDTA or the bicyclic acid anhydrides of DTPA and the alcohol containing nitroimidazole Match as 1:2, but the alcohol containing nitroimidazole is somewhat excessive, makes reaction more thorough, properly increases yield, appropriate scope For 1:2~1:2.5；Reaction temperature is controlled at 100~110 DEG C, and the reaction time is 20~30min, reacts ratio more thoroughly, side reaction Also less, obtained reacting coarse product can be purified using recrystallization method, avoid the cumbersome of pillar layer separation method and consumption When.The method wherein recrystallized is：Ether is added in semisolid mixture, is ground, then plus appropriate frozen water is dissolved, Again with appropriate cold 0.5molL-1Between citric acid solution adjusts pH to 4.5~5.5, in 36~60h of placement in 4 DEG C of refrigerators.Filtering, Precipitation is washed with appropriate absolute ether, acetone, then is recrystallized with absolute ethyl alcohol.This process for separation and purification is compared with column chromatography, work Skill is relatively easy, and yield is higher.
Using more ammonia multi-carboxylic acid compounds of the above-mentioned functional group containing nitroimidazole as part, and with 7 unpaired electrons Rare earth gadolinium ion Gd3+Coordination, prepares corresponding paramagnetic metal chelates.Prepare preferred gadolinium oxide during metallo-chelate Gd2O3As raw material, rather than conventional rare-earth salts, such as halide, acetate, carbonate, perchlorate, nitrate or sulphur Hydrochlorate etc..This be due to the functional group of the present invention containing nitroimidazole more ammonia polycarboxylic acid parts and coordination after the gold that generates It is water miscible to belong to chelate, is markedly different from the other more ammonia polycarboxylic acid derivatives and metallo-chelate of document report not It is dissolved in the characteristic of water.Using Gd2O3As raw material, excessive Gd2O3Filtering can remove, and be easy to separate.The temperature of complexation reaction Most important with the time, reaction temperature control is at 50~60 DEG C, 20~30min of reaction time；Temperature is more than higher than 60 DEG C, time 30min, the ester bond of organic ligand can partial hydrolysis；Temperature is less than 20min less than 50 DEG C, reaction time, and complexation reaction is not thorough, Separation is difficult, and yield is relatively low.Reaction solution is filtered to remove excessive Gd while hot2O3, then existed with the alkali of physiological compatibility regulation pH value Between 6.5~8.0, common alkali can be N- methyl glucoses osamine, triethanolamine, ammoniacal liquor, NaOH, Na2CO3Or NaHCO3Deng.Instead The chelate of gained is answered such as to be separated by conventional method with the poor solvent precipitation method from reaction system, crude product can It is further purified with the methods of recrystallization.
The paramagnetic metal chelates that the present invention synthesizes are water solubility, are ionic or nonionic.If metal ion When the positive changes of institute's band are equal with the group numbers that chelator molecule forms anion, the chelate of nonionic is formed, this Sample can avoid hyperosmosis caused by ionic contrast agent and thus caused toxic side effect when being used as contrast agent；For shape Total electrical charge number is not zero situation after into chelate, can be by the cation such as Na of physiological compatibility+、NH4 +Or organic derivative is such as N- methyl glucoses osamine, triethanolamine or its institute is electrically charged with the anion balance of physiological compatibility.
Intestinal canal administration preparation such as oral liquid can be made as contrast agent in chelate prepared by the present invention, can also be made non- Intestinal canal administration preparation such as injection.Wherein injection can use sodium chloride injection, glucose injection, glucose-sodium chloride to note Penetrate liquid, distilled water or it is other《Pharmacopoeia of People's Republic of China》Carrier prepares the paramagnetic complex of the present invention as defined in upper It is 0.001~5molL into concentration-1Solution, wherein convenient concentration is 0.1~0.5molL-1, and use PHYSIOLOGICALLY COMPATIBLE Property acid or physiological compatibility alkali regulation pH be 7.0 or so.According further to needing that antioxidant, stably can also be properly added Agent or the injection preparation of other medicinal auxiliary.
The contrast agent of the present invention can use according to a conventional method, and this method includes giving diagnosis object (human body or other food in one's mouths Newborn animal) a kind of above-mentioned paramagnetic metal chelates, MRI scan is then carried out, observation contrast agent is in Different Organs Distribution and metabolic process, preferably mammal is rabbit or small white mouse.The dosage of the contrast agent of the present invention is according to paramagnetism The difference of the species of complex, the tissue for diagnosing object or organ and diagnostic device type and be changed, diagnosis object is People or other mammals, general dosage of injecting is 0.001~5.0mmol, preferably 0.05~0.5mmol.It is wherein representative dynamic Thing imaging experiment is as follows：Use Shanghai Science and Education Equipment Co., Ltd. Huan Tong whole body nmr molecular image system (HT- MRSI50-60KY types, 49.87MHz, magnet strength 1.2T), using self-rotary echo-pulse series (spin echo, SE), T1Add Weigh imaging mode, wherein repetition time (TR) it is 100mS, echo time (TE) it is 4.8mS.Acquisition matrix：128 × 128, image Pixel：512×512.Experiment with kunming mice through intraperitoneal injection yellow Jackets (30mg/kg) anesthesia after carry out coronal scan into Blank picture, then via tail vein injection contrast agent (0.1mmol Gd/kg body weight), random continuous carries out coronal scan imaging, right The isodose Gd-DTPA dimeglumines aqueous solution is used according to a group experiment.As a result show, using the contrast agent of the present invention with using phase Compared with dosage Gd-DTPA dimeglumines, the former is remarkably reinforced the radiography to kidney, and contrast improves, and shows with good Good kidney targeting, optimal imaging time are 20min after injection or so, have injected the MR image enhancement effects after 35min Start slowly to weaken, illustrate that the contrast agent stop in vivo of invention and metabolism time are suitable, will not cause stagnant in vivo for a long time Stay and cause significant toxicity.
The beneficial effects of the invention are as follows：
1. the water-soluble magnetic resonance imaging contrast for the base containing nitroimidazole that the present invention synthesizes maintains the corresponding more carboxylics of polyamines The design feature of sour chelate, thus there is good stability and relaxation rate.Subtract after the carboxyl esterification at polyamines polycarboxylic acid both ends Lack the quantity of carboxyl in part, be more beneficial for forming nonionic or the contrast agent of electroneutral, thus can also overcome ionic Side effect caused by contrast agent hyperosmosis.
2. more ammonia multi-carboxylic acid compounds of the functional group containing nitroimidazole in the present invention are as part, acceptable and heavy metal Ion such as lead or gold etc. form complex, for ultrasonic imaging or X-ray；Or and radioactive metal ion99mTc or62Cu etc. Chelating forms radiometal complex, for tumor hypoxia developer or radiotherapeutic agent.
3. the water-soluble magnetic resonance imaging contrast of the base containing nitroimidazole in the present invention, due to nitro glyoxaline compound pair Tumor hypoxia cell has the targeting feature of selective binding, therefore this kind of contrast agent has preferably to tumour cell in the present invention Selectivity and targeting, early diagnosis to improving tumour is horizontal to have preferable effect.
