CN102188722A - Ferrous iron-containing magnetic resonance imaging contrast agent - Google Patents
Ferrous iron-containing magnetic resonance imaging contrast agent Download PDFInfo
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- CN102188722A CN102188722A CN2010101275588A CN201010127558A CN102188722A CN 102188722 A CN102188722 A CN 102188722A CN 2010101275588 A CN2010101275588 A CN 2010101275588A CN 201010127558 A CN201010127558 A CN 201010127558A CN 102188722 A CN102188722 A CN 102188722A
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- magnetic resonance
- resonance imaging
- imaging contrast
- contrast agent
- do3a
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Abstract
The invention discloses a ferrous iron-containing magnetic resonance imaging contrast agent, which has a chemical formula of Fe(tpy-ph-CH2-DO3A)2Gd2. The magnetic resonance imaging contrast agent ligand is synthesized by liquid phase reaction in an organic solvent, and forms a complex with ferrous iron ions in a ratio of 2:1; and the complex can be subjected to complexing with trivalent ions of lanthanide rare-earth elements to obtain a required complex. The magnetic resonance imaging contrast agent has high relaxation efficiency and is used for magnetic resonance imaging diagnosis and an X-ray computed tomography (CT) or gamma scintigraphy diagnosis technology.
Description
Technical field
The present invention relates to a kind of magnetic resonance imaging contrast, be specifically related to a kind of ferrous magnetic resonance imaging contrast that contains.
Background technology
(magnetic resonance imaging is the great achievement of another universally acknowledged medical science that occurs after X-ray CT MRI), and medical practice has been produced tremendous influence in nuclear magnetic resonance.In clinical imaging,, need use magnetic resonance contrast agent above 35% diagnosis in order to improve the contrast of signal between diseased region and normal structure.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 that is used for the clinical magnetic resonance imaging diagnosis at present is mainly the coordination compound of gadolinium or manganese: Gd-DTPA (Magnevist, magnevist), Gd-DOTA (Dotarem, many its spirits), Mn-DPDP (Teslascan, safe happy shadow), Gd-DTPA-BMA (Omniscan, Ou Naiying), Gd-HP-DO3A (Prohance, general network shows to be thought), Gd-BOPTA (MultiHance, Mo Disi) etc., these micromolecule contrast agent have good imaging effect to brain and central nervous system etc., renal metabolism has limited its application but its extracellular distribution reaches faster, particularly to more intravital internal organs such as liver, the radiography effect of kidney is not ideal enough, can not satisfy tissue, organ is requirement optionally.Therefore, developing cheap, hypotoxicity, relaxation efficient is high and particular organization or organ are had the contrast agent of selectivity or targeting, is the developing direction of present magnetic resonance imaging contrast.
In recent years, the main flow of contrast agent research and exploitation is that (Diethylenetriaminepentaacetic acid is DTPA) with 1 to diethylenetriamine pentaacetic acid both at home and abroad, 4,7,10-tetraazacyclododecane ten bicyclo--1,4,7,10-tetraacethyl (1,4,7,10-tetraazacyclododecane-N, N ', N ", N ' " tetraacetic acid, DOTA) and derivant carry out chemical modification, make various types of contrast agent, wherein preparing the magnetic resonance imaging contrast that biological in-vivo metal ion is had response is to study focus (Chem.Soc.Rev., 2010 now, 39,51-60).Ferrum is body burden's essential trace element, and the about 4-5 gram of the total amount of ferrum is the pith of hemoglobin in the human body, and people's whole body all needs it, and it is present in to muscle supplies with in the erythrocyte of oxygen, still needs the composition of multienzyme and immune system chemical compound.The bivalence and the trivalent ion of ferrum are paramagnetic ion, are introduced into magnetic resonance imaging contrast, can play and improve relaxation efficient and particular organization or organ are had selectivity or targeting.
Summary of the invention
The purpose of this invention is to provide a kind of ferrous magnetic resonance imaging contrast that contains.
This magnetic resonance imaging contrast chemical formula is: Fe (tpy-ph-CH
2-DO3A)
2Ln
2, wherein tpy is 2,2:6 ', 2, and " terpyridyl, DO3A are 1,4,7, and 10-tetraazacyclododecanand-1,4,7-triacetic acid, Ln are the trivalent ions of lanthanide series rare-earth elements; This contrast agent has following structure:
This magnetic resonance imaging contrast be by 4 '-(4-toluene bromide base)-2,2:6 ', 2 " terpyridyl (tpy-ph-Br) and 1; 4; 7,10-tetraazacyclododecanand-1,4; part that 7-triacetic acid (DO3A) forms forms 2: 1 coordination compound with ferrous ion, this coordination compound further with the paramagnetic metal complex of the trivalent ion coordination acquisition of lanthanide series rare-earth elements.
Ln is the trivalent lanthanide ion.The trivalent ion of preferred lanthanide series is: Gd
3+, Dy
3+Or Nd
3+
Part (the tpy-ph-CH of the DO3A that described tpy-ph-Br modifies
2-DO3A) have a following structure:
Have the characteristics of very strong coordination ability according to terpyridyl and ferrous iron, with tpy-ph-Br and DO3A reaction, formed part terpyridyl part can with the ferrous iron coordination, then with this coordination compound and the further coordination of paramagnetic metal ion, can obtain good water solubility, the paramagnetic metal complex magnetic resonance imaging contrast that relaxation efficient is high.
The specific embodiment
Concrete enforcement is as follows:
Step 1: three-(tertiary butyloxycarbonyl ylmethyl)-1,4,7,10-tetraazacyclododecanand (DO3A-
tBu) press the literature method preparation.Get an amount of 1,4,7,10-tetraazacyclododecanand, sodium bicarbonate and bromo-acetic acid tert-butyl stirring at room 48 hours in other acetonitrile of HPLC level, 1,4,7, the amount ratio of 10-tetraazacyclododecanand, sodium bicarbonate and bromo-acetic acid tert-butyl is 1:: 3.2: 3.Filter, add a large amount of ether behind the filtrate evaporate to dryness, filter, the insoluble matter vacuum drying gets product.Productive rate 40%.Structure is as follows:
Step 2:4 '-(4-toluene bromide base)-2, " terpyridyl is pressed the literature method preparation for 2:6 ', 2.Get an amount of 4 '-(4-aminomethyl phenyl)-2,2:6 ', 2 " terpyridyl and N-bromo-succinimide are dissolved in the carbon tetrachloride solution, add the azodiisobutyronitrile of catalytic amount, 4 '-(4-aminomethyl phenyl)-2; 2:6 '; 2 " the amount ratio of-terpyridyl and N-bromo-succinimide is 1: 1.1, refluxes filtered while hot 4 hours, filtrate is spin-dried for, and recrystallization gets product.Productive rate 82%.Structure is as follows:
Step 3:tpy-ph-CH
2-DO3A-
tThe preparation of Bu.The product of getting the step 1 of equivalent and step 2 is in acetonitrile and dichloromethane mixed solution, and the volume ratio of acetonitrile and dichloromethane is 1: 1, is warming up to 40 ℃ of reactions 24 hours.Adopt the silica gel chromatographic column isolation technics, obtain product tpy-ph-CH as eluent with methylene chloride-methanol (volume ratio is 25: 1)
2-DO3A-
tBu.Productive rate 60%.Proton nmr spectra (CDCl
3, ppm): 8.77-8.65 (br, 6H), 7.99-7.84 (br, 4H), 7.73 (t, 2H), 7.39 (m, 2H) .ESI-MS (m/z): 837 (M+H
+); 859 (M+Na
+).Structure is as follows:
Step 4:tpy-ph-CH
2The preparation of-DO3A.With tpy-ph-CH
2-DO3A-
tBu is dissolved in trifluoroacetic acid and the dichloromethane mixed solution, and the volume ratio of trifluoroacetic acid and dichloromethane is 1: 1, and stirring at room 24 hours is except that after desolvating, be dissolved in small amount of methanol, add a large amount of oxolane precipitations, filter, vacuum drying obtains product, productive rate 52%.Proton nmr spectra (D
2O, ppm): 8.50 (d, 2H), 8.23 (d, 2H), 8.15 (t, 2H), 7.97 (s, 2H), 7.68 (t, 2H), 7.39 (m, 4H), 3.73 (s, 2H), 3.65-2.76 (br, 22H).Structure is as follows:
Step 5:Fe (tpy-ph-CH
2-DO3A)
2Gd
2Preparation: get tpy-ph-CH
2-DO3A and FeSO
4* 6H
2O is dissolved in an amount of distilled water, tpy-ph-CH
2-DO3A and FeSO
4* 6H
2The amount ratio of O is 2: 1, and stirring at room 4 hours is transferred pH value of solution=6.8 with 1M NaOH, dropwise adds GdCl
3Solution, tpy-ph-CH
2-DO3A and GdCl
3The amount ratio be 1: 1, keep about pH value of solution=6.8 with 1M NaOH, stirring at room 24 hours, solvent evaporated is dissolved in methanol, filters, filtrate is concentrated into small size, adds a large amount of ether, filter, vacuum drying, product, productive rate 81%.Structure is as follows:
Step 6: an amount of step 5 product is dissolved in the heavy water, measures the relaxation time (t of hydrone proton with the inversion recovery method in bruker Avance III (400MHz)
1), recording relaxation efficient is 7.5mM
-1S
-1, be about about 1.5 times of present clinical used contrast agent Gd-DTPA.
Claims (3)
1. one kind contains ferrous magnetic resonance imaging contrast, it is characterized in that: this magnetic resonance imaging contrast chemical formula is: Fe (tpy-ph-CH
2-DO3A)
2Ln
2, wherein tpy is 2,2:6 ', 2, and " terpyridyl, DO3A are 1,4,7, and 10-tetraazacyclododecanand-1,4,7-triacetic acid, Ln are the trivalent ions of lanthanide series rare-earth elements; This contrast agent has following structure:
2. magnetic resonance imaging contrast as claimed in claim 1, it is characterized in that: this contrast agent be by 4 '-(4-toluene bromide base)-2,2:6 ', 2 " terpyridyl and 1,4,7; 10-tetraazacyclododecanand-1; 4, the part that the 7-triacetic acid forms forms 2: 1 coordination compound with ferrous ion, and this coordination compound is further with the trivalent ion coordination acquisition of lanthanide series rare-earth elements.
3. magnetic resonance imaging contrast 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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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552941A (en) * | 2011-12-28 | 2012-07-11 | 中国科学院长春应用化学研究所 | Two-nuclear magnetic resonance imaging contrast agent taking 2,5-dimethylpyrazine as connector and preparation method of two-nuclear magnetic resonance imaging contrast agent |
| CN102584869A (en) * | 2011-12-28 | 2012-07-18 | 中国科学院长春应用化学研究所 | 2-nuclear magnetic resonance imaging contrast agent taking 2, 3-biquinoxaline as connecting body and preparation method thereof |
| CN102614531A (en) * | 2012-04-06 | 2012-08-01 | 中国科学院长春应用化学研究所 | Multi-core non-ion type magnetic resonance imaging contrast agent using diacetyl benzene or triacetyl benzene as linker |
Citations (2)
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| CN1215341A (en) * | 1996-04-01 | 1999-04-28 | Epix医学公司 | Bioactivated diagnostic imaging contrast agents |
| CN1635855A (en) * | 2001-07-30 | 2005-07-06 | 埃匹克斯医疗股份有限公司 | Systems and methods for targeted magnetic resonance imaging of the vascular system |
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2010
- 2010-03-18 CN CN2010101275588A patent/CN102188722A/en active Pending
Patent Citations (2)
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|---|---|---|---|---|
| CN1215341A (en) * | 1996-04-01 | 1999-04-28 | Epix医学公司 | Bioactivated diagnostic imaging contrast agents |
| CN1635855A (en) * | 2001-07-30 | 2005-07-06 | 埃匹克斯医疗股份有限公司 | Systems and methods for targeted magnetic resonance imaging of the vascular system |
Non-Patent Citations (4)
| Title |
|---|
| 《Chem. Commun.》 20040226 Robert Ruloff, et al. "Novel heteroditopic chelate for self-assembled gadolinium(III) complex with high relaxivity 第842页左栏第1段、右栏第2段，第843页图1 1-3 第7卷, 第7期 * |
| ROBERT RULOFF, ET AL.: ""Novel heteroditopic chelate for self-assembled gadolinium(III) complex with high relaxivity", 《CHEM. COMMUN.》 * |
| TZU-MING LEE,ET AL.: "Physicochemical characterization of the dimeric lanthanide complexes [enfLn(DO3A)(H2O)g2] and [pifLn(DTTA)(H2O)g2]2−: a variable-temperature 17O NMR study", 《MAGN. RESON. CHEM.》 * |
| TZU-MING LEE,ET AL.: "Physicochemical characterization of the dimeric lanthanide complexes [enfLn(DO3A)(H2O)g2] and [pifLn(DTTA)(H2O)g2]2−: a variable-temperature 17O NMR study", 《MAGN. RESON. CHEM.》, vol. 42, no. 3, 31 March 2004 (2004-03-31), pages 329 - 336 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552941A (en) * | 2011-12-28 | 2012-07-11 | 中国科学院长春应用化学研究所 | Two-nuclear magnetic resonance imaging contrast agent taking 2,5-dimethylