CN102973955B - A kind of magnetic resonance imaging contrast containing trivalent aluminium - Google Patents
A kind of magnetic resonance imaging contrast containing trivalent aluminium Download PDFInfo
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- CN102973955B CN102973955B CN201110260982.4A CN201110260982A CN102973955B CN 102973955 B CN102973955 B CN 102973955B CN 201110260982 A CN201110260982 A CN 201110260982A CN 102973955 B CN102973955 B CN 102973955B
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Abstract
The invention discloses a kind of magnetic resonance imaging contrast containing trivalent aluminium.This magnetic resonance imaging contrast part is obtained by the liquid phase reactor synthesis in organic solvent, and itself and lanthanide series rare-earth elements 1:1 form coordination compound, and this coordination compound can obtain required coordination compound with the aluminium ion of trivalent by 3:1 coordination further.This magnetic resonance imaging contrast has higher relaxivity.Contrast agent of the present invention, except for except magnetic resonance image-forming diagnose, also can be used for X-ray CT or γ scintillography diagnostic techniques.
Description
Technical field
The present invention relates to a kind of magnetic resonance imaging contrast, be specifically related to a kind of magnetic resonance imaging contrast containing trivalent aluminium.
Background technology
Nuclear magnetic resonance (magneticresonanceimaging, MRI) is another the universally acknowledged medical science greatness achievement occurred after X-ray CT, creates tremendous influence to medical practice.In clinical imaging, in order to improve the contrast of signal between diseased region and normal structure, the diagnosis more than 35% needs to use magnetic resonance imaging contrast.Magnetic resonance imaging contrast is the diagnostic agent that a class can shorten imaging time, raising image contrast and definition, display organization organ dysfunction state.The contrast agent diagnosed for clinical magnetic resonance imaging is at present mainly the coordination compound of gadolinium or manganese: Gd-DTPA (Magnevist, magnevist), Gd-DOTA (Dotarem, its spirits many), Mn-DPDP(Teslascan, safe happy shadow), Gd-DTPA-BMA (Omniscan, Ou Naiying), Gd-HP-DO3A (Prohance, general network is aobvious to be thought), Gd-BOPTA (MultiHance, Mo Disi) etc., these micromolecule contrast agent have good imaging effect to brain and central nervous system etc., but the distribution of its extracellular and faster renal metabolism limit its application, particularly to some internal organs in body as liver, the contrasting effects of kidney is not ideal enough, tissue can not be met, the requirement of Organic selection.Therefore, develop cheap, hypotoxicity, relaxivity are high and particular organization or organ are had to the contrast agent of selectivity or targeting, are the developing direction of current magnetic resonance imaging contrast.
In recent years, the main flow of domestic and international contrast agent research and exploitation is to diethylenetriamine pentaacetic acid (Diethylenetriaminepentaaceticacid, DTPA) and 1, 4, 7, 10-tetraazacyclododecane ten bicyclo--1, 4, 7, 10-tetraacethyl (1, 4, 7, 10-tetraazacyclododecane-N, N ', N ", N ' ' '-tetraaceticacid, DOTA) and derivant carry out chemical modification, manufacture various types of contrast agent, wherein prepare high relaxation efficiency and organism had to the magnetic resonance imaging contrast of selectivity and targeting, it is the Main way of magnetic resonance imaging contrast research always.The present invention has prepared a kind of magnetic resonance imaging contrast of Al-Gd self assembly by the method for chemosynthesis, and it has higher relaxivity and good water solublity.
Summary of the invention
The object of this invention is to provide a kind of magnetic resonance imaging contrast containing trivalent aluminium.This magnetic resonance imaging contrast is by 5-bromomethyl-oxine and 1,4,7,10-tetraazacyclododecanand-1,4, the part formed after 7-triacetic acid (DO3A) reaction and trivalent lanthanide ion form the coordination compound of 1:1, this coordination compound press with trivalent aluminium ion further 3:1 coordination obtain required for paramagnetic metal complex; This paramagnetic metal complex has following structure:
。
Ln is trivalent lanthanide ion.The trivalent ion of preferred lanthanide series is: Gd
3+, Dy
3+or Nd
3+.
The part of the DO3A that described 5-bromomethyl-oxine is modified has following structure:
。
There is according to 8-hydroxy-quinoline and trivalent aluminium the feature of very strong coordination ability, 5-bromomethyl-oxine and DO3A are reacted, formed part DO3A part can with paramagnetic metal ion coordination, oxine part and the further coordination of trivalent aluminium ion, thus acquisition good water solubility, the paramagnetic metal complex magnetic resonance imaging contrast that relaxivity is high.This magnetic resonance imaging contrast has higher relaxivity.Contrast agent of the present invention, except for except magnetic resonance image-forming diagnose, also can be used for X-ray CT or γ scintillography diagnostic techniques.
Detailed description of the invention
The object of the invention is to implement by the following technical programs.
Specifically be implemented as follows:
Step 1: three-(tert-Butoxycarbonylmethyl)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand (DO3A-
tbu) prepare by literature method.Get appropriate Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand, sodium bicarbonate and bromo-acetic acid tert-butyl stirring at room temperature 48 hours in the acetonitrile of HPLC rank, Isosorbide-5-Nitrae, the thing mass ratio of 7,10-tetraazacyclododecanand, sodium bicarbonate and bromo-acetic acid tert-butyl is 1:3.2:3.Filter, add a large amount of ether after filtrate evaporate to dryness, filter, insoluble matter vacuum drying obtains product.Productive rate 40%.Structure is as follows:
。
Literature method preparation pressed by step 2:5-methyl-8-butyloxycarbonyl quinoline.Get appropriate 5-methyl-oxine and Bis(tert-butoxycarbonyl)oxide is dissolved in hexane solution, add the DMAP of catalytic amount, the thing mass ratio of 5-methyl-oxine and Bis(tert-butoxycarbonyl)oxide is 1:1, in stirring at room temperature 48h, filtrate is spin-dried for, and recrystallization obtains product.Productive rate 90%.Proton nmr spectra (CDCl
3, ppm): 8.93 (m, 1H), 8.32 (m, 1H), 7.45 (m, 1H), 7.41 (d, 1H), 7.33 (d, 1H), 2.66 (br, 3H), 1.60 (s, 9H) .ESI-MS (m/z): 260 (M+H
+); 282 (M+Na
+).Structure is as follows:
。
The preparation of step 3:5-bromomethyl-8-butyloxycarbonyl quinoline.Get appropriate 5-methyl-8-butyloxycarbonyl quinoline and N-bromo-succinimide is dissolved in carbon tetrachloride solution, add the azodiisobutyronitrile of catalytic amount, the thing mass ratio of 5-methyl-8-butyloxycarbonyl quinoline and N-bromo-succinimide is 1:1.1, reflux 4 hours, filtered while hot, filtrate is spin-dried for, and obtains product through column chromatography for separation.Productive rate 40%.Proton nmr spectra (CDCl
3, ppm): 8.97 (m, 1H), 8.48 (m, 1H), 7.58 (m, 1H), 7.55 (d, 1H), 7.45 (d, 1H), 4.89 (s2H), 1.60 (s, 9H) .ESI-MS (m/z): 339 (M+H
+); 361 (M+Na
+).Structure is as follows:
。
Step 4:5-OL-DO3A-
tthe preparation of Bu.Get the DO3A-of equivalent
tbu and 5-bromomethyl-8-butyloxycarbonyl quinoline, in acetonitrile solution, adds appropriate K
2cO
3, DO3A-
tbu, 5-bromomethyl-8-butyloxycarbonyl quinoline and K
2cO
3ratio be 1:1:5, be warming up to 40 DEG C reaction 24 hours.Adopt silica gel chromatographic column isolation technics, obtain product 5-OL-DO3A-with methylene chloride-methanol (volume ratio is 25:1) as eluent
tbu.Productive rate 60%.Proton nmr spectra (CDCl
3, ppm): 8.96 (m, 1H), 8.62 (m, 1H), 7.54-7.46 (br, 3H), 3.65-2.76 (br, 24H), 1.60 (s, 9H), 1.49 (s, 27H) .ESI-MS (m/z): 672 (M+H
+); 694 (M+Na
+).Structure is as follows:
。
Step 5: part
lpreparation.By 5-OL-DO3A-
tbu is dissolved in trifluoroacetic acid and dichloromethane mixed solution, and the volume ratio of trifluoroacetic acid and dichloromethane is 1:1, and stirring at room temperature 24 hours after desolventizing, is dissolved in a small amount of methanol, adds a large amount of ether sedimentation, and filter, vacuum drying, obtains product, productive rate 80%.Proton nmr spectra (D
2o, ppm): 8.95 (m, 1H), 8.61 (m, 1H), 7.53-7.45 (br, 3H), 3.62-2.73 (br, 24H).Structure is as follows:
。
Step 6:Al (GdL)
3preparation: get part
land GdCl
36H
2o is dissolved in appropriate distilled water, and with 1MNaOH, solution being adjusted to pH is about 10, after stirring at room temperature 24h, adjusts pH value of solution=6.8,5-OL-DO3A and GdCl with 1MNaOH
36H
2the thing mass ratio of O is 1:1; Then dropwise AlCl is added
3solution, 5-OL-DO3A and AlCl
3thing mass ratio be 3:1, about maintaining pH value of solution=6.8 with 1MNaOH, stirring at room temperature 24 hours, solvent evaporated, is dissolved in methanol, filter, filtrate is concentrated into small size, adds a large amount of ether, filter, vacuum drying, obtains product, productive rate 85%.Tested by ICP, the atom number of Gd:Al is than being 3:1.Structure is as follows:
。
Step 7: be dissolved in heavy water by appropriate step 6 product, measures the relaxation time (t of hydrone proton in brukerAvanceIII (400MHz) with reverse-revert method
1), recording relaxivity is 21.5mM
-1s
-1, be about about 4 times of current clinical contrast agent Gd-DTPA used.
Claims (2)
1. the magnetic resonance imaging contrast containing trivalent aluminium, it is characterized in that: this magnetic resonance imaging contrast is by 5-bromomethyl-oxine and 1,4,7,10-tetraazacyclododecanand-1, the part that 4,7-triacetic acid is formed and lanthanide series rare-earth elements 1:1 form coordination compound, and this coordination compound can obtain required coordination compound with the aluminium ion of trivalent by 3:1 coordination further; This paramagnetic metal complex has following structure:
Wherein Ln is the trivalent ion of lanthanide series rare-earth elements.
2. a kind of magnetic resonance imaging contrast containing trivalent aluminium as claimed in claim 1, the trivalent ion of described lanthanide series rare-earth elements is: Gd
3+, Dy
3+or Nd
3+.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP3101012A1 (en) | 2015-06-04 | 2016-12-07 | Bayer Pharma Aktiengesellschaft | New gadolinium chelate compounds for use in magnetic resonance imaging |
| JP7034160B2 (en) | 2016-11-28 | 2022-03-11 | バイエル・ファルマ・アクティエンゲゼルシャフト | High relaxation gadolinium chelate compound for use in magnetic resonance imaging |
| PE20211471A1 (en) | 2018-11-23 | 2021-08-05 | Bayer Ag | FORMULATION OF CONTRAST MEANS AND PROCESS TO PREPARE THEM |
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Non-Patent Citations (2)
| Title |
|---|
| Designing new MRI contrast agents: a coordination chemistry challenge;Vinciane Comblin et al.;《Coordination Chemistry Reviews》;19991231;第185–186卷;第451-470页 * |
| Preparation and Characterization of Blue-Luminescent Tris(8-hydroxyquinoline)aluminum(Alq3);Michael CÖlle et al.;《Adv. Funct. Mater.》;20030228;第13卷(第2期);第108-112页 * |
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