4. the present invention contrast agent in atmosphere be stabilized in the aqueous solution, it may have good photostability and heat is steady It is qualitative, it is suitable for pressure sintering sterilization.The contrast agent of the present invention has fabulous water solubility, can conventionally be configured to Ejection preparation, it is easy to use beneficial to storage by intravenous injection to diagnosis subject, directly carrying out magnetic resonance imaging detection.
Compared with the monokaryon small molecule gadolinium class contrast agent of present clinical practice, 5. relaxivity has aobvious the contrast agent of the present invention Write and improve, thus clinical administration amount is by decrease to some degree, specific dosage because diagnostic instrments model (magnetic field intensity), Diagnose the different and different of the external conditions such as object, agents area.The contrast agent of the present invention and the monokaryon of clinical practice are small Molecule gadolinium class contrast agent is compared, and other remarkable result is shown to be remarkably reinforced to the radiography of kidney, and contrast improves, and is had good Good kidney targeting, optimal imaging time are 20min after injection or so, have injected the MR image enhancement effects after 35min Start slowly to weaken, the residence time is appropriate in vivo, will not cause significant toxicity.
6. the synthesis of the organic ligand of the base containing nitroimidazole uses microwave method in the present invention, the esterification phase with routine Than the reaction time shortens to 20~30min from 20~24h, and accessory substance is reduced, and crude product can be pure using the method for recrystallization Change, yield reaches more than 80%, and synthetic route is simpler and more direct, and yield is higher, and reaction condition is gentle, is adapted to a large amount of preparations and industrialization Production.
Brief description of the drawings
Fig. 1 shows the FT-IR spectrograms of the part prepared by embodiment 1 and chelate；
Ligand L 1:In 3400.6cm-1Place has one by intermolecular hydrogen bonding νOHStretching vibration peak caused by Bao Feng； 1742.3cm-1The absworption peak at place is attributed to ester carbonyl group νC=OVibration absorption peak；1635.5cm-1It is attributed to carboxylic acid (- COOH) Carbonyl vibration absorption peak；1539.5cm-1And 1361.3cm-1For NO2Two stretching vibration absworption peaks；1163.2cm-1With 835.4cm-1ν can be attributed toC-O-CStretching vibration peak；
Complex Gd-L1:；3430.6cm-1Place absorb peak width and it is strong, illustrate to contain water of coordination or the crystallization water in complex； 1635.5cm-1The carbonyl absorption of vibrations of place's carboxylic acid moves to 1608.9cm-1Place, about 27cm is moved to low ripple direction-1, this shows Ketonic oxygen and Gd coordinations in carboxylic acid；Ligand L1C-N vibration absorption peaks, in complex Gd-L1In then by 1067.7cm-1Place moves to To 1033.0cm-1, about 35cm is moved to low ripple direction-1, suggest the formation of new Gd-N coordinate bonds；Ligand L1Middle ester carbonyl group Absworption peak is 1742.3cm-1, and in complex Gd-L1In ester carbonyl group be then moved to 1733.7cm-1Place, this shows ester carbonyl group In oxygen also assisted in coordination；In 574.6cm-1The flexible of Gd-O keys in complex can be attributed to by locating emerging vibration absorption peak Vibration peak；
Fig. 2 is shown prepares part by embodiment 11HNMR spectrograms；
Ligand L1Nuclear magnetic resoance spectrum (1H NMR, 400MHz, DMSO-d6, ppm) data and its it is attributed to:：δ 2.50 [s, 4H, N (CH2)2N], 3.35 (s, 4H, N-CH2- COOH), 3.39 (s, 4H, N-CH2- COOC), 4.45 (d, 4H, CH2, J= 4.0Hz), 4.65 (d, 4H, CH2, J=4.0Hz), the hydrogen in 7.14and 7.63 (s, 4H, CH=CH) ,-COOH is in nuclear-magnetism figure Do not occur in spectrum；
Fig. 3 shows the TG-DTA figure that chelate is prepared by embodiment 1；
Complex Gd-L1There are four heated decomposition peaks between 50 DEG C to 500.4 DEG C, occur first at 50~124 DEG C Endothermic peak, and 7.01% weight-loss ratio shows that complex carries 3 hydrones, it is consistent with the result of elementary analysis.Second suction Thermal spike should be that the 3rd endothermic peak should be by the more carboxylics of polyamines as caused by the heated gradually decomposition heat absorption of the imidazole ring of organic matter Sour skeleton is gradually decomposed caused by heat absorption, and complex starts rapid weight loss again afterwards, and TG curves cave in downslide therewith, DSC curve There is highly endothermic peak].When temperature reaches 550 DEG C, TG and DSC curve have tended to be flat, it is believed that complex decomposes base This is complete, and system reaches constant weight, due to being pure oxygen atmosphere, can speculate that the final residue that decomposes should be metal oxide Gd2O3, content is 22.68% (theoretical value 23.26%)；
Fig. 4 shows the longitudinal relaxation rate 1/T that chelate contrast agent is prepared by embodiment 11With metal Gd3+Change in concentration Linear relationship chart；
Determined with reverse-revert method on HT-MRSI50-60KY types NMR (1.2T) and chelating is prepared by embodiment 1 Longitudinal relaxation time T during thing contrast agent sample solution room temperature (22 DEG C)1, with 1/T1With metal Gd3+Change in concentration relation is mapped, The slope of straight line is the longitudinal relaxation rate of contrast agent, and R is obtained from figure1For 6.90mM-1S-1, small point with present clinical practice The relaxation rate R of sub- contrast agent Gd-DTPA dimeglumines1(4.33mM-1S-1) compare, improve more than 50%；
Fig. 5 shows that embodiment 1 prepares chelate contrast agent T in mouse kidney (a) and bladder (b)1Weighted imaging pair Than figure；
Embodiment 1 prepares chelate contrast agent compared with the Gd-DTPA monokaryon small molecule gadolinium class contrast agent of clinical practice, shows Work effect is shown to be remarkably reinforced to the radiography of kidney (kidney), and contrast improves, and has good kidney targeting, in kidney The dirty optimal imaging time is 20min after injection or so, injects the MR image enhancement effects after 35min and has begun to slowly weaken, And it is now notable in the MR image enhancement effects of bladder (Bladder), illustrate that largely metabolism has entered bladder to contrast agent, this With regard to illustrating this contrast agent, the residence time is appropriate in vivo, will not cause significant toxicity.
Embodiment
The present invention is described in further details below by example, these examples are only used for illustrating the present invention, and unlimited The scope of the present invention processed；
Embodiment 1
Ethylenediamine tetra-acetic acid-α, δ-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate
The preparation of the double acid anhydrides (EDTAA) of step 1. ethylenediamine tetra-acetic acid ring
Weigh 5.80g (0.02mol) ethylenediamine tetra-acetic acid (EDTA) to be placed in 50mL round-bottomed flasks, add 8mL (0.08mol) acetic anhydride and 10mL (0.12mol) pyridine, the one straight condenser with drying tube of flask top installation, at 65 DEG C Under be stirred at reflux 24h, filtered after being cooled to room temperature, washed respectively with acetic anhydride, cold DMF and ether, and with DMF- ether Recrystallization, vacuum drying, white powder is obtained as the double acid anhydrides (EDTAA) of ethylenediamine tetra-acetic acid ring, yield 74%.M.p. for 189~ 191℃；Elementary analysis measured value (%, calculated value)：C 46.51(46.87)、H 4.98(4.69)、N 10.27(10.94).
Step 2. ethylenediamine tetra-acetic acid α, δ-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester (L1) synthesis
The double acid anhydrides of 1.63g (6mmol) ethylenediamine tetra-acetic acids ring, 2.00g are sequentially added into 35mL stress reaction tanks (12mmol) 1- (2- nitro -1H- imidazoles) ethanol, 1mL DMAPs (DMAP) and 15mL anhydrous pyridines, mixing are equal Retort is put in microwave reactor after even, reacts 30min in 100 DEG C/300W under magnetic agitation.Room temperature is cooled to, pyrrole is evaporated off Pyridine, yellow semisolid is obtained, add ether, grinding, obtain crude product.It is dissolved with appropriate frozen water, then with appropriate precooled 0.5mol·L-1Citric acid adjusts pH to 5.0, in placing 48h in 4 DEG C of refrigerators.Filtering, absolute ethyl alcohol recrystallization, obtained after drying yellowish Color powder 3.16g, yield 87%；FT-IR (KBr, cm-1) (such as accompanying drawing 1)：3400.6(nOH), 1742.3 (νC=O,-COOR), 1635.5(νC=O,-COOH), (n of 1539.5and 1361.3NO2), (n of 1163.2and 835.4C-O-C)；1H NMR (400MHz, DMSO-d6, ppm) and (such as accompanying drawing 2)：[s, 4H, the N (CH of δ 2.502)2N], 3.35 (s, 4H, N-CH2- COOH), 3.39 (s, 4H, N- CH2- COOC), 4.45 (d, 4H, CH2, J=4.0Hz), 4.65 (d, 4H, CH2, J=4.0Hz), 7.14and 7.63 (s, 4H, CH =CH)；HRMS (ESI, positive mode) (such as accompanying drawing 3)：C20H26N8O12for[M+H]+, calculated 571.1748, found 571.1743；Elementary analysis Anal.calculated for C20H26N8O12：C 42.11, H 4.56, N 19.65； Found C 42.03, H 4.68, N 19.72.
Step 3. ethylenediamine tetra-acetic acid α, δ-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate Synthesis
By 0.06g (0.18mmol) Gd2O3It is suspended in 20mL water, adds 0.10g (0.18mmol) ethylenediamine tetra-acetic acid α, δ-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester part, 60 DEG C of stirring reaction 20min (pH ≈ 6), is filtered to remove not while hot The Gd of reaction2O3Solid, filtrate use NaHCO3PH value is adjusted 6.5 or so, is concentrated under reduced pressure into dry, then adds distilled water to be dissolved, Filtering, evaporated under reduced pressure, gained solid absolute methanol-Diethyl ether recrystallization, there must be the glassy yellow powder of metallic luster after drying 0.08g, yield 80%.Elementary analysis measured value (%, calculated value)：Gd 20.23(20.18)、C 31.20(30.80)、H 3.45(3.85)、N 14.76(14.37)；FT-IR analyzes (KBr, cm-1), such as accompanying drawing 1：3430.6(νOH), 1733.7 (νC=O,- COOR), 1608.9 (νC=O,-COO-), 1033.0 (νC-N), (ν of 1540.8and 1365.8NO2), 1165.1and 836.8 (νC-O-C), 574.6 (νGd-O)；The thermogravimetric analysis (air atmosphere, 25 DEG C~650 DEG C) of chelate, such as accompanying drawing 4：50~124 DEG C go out Existing endothermic peak, weight-loss ratio 7.01% show to lose 3 water of coordination molecule, 550 DEG C of constant weights later, residue Gd2O3, content is 22.68% (theoretical value 23.26%).
Step 4. ethylenediamine tetra-acetic acid α, δ-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate Contrast agent performance test
(1) by above-mentioned chelate and contrast agents Gd-DTPA dimeglumines with ultra-pure water be made into series concentration (0.5~ 10mmol·L-1) solution, appropriate solution is injected into NMR sample cells, adds and is sealed with D2O capillary, with reversion Longitudinal relaxation of the restoring method in determination sample solution room temperature (22 DEG C) on HT-MRSI50-60KY types NMR (1.2T) Time T1, with 1/T1With metal Gd3+Change in concentration relation is mapped, and (accompanying drawing 5), the slope of straight line is the longitudinal relaxation of contrast agent Rate R1.It can be seen that the relaxation rate R of the contrast agent synthesized in the present embodiment1Reach 6.90mM-1S-1, with present clinical practice Contrast agents small molecule contrast preparation Gd-DTPA dimeglumines relaxation rate R1(4.33mM-1S-1) compare, improve 50% with On, this is perhaps relevant with the structural change of part.The introducing of two nitro imidazole derivatives groups increases molecular co-volume, Cause molecule slow its rotation in aqueous, related rotational time extends, and then improves the relaxivity of complex；In addition match somebody with somebody Compound is highly soluble in water, and hydrophily is strong, it is thus possible to causes around complex many hydrones of constriction, so as to improve The outer layer relaxivities of Gd complexs, and then strengthened total relaxivity.
(2) above-mentioned chelate and contrast agents Gd-DTPA dimeglumines are made into series concentration with sodium chloride injection (0.1~0.5molL-1) solution, and adjust pH as 7.0 or so, place 24h.Use the red limited public affairs of science and education equipment in Shanghai extensive region Whole body nmr molecular image system (HT-MRSI50-60KY types, 49.87MHz, magnet strength 1.2T) is taken charge of, using from cycle Pulse sequence (spin echo, SE), T1Weighted imaging mode, wherein repetition time (TR) it is 100mS, echo time (TE) be 4.8mS.Acquisition matrix：128 × 128, image pixel：512×512.Experiment kunming mice is through being injected intraperitoneally yellow Jackets Coronal scan is carried out after (30mg/kg) anesthesia into blank picture, then via tail vein injection contrast agent (0.1mmol Gd/kg bodies Weight), control group experiment uses the isodose Gd-DTPA dimeglumines aqueous solution.Mouse random continuous carries out coronal scan imaging, 5min, 20min, 35min T in mouse kidney (a) and bladder (b) before injection and after injection1Weighted imaging contrasts, this implementation Compared with the Gd-DTPA monokaryon small molecule gadolinium class contrast agent of clinical practice, remarkable result is shown to kidney the contrast agent of example Radiography is remarkably reinforced, and contrast improves, and has good kidney targeting, the 20min after the kidney optimal imaging time is injection Left and right, inject the MR image enhancement effects after 35min and have begun to slowly weaken, and now in the MR image enhancement effects of bladder Significantly, illustrate that largely metabolism enters bladder to contrast agent, this also just illustrates this contrast agent, and the residence time is appropriate in vivo, will not Cause significant toxicity.
Embodiment 2
Diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate
The preparation of the double acid anhydrides (DTPAA) of step 1. diethylenetriamine pentaacetic acid ring
Weigh 7.86g (0.02mol) diethylenetriamine pentaacetic acid to be placed in 50mL three-necked flasks, add the anhydrous pyrroles of 15.0mL Pyridine, 8.0mL (0.08mol) acetic anhydride is slowly added dropwise under nitrogen protection, reaction 24h is stirred at reflux at 60 DEG C, room temperature is cooled to, takes out Filter, gained solid are washed till without amber with acetic anhydride, and DMF- Diethyl ether recrystallizations obtain white powder 6.68g, yield 85%； M.p.189~191 DEG C (literature value：190℃)；FT-IR (KBr, cm-1)：3430.7(nOH), 1820.7and 1773.5 (nAcid anhydrides carbonyl)；1639.7(nCOOH),1108.4(nC-O-C).Anal.calculated for C14H19N3O8：C 47.06, H 5.32, N 11.76；Found C 46.85, H 5.52, N 11.58.
Step 2. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester (L2) synthesis
By 2.14g (6mmol) DTPAA, 2.50g (15mmol) 1- (2- nitro -1H- imidazoles) ethanol, 1mL 4- diformazan ammonia It is put into after yl pyridines (DMAP) and the mixing of 15mL anhydrous pyridines in 35mL stress reaction tanks, retort is placed in microwave reactor, Under magnetic agitation 20min is reacted in 100 DEG C/300W.Pyridine is distilled off after completion of the reaction, obtains yellow semisolid mixture, adds Enter ether, grind, obtain crude product, absolute ethyl alcohol-Diethyl ether recrystallization, pale yellow powder 3.50g, yield 87% are obtained after drying；FT- IR (KBr, cm-1)：3425.5(nOH), 1739.9 (νC=O,-COOR), 1634.0 (νC=O,-COOH), 1362.5and 1539.6 (nNO2), (n of 1165.2and 834.0C-O-C)；1H NMR (400MHz, D2O, ppm)：δ 3.07~3.90 (m, 22H, it is a series of multiple Miscellaneous signal NCH2CH2N、CH2COOCH2、NCH2COOH), 4.56 (t, 4H, CH2N, J=20.0Hz), 7.14and 7.41 (s, 4H, CH=CH)；HRMS (ESI, positive mode)：C24H33N9O14for[M+H]+, calculated 672.2225, found 672.2220；Anal.calculated for C24H33N9O14：C 42.92, H 4.92, N 18.78；found C 43.06, H 5.08, N 18.63.
Step 3. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelating The synthesis of thing
By 0.05g (0.15mmol) Gd2O3It is suspended in 20mL water, adds the second of 0.10g (0.15mmol) Diethylenetriamine five Acid-α, η-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester part, 50 DEG C of stirring reaction 30min (pH ≈ 6), cross filter out while hot Remove unreacted Gd2O3Solid, filtrate adjust pH value 7.0 or so with ammoniacal liquor, are concentrated under reduced pressure into dry, then add distilled water that its is molten Solution, filtering, evaporated under reduced pressure, gained solid absolute methanol-Diethyl ether recrystallization, there must be the bright orange toner of metallic luster after drying Last 0.10g, yield 75%.Elementary analysis measured value (%, calculated value)：Gd 18.26(18.65)、C 32.95(34.15)、H 3.92(3.79)、N 14.55(14.94)；FT-IR analyzes (KBr, cm-1)：3421.0, (νOH), 1734.0 (νC=O,-COOR), 1601.4, (νC=O,-COO-), 1029.9 (νC-N), (ν of 1540.7and 1363.5NO2), 1163.8and835.3 (νC-O-C), 575.8(νGd-O)；The thermogravimetric analysis (air atmosphere, 25 DEG C~650 DEG C) of chelate：85~130 DEG C there is endothermic peak, weight-loss ratio 2.38% shows to lose 1 water of coordination molecule, 550 DEG C of constant weights later, residue Gd2O3, content is 19.23% (theoretical value 21.49%).
Step 4. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelating Thing contrast agent performance test
(1) by above-mentioned chelate and contrast agents Gd-DTPA dimeglumines with ultra-pure water be made into series concentration (0.5~ 10mmol·L-1) solution, appropriate solution is injected into NMR sample cells, adds and is sealed with D2O capillary, with reversion Longitudinal relaxation of the restoring method in determination sample solution room temperature (22 DEG C) on HT-MRSI50-60KY types NMR (1.2T) Time T1, with 1/T1With metal Gd3+Change in concentration relation is mapped, and the slope of straight line is relaxation rate R1.Contrast agent in the present embodiment Relaxation rate R1Reach 7.56mM-1S-1, the relaxation rate R with the small molecule contrast preparation Gd-DTPA dimeglumines of present clinical practice1 (4.33mM-1S-1) compare, improve more than 50%.
(2) above-mentioned chelate and contrast agents Gd-DTPA dimeglumines are made into concentration with glucose injection is (0.1~0.5molL-1) solution, and adjust pH as 7.0 or so, place 24h.Use the red limited public affairs of science and education equipment in Shanghai extensive region Whole body nmr molecular image system (HT-MRSI50-60KY types, 49.87MHz, magnet strength 1.2T) is taken charge of, using from cycle Pulse sequence (spin echo, SE), T1Weighted imaging mode, wherein repetition time (TR) it is 100mS, echo time (TE) be 4.8mS.Acquisition matrix：128 × 128, image pixel：512×512.Experiment kunming mice is through being injected intraperitoneally yellow Jackets Coronal scan is carried out after (30mg/kg) anesthesia into blank picture, then via tail vein injection contrast agent (0.1mmol Gd/kg bodies Weight), control group experiment uses the isodose Gd-DTPA dimeglumines aqueous solution.Mouse random continuous carries out coronal scan imaging, Injection before and injection after 5min, 20min, 35min T in Mice Body1Weighted imaging shows that the contrast agent of the present embodiment is with facing The Gd-DTPA monokaryon small molecule gadolinium class contrast agent of bed application is compared, and remarkable result is shown to be remarkably reinforced to the radiography of kidney, right Improved than degree, there is good kidney targeting, 20min or so after the kidney optimal imaging time is injection, after injecting 35min MR image enhancement effects have begun to slowly weaken, it is and now notable in the MR image enhancement effects of bladder.
Embodiment 3
Ethylenediamine tetra-acetic acid-α, δ-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelating Thing
The preparation of the double acid anhydrides (EDTAA) of step 1. ethylenediamine tetra-acetic acid ring
Weigh 5.80g (0.02mol) ethylenediamine tetra-acetic acid (EDTA) to be placed in 50mL round-bottomed flasks, add 8mL (0.08mol) acetic anhydride and 10mL (0.12mol) pyridine, the one straight condenser with drying tube of flask top installation, at 65 DEG C Under be stirred at reflux 24h, filtered after being cooled to room temperature, washed respectively with acetic anhydride, cold DMF and ether, and with DMF- ether Recrystallization, vacuum drying, white powder is obtained as the double acid anhydrides (EDTAA) of ethylenediamine tetra-acetic acid ring, yield 74%.M.p. for 189~ 191℃；Elementary analysis measured value (%, calculated value)：C 46.51(46.87)、H 4.98(4.69)、N 10.27(10.94).
Step 2. ethylenediamine tetra-acetic acid-α, δ-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester (L3) conjunction Into
The double acid anhydrides of 1.20g (4.8mmol) ethylenediamine tetra-acetic acids ring, 2.10g are sequentially added into 35mL stress reaction tanks (12mmol) 1- (2- 5-nitro imidazoles -1H) ethanol, 1mL DMAPs (DMAP) and 15mL anhydrous pyridines, Retort is put in microwave reactor after well mixed, reacts 25min in 110 DEG C/300W under magnetic agitation.It is cooled to room temperature, Pyridine is evaporated off, obtains yellow semisolid, adds ether, grinding, obtains crude product.It is dissolved with appropriate frozen water, then with appropriate precooled 0.5molL-1Citric acid adjusts pH to 5.0, in placing 48h in 4 DEG C of refrigerators.Filtering, absolute ethyl alcohol recrystallization, obtained after drying light Yellow powder 2.24g, yield 80%；FT-IR (KBr, cm-1)：3427.8(nOH), 2963.8 (nC-H,CH3), 1749.1 (νC=O,- COOR), 1640.5 (νC=O,-COOH), (n of 1365.1and 1531.8NO2), (n of 1189.1and 826.1C-O-C)；1H NMR (400MHz, D2O, ppm)：δ 2.46 (s, 6H, N=C-CH3), 3.13 [s, 4H, N (CH2)2N], 3.61 (s, 4H, N-CH2- COOC), 3.88 (s, 4H, N-CH2- COOH), 4.51 (t, 4H, CH2N, J=8.0Hz), 4.65 (t, 4H, CH2O, J=8.0Hz), 7.98 (s, 2H, C=CH)；HRMS (ESI, positive mode)：C22H30N8O12for[M+Na]+, calculated 621.1881 found 621.1875；Elementary analysis Anal.calculated for C22H30N8O12：C 44.15, H 5.02, N 18.73；Found C 44.06, H 5.08, N 18.81.
Step 3. ethylenediamine tetra-acetic acid-α, δ-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) synthesis of chelate
By 0.06g (0.18mmol) Gd2O3It is suspended in 20mL water, addition 0.12g (0.18mmol) ethylenediamine tetra-acetic acid- α, δ-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester part, 60 DEG C of stirring reaction 25min (pH ≈ 6), while hot mistake Filter out unreacted Gd2O3Solid, filtrate adjust pH value 8.0 or so with NaOH solution, are concentrated under reduced pressure into dry, then add distillation Water is dissolved, filtering, evaporated under reduced pressure, gained solid absolute methanol-Diethyl ether recrystallization, must have metallic luster after drying Glassy yellow powder 0.08g, yield 80%.Elementary analysis：Measured value (%, calculated value) Gd 19.07 (19.48), C 32.42 (32.70)、H 4.53(4.21)、N 14.26(13.87)；FT-IR analyzes (KBr, cm-1)：3426.3, (νOH), 1743.2 (νC=O,-COOR), 1608.9, (νC=O,-COO-), 1036.1 (νC-N), (ν of 1536.3and 1365.8NO2), 1188.3and 825.1(νC-O-C), 559.0 (νGd-O)；The thermogravimetric analysis (air atmosphere, 25 DEG C~650 DEG C) of chelate：50~124 DEG C of appearance Endothermic peak, weight-loss ratio 6.26% show to lose 3 water of coordination molecule, 550 DEG C of constant weights later, residue Gd2O3, content is 21.98% (theoretical value 22.45%).
Step 4. ethylenediamine tetra-acetic acid-α, δ-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate contrast agent performance test
(1) above-mentioned chelate and contrast agents Gd-DTPA dimeglumines are made into series concentration (0.5- with ultra-pure water 10m mol·L-1) solution, appropriate solution is injected into NMR sample cells, adds and is sealed with D2O capillary, with reversion Restoring method is relaxed on HT-MRSI50-60KY types NMR (1.2T) corresponding to determination sample solution room temperature (22 DEG C) phase Henan longitudinal direction time T1, with 1/T1With metal Gd3+Change in concentration relation is mapped, and the slope of straight line is relaxation rate R1.In the present embodiment The relaxation rate R of the contrast agent of synthesis1Reach 8.47mM-1S-1, the small molecule contrast preparation Gd-DTPA diformazans Portugal with present clinical practice The relaxation rate R of amine1(4.33mM-1S-1) compare, improve by about one time.
(2) above-mentioned chelate and contrast agents Gd-DTPA dimeglumines are made into sodium chloride-glucose injection dense Spend for (0.1-0.5molL-1) solution, and adjust pH as 7.0 or so, place 24h.It is limited using the red science and education equipment in Shanghai extensive region Company's whole body nmr molecular image system (HT-MRSI50-60KY types, 49.87MHz, magnet strength 1.2T), using spin Echo pulse sequence (spin echo, SE), T1Weighted imaging mode, wherein repetition time (TR) it is 100mS, echo time (TE) For 4.8mS.Acquisition matrix：128 × 128, image pixel：512×512.Experiment kunming mice is through being injected intraperitoneally amobarbital Coronal scan is carried out after sodium (30mg/kg) anesthesia into blank picture, then via tail vein injection contrast agent (0.1mmol Gd/kg bodies Weight), control group experiment uses the isodose Gd-DTPA dimeglumines aqueous solution.Mouse random continuous carries out coronal scan imaging, Injection before and injection after 5min, 20min, 35min T in Mice Body1Weighted imaging shows that the contrast agent of the present embodiment is with facing The Gd-DTPA monokaryon small molecule gadolinium class contrast agent of bed application is compared, and remarkable result is shown to be remarkably reinforced to the radiography of kidney, right Improved than degree, there is good kidney targeting, 20min or so after the kidney optimal imaging time is injection, after injecting 35min MR image enhancement effects have begun to slowly weaken, it is and now notable in the MR image enhancement effects of bladder.
Embodiment 4
Diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chela Compound
The preparation of the double acid anhydrides (DTPAA) of step 1. diethylenetriamine pentaacetic acid ring
Weigh 7.86g (0.02mol) diethylenetriamine pentaacetic acid to be placed in 50mL three-necked flasks, add the anhydrous pyrroles of 15.0mL Pyridine, 8.0mL (0.08mol) acetic anhydride is slowly added dropwise under nitrogen protection, reaction 24h is stirred at reflux at 60 DEG C, room temperature is cooled to, takes out Filter, gained solid are washed till without amber with acetic anhydride, and DMF- Diethyl ether recrystallizations obtain white powder 6.68g, yield 85%； M.p.189~191 DEG C (literature value：190℃)；FT-IR (KBr, cm-1)：3430.7(nOH), 1820.7and 1773.5 (nAcid anhydrides carbonyl)；1639.7(nCOOH),1108.4(nC-O-C).Anal.calculated for C14H19N3O8：C 47.06, H 5.32, N 11.76；Found C 46.85, H 5.52, N 11.58.
Step 2. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester (L4) Synthesis
By 2.14g DTPAA (6mmol), 2.54g (15mmol) 1- (2- methyl-5-nitro -1H- imidazoles)] ethanol, 1mL It is put into after DMAP (DMAP) and the mixing of 15mL anhydrous pyridines in 35mL stress reaction tanks, it is anti-that retort is placed in microwave Answer in device, react 25min in 110 DEG C/300W under magnetic agitation.Pyridine is distilled off after completion of the reaction, obtains yellow semisolid and mixes Compound, ether is added, grinding, crude product is obtained, absolute ethyl alcohol-Diethyl ether recrystallization, white powder 2.85g, yield is obtained after drying 85%；FT-IR (KBr, cm-1)：3430.8(nOH), 2932.8 (nC-H,CH3), 1734.3 (νC=O,-COOR), 1635.2 (νC=O,-COOH), (n of 1368.5and 1535.5NO2), (n of 1188.5and 826.0C-O-C)；1H NMR (400MHz, D2O, ppm)：δ 2.49 (s, 6H, N=C-CH3), 3.06~3.90 (m, 22H, the signal NCH of a series of complex2CH2N、CH2COOCH2、 CH2COOH), 4.48~4.56 (m, 4H, CH2N), 8.04 (s, 2H, C=CH)；HRMS (ESI, positive mode)： C26H37N9O14for[M+H]+, calculated 700.2538, found 700.2533；Anal.calculated for C26H37N9O14：C 44.64, H 5.29, N 18.03；Found C 44.56, H 5.18, N 18.15.
Step 3. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) synthesis of chelate
By 0.05g Gd2O3(0.15mmol) is suspended in 20mL water, adds the second of 0.10g (0.15mmol) Diethylenetriamine five Acid-α, η-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester part, 60 DEG C of stirring reaction 30min (pH ≈ 6), take advantage of Heat filtering removes unreacted Gd2O3Solid, filtrate adjust pH value 6.5 or so with N- methyl glucoses osamine, are concentrated under reduced pressure into It is dry, then add distilled water to be dissolved, filter, evaporated under reduced pressure, gained solid absolute methanol-Diethyl ether recrystallization, must have after drying There are the glassy yellow powder 0.10g of metallic luster, yield 75%.Elementary analysis：Measured value (%, calculated value)：Gd 18.00 (18.05)、C:36.28(35.81)、H 3.85(4.13)、N 14.22(14.46)；FT-IR analyzes (KBr, cm-1)：3420.6 (νOH), 1741.4 (νC=O,-COOR), 1607.0 (νC=O,-COO-), 1038.9 (νC-N), (ν of 1532.7and 1365.3NO2), 1189.0and 825.5(νC-O-C), 558.7 (νGd-O)；The thermogravimetric analysis (air atmosphere, 25 DEG C~650 DEG C) of chelate：85~ 130 DEG C there is endothermic peak, and weight-loss ratio 2.23% shows to lose 1 water of coordination molecule, 550 DEG C of constant weights later, residue Gd2O3, Content is 20.75% (theoretical value 20.80%).
Step 4. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate contrast agent performance test
(1) by above-mentioned chelate and contrast agents Gd-DTPA dimeglumines with ultra-pure water be made into series concentration (0.1~ 8.0mol·L-1) solution, appropriate solution is injected into NMR sample cells, adds and is sealed with D2O capillary, with reversion Restoring method is relaxed on HT-MRSI50-60KY types NMR (1.2T) corresponding to determination sample solution room temperature (22 DEG C) phase Henan longitudinal direction time T1, with 1/T1With metal Gd3+Change in concentration relation is mapped, and the slope of straight line is relaxation rate R1.In the present embodiment The relaxation rate R of the contrast agent of synthesis1Reach 5.76mM-1S-1, the small molecule contrast preparation Gd-DTPA diformazans Portugal with present clinical practice The relaxation rate R of amine1(4.33mM-1S-1) compare, improve more than 30%.
(2) by above-mentioned chelate and contrast agents Gd-DTPA dimeglumines with water for injection be made into concentration for (0.1~ 0.5mol·L-1) solution, and adjust pH as 7.0 or so, place 24h.Use Shanghai Science and Education Equipment Co., Ltd. Huan Tong's whole body Nmr molecular image system (HT-MRSI50-60KY types, 49.87MHz, magnet strength 1.2T), using spin echo pulse Sequence (spin echo, SE), T1Weighted imaging mode, wherein repetition time (TR) it is 100mS, echo time (TE) it is 4.8mS. Acquisition matrix：128 × 128, image pixel：512×512.Experiment kunming mice is through being injected intraperitoneally yellow Jackets (30mg/ Kg coronal scan is carried out after) anaesthetizing into blank picture, then via tail vein injection contrast agent (0.1mmol Gd/kg body weight), control Group experiment uses the isodose Gd-DTPA dimeglumines aqueous solution.Mouse random continuous carry out coronal scan imaging, injection before with And 5min, 20min, 35min T in Mice Body after injection1Weighted imaging shows, the contrast agent of the present embodiment and clinical practice Gd-DTPA monokaryon small molecule gadolinium class contrast agent is compared, and remarkable result is shown to be remarkably reinforced to the radiography of kidney, and contrast carries Height, there is good kidney targeting, 20min or so after the kidney optimal imaging time is injection, inject the MR figures after 35min Image intensifying effect has begun to slowly weaken, and now notable in the MR image enhancement effects of bladder.
The those skilled in the art of chemistry and medicine and pharmacology technical field can synthesize more according to the microwave method in above example Amine polycarboxylic acid forms the compound of the representative of formula 1 containing nitro imidazole derivatives with other, and thus easily prepares paramagnetic metal Chelate contrast agent, anyone other any identical with the present invention or approximate products drawn under the enlightenment of the present invention, The scope of protection of the invention should be belonged to.

Claims (4)

  1. A kind of 1. preparation method of the water-soluble magnetic resonance imaging contrast of base containing nitroimidazole, it is characterised in that：The contrast agent Esterification occurs under microwave action by the compound of the polycarboxylic reactive derivative of polyamines and the base containing nitroimidazole, is prepared into To the organic ligand of the base containing nitroimidazole, such part occurs chelatropic reaction with paramagnetic metal ion and obtains corresponding paramagnetism Chelates contrast medium；
    Ethylenediamine tetra-acetic acid-α, δ-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate
    The double acid anhydrides of step 1. ethylenediamine tetra-acetic acid ring（EDTAA）Preparation
    Weigh 5.80g ethylenediamine tetra-acetic acids（EDTA）It is placed in 50mL round-bottomed flasks, adds 8mL acetic anhydrides and 10mL pyridines, burns The one straight condenser with drying tube of bottle top installation, is stirred at reflux 24h at 65 DEG C, is filtered after being cooled to room temperature, point Do not washed with acetic anhydride, cold DMF and ether, and with DMF- Diethyl ether recrystallizations, vacuum drying, it is ethylenediamine tetraacetic to obtain white powder The double acid anhydrides of acetic acid ring（EDTAA）, yield 74%；
    The synthesis of step 2. ethylenediamine tetra-acetic acid α, δ-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester
    The double acid anhydrides of 1.63 g ethylenediamine tetra-acetic acids rings, 2.00 g 1- (2- nitros -1H- are sequentially added into 35 mL stress reaction tanks Imidazoles) ethanol, 1 mL DMAPs (DMAP) and 15 mL anhydrous pyridines, it is anti-that retort put into microwave after well mixed Answer in device, react 30 min in 100 DEG C/300W under magnetic agitation, be cooled to room temperature, pyridine is evaporated off, obtain yellow semisolid, add Ether, grinding, obtains crude product, dissolves it with appropriate frozen water, then with precooled 0.5 molL in right amount-1Citric acid adjusts pH extremely 5.0, in placing 48 h in 4 DEG C of refrigerators, filter, absolute ethyl alcohol recrystallization, the g of pale yellow powder 3.16, yield are obtained after drying 87%；
    Step 3. ethylenediamine tetra-acetic acid α, δ-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate Synthesis
    By 0.06 g Gd2O3It is suspended in 20 mL water, adds 0.10 g ethylenediamine tetra-acetic acids α, δ-bis- [1- (2- nitros -1H- Imidazoles)] ethanol diester part, 60 DEG C of stirring reaction 20min, pH 6, unreacted Gd is filtered to remove while hot2O3Solid, filtrate Use NaHCO3Adjust pH value be 6.5, be concentrated under reduced pressure into it is dry, then add distilled water dissolved, filter, evaporated under reduced pressure, gained solid With absolute methanol-Diethyl ether recrystallization, the g of glassy yellow powder 0.08 with metallic luster, yield 80% are obtained after drying.
  2. A kind of 2. preparation method of the water-soluble magnetic resonance imaging contrast of base containing nitroimidazole, it is characterised in that：The contrast agent Esterification occurs under microwave action by the compound of the polycarboxylic reactive derivative of polyamines and the base containing nitroimidazole, is prepared into To the organic ligand of the base containing nitroimidazole, such part occurs chelatropic reaction with paramagnetic metal ion and obtains corresponding paramagnetism Chelates contrast medium；
    Diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate
    The double acid anhydrides of step 1. diethylenetriamine pentaacetic acid ring（DTPAA）Preparation
    Weigh 7.86 g diethylenetriamine pentaacetic acids to be placed in 50 mL three-necked flasks, add 15.0 mL anhydrous pyridines, nitrogen protection Under 8.0 mL acetic anhydrides are slowly added dropwise, be stirred at reflux at 60 DEG C reaction 24 h, be cooled to room temperature, filter, gained solid acetic acid Acid anhydride is washed till without amber, and DMF- Diethyl ether recrystallizations obtain the g of white powder 6.68, yield 85%；
    The synthesis of step 2. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester
    By 2.14 g DTPAA, 2.50 g 1- (2- nitro -1H- imidazoles) ethanol, 1 mL DMAPs (DMAP) and 15 mL anhydrous pyridines mixing after be put into 35 mL stress reaction tanks, retort is placed in microwave reactor, under magnetic agitation in 100 DEG C/300W reacts 20 min, and pyridine is distilled off after completion of the reaction, obtains yellow semisolid mixture, adds ether, grinds, Crude product is obtained, absolute ethyl alcohol-Diethyl ether recrystallization, the g of pale yellow powder 3.50, yield 87% are obtained after drying；
    Step 3. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate Synthesis
    By 0.05 g Gd2O3 It is suspended in 20mL water, 0.10 g diethylenetriamine pentaacetic acids-α, η of addition-bis- [1- (2- nitros- 1H- imidazoles)] ethanol diester part, 50 DEG C of stirring reaction 30min, pH 6, unreacted Gd is filtered to remove while hot2O3Solid, filter Liquid ammoniacal liquor regulation pH value be 7.0, be concentrated under reduced pressure into it is dry, then add distilled water dissolved, filter, evaporated under reduced pressure, gained solid With absolute methanol-Diethyl ether recrystallization, the g of glassy yellow powder 0.10 with metallic luster, yield 75% are obtained after drying.
  3. A kind of 3. preparation method of the water-soluble magnetic resonance imaging contrast of base containing nitroimidazole, it is characterised in that：The contrast agent Esterification occurs under microwave action by the compound of the polycarboxylic reactive derivative of polyamines and the base containing nitroimidazole, is prepared into To the organic ligand of the base containing nitroimidazole, such part occurs chelatropic reaction with paramagnetic metal ion and obtains corresponding paramagnetism Chelates contrast medium；
    Ethylenediamine tetra-acetic acid-α, δ-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate
    The double acid anhydrides of step 1. ethylenediamine tetra-acetic acid ring（EDTAA）Preparation
    Weigh 5.80g ethylenediamine tetra-acetic acids（EDTA）It is placed in 50mL round-bottomed flasks, adds 8mL acetic anhydrides and 10mL pyridines, burns The one straight condenser with drying tube of bottle top installation, is stirred at reflux 24h at 65 DEG C, is filtered after being cooled to room temperature, point Do not washed with acetic anhydride, cold DMF and ether, and with DMF- Diethyl ether recrystallizations, vacuum drying, it is ethylenediamine tetraacetic to obtain white powder The double acid anhydrides of acetic acid ring（EDTAA）, yield 74%；
    The synthesis of step 2. ethylenediamine tetra-acetic acid-α, δ-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester
    The double acid anhydrides of 1.20 g ethylenediamine tetra-acetic acids rings, 2.10 g1- (2- methyl -5- nitre are sequentially added into 35 mL stress reaction tanks Base imidazoles -1H) ethanol, 1 mL DMAPs (DMAP) and 15 mL anhydrous pyridines, retort is put after well mixed In microwave reactor, 25 min are reacted in 110 DEG C/300W under magnetic agitation, room temperature is cooled to, pyridine is evaporated off, it is solid to obtain yellow half Body, ether is added, grinding, crude product is obtained, dissolves it with appropriate frozen water, then with precooled 0.5 molL in right amount-1Citric acid PH to 5.0 is adjusted, in placing 48 h in 4 DEG C of refrigerators, is filtered, absolute ethyl alcohol recrystallization, the g of pale yellow powder 2.24 is obtained after drying, Yield 80%；
    Step 3. ethylenediamine tetra-acetic acid-α, δ-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) The synthesis of chelate
    By 0.06 g Gd2O3It is suspended in 20 mL water, adds 0.12 g ethylenediamine tetra-acetic acids-α, δ-bis- [1- (2- methyl -5- Nitro -1H- imidazoles)] ethanol diester part, 60 DEG C of stirring reaction 25min, pH 6, unreacted Gd is filtered to remove while hot2O3Gu Body, filtrate NaOH solution regulation pH value be 8.0, be concentrated under reduced pressure into it is dry, then add distilled water dissolved, filter, evaporated under reduced pressure, Gained solid absolute methanol-Diethyl ether recrystallization, must have the g of glassy yellow powder 0.08 of metallic luster, yield after drying 80%.
  4. A kind of 4. preparation method of the water-soluble magnetic resonance imaging contrast of base containing nitroimidazole, it is characterised in that：The contrast agent Esterification occurs under microwave action by the compound of the polycarboxylic reactive derivative of polyamines and the base containing nitroimidazole, is prepared into To the organic ligand of the base containing nitroimidazole, such part occurs chelatropic reaction with paramagnetic metal ion and obtains corresponding paramagnetism Chelates contrast medium；
    Diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) chelate
    The double acid anhydrides of step 1. diethylenetriamine pentaacetic acid ring（DTPAA）Preparation
    Weigh 7.86 g diethylenetriamine pentaacetic acids to be placed in 50 mL three-necked flasks, add 15.0 mL anhydrous pyridines, nitrogen protection Under 8.0 mL acetic anhydrides are slowly added dropwise, be stirred at reflux at 60 DEG C reaction 24 h, be cooled to room temperature, filter, gained solid acetic acid Acid anhydride is washed till without amber, and DMF- Diethyl ether recrystallizations obtain the g of white powder 6.68, yield 85%；
    The synthesis of step 2. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester
    By 2.14 g DTPAA, 2.54 g 1- (2- methyl-5-nitro -1H- imidazoles)] ethanol, 1 mL DMAPs (DMAP) and after the mixing of 15 mL anhydrous pyridines it is put into 35 mL stress reaction tanks, retort is placed in microwave reactor, magnetic force Under stirring 25 min are reacted in 110 DEG C/300W；Pyridine is distilled off after completion of the reaction, obtains yellow semisolid mixture, adds second Ether, grinding, crude product is obtained, absolute ethyl alcohol-Diethyl ether recrystallization, the g of white powder 2.85, yield 85% are obtained after drying；
    Step 3. diethylenetriamine pentaacetic acid-α, η-bis- [1- (2- methyl-5-nitro -1H- imidazoles)] ethanol diester metal gadolinium (III) synthesis of chelate
    By 0.05 g Gd2O3It is suspended in 20 mL water, 0.10 g diethylenetriamine pentaacetic acids-α, η of addition-bis- [1- (2- methyl- 5- nitro -1H- imidazoles)] ethanol diester part, 60 DEG C of stirring reaction 30min, pH 6, unreacted Gd is filtered to remove while hot2O3 Solid, filtrate with N- methyl glucoses osamine regulation pH value be 6.5, be concentrated under reduced pressure into it is dry, then add distilled water dissolved, filter, Evaporated under reduced pressure, gained solid absolute methanol-Diethyl ether recrystallization, there must be the glassy yellow powder 0.10 of metallic luster after drying G, yield 75%.
CN201410616994.XA 2014-11-05 2014-11-05 A kind of water-soluble magnetic resonance imaging contrast of the base containing nitroimidazole and preparation method thereof Active CN104436219B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410616994.XA CN104436219B (en) 2014-11-05 2014-11-05 A kind of water-soluble magnetic resonance imaging contrast of the base containing nitroimidazole and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410616994.XA CN104436219B (en) 2014-11-05 2014-11-05 A kind of water-soluble magnetic resonance imaging contrast of the base containing nitroimidazole and preparation method thereof

Publications (2)

Publication Number Publication Date
CN104436219A CN104436219A (en) 2015-03-25
CN104436219B true CN104436219B (en) 2017-12-22

Family

ID=52883471

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410616994.XA Active CN104436219B (en) 2014-11-05 2014-11-05 A kind of water-soluble magnetic resonance imaging contrast of the base containing nitroimidazole and preparation method thereof

Country Status (1)

Country Link
CN (1) CN104436219B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105903039A (en) * 2016-05-06 2016-08-31 李彬 Nuclear magnetic resonance contrast agent

Also Published As

Publication number Publication date
CN104436219A (en) 2015-03-25

Similar Documents

Publication Publication Date Title
JP2854159B2 (en) Diethylenetriaminepentaacetic acid-monoamide and complexes and complex salts thereof, methods for preparing the same, NMR-, radiographic and radiological diagnostic agents containing the same, and methods for preparing radiation- or radiation therapy agents and the drugs
US5650133A (en) Macrocyclic polyaza dichelates linked through ring nitrogens via an amide or ester functionality
EP0336879A1 (en) Meso-tetraphenylporphyrin complex compounds,process for their preparation and pharmaceuticals containing them
JPH0339045B2 (en)
JP2001335578A (en) Chlorin or bacteriochlorin bonded aminophenyl dtpa or n2s2 for mr contrast medium or radioactive medicine
CN103911017B (en) Cyanine dye compound and preparation method thereof, for dual-use function agent of photodynamic therapy and preparation method thereof
CN109963838A (en) Dimerization contrast agent
WO1994001393A1 (en) Novel chelating agent, complex compound composed of said agent and metallic atom, and diagnostic agent containing said compound
JPH09503500A (en) Polyazacycloalkanes as dichelating agents
US5399340A (en) Use of amide complex compounds
CN107445911B (en) Two core mr contrast agents containing gadolinium of one kind and its preparation and application
CN101642579B (en) Chitosan modified paramagnetic metal ion magnetic resonance imaging contrast agent preparation method
WO2000056723A1 (en) Perfluoroalkylamide, the production thereof and the use thereof in diagnostics
CN104436219B (en) A kind of water-soluble magnetic resonance imaging contrast of the base containing nitroimidazole and preparation method thereof
CN106187800A (en) A kind of class EDTA part containing adjacent two phenolic hydroxyl groups and non-gadolinium magnetic resonance contrast agent and preparation method thereof
Lin et al. In vivo MR/optical imaging for gastrin releasing peptide receptor of prostate cancer tumor using Gd-TTDA-NP-BN-Cy5. 5
CN110357828B (en) Nuclear magnetic resonance contrast agent and preparation method and application thereof
WO1998039277A1 (en) Triarylmethyl free radicals as image enhancing agents
CN114276309A (en) Gadolinium magnetic resonance contrast agent containing ethoxy aromatic ring and preparation method and application thereof
CN114276308A (en) Magnetic resonance contrast agent and preparation method and application thereof
CN103897118A (en) Method for preparing visual carbene derivatives containing tetramethyl-piperidin-1-oxyl (TEMPO)
CN109602920B (en) Dendritic molecular image probe and preparation method thereof
CN102188722A (en) Ferrous iron-containing magnetic resonance imaging contrast agent
CN1986549A (en) Tumor-targeting dendritic macromolecular paramagnetic metal complex and its synthesis process and use
CN101002950B (en) Magnetic resonace imaging contrast medium with glycyrrhizic acid as carrier

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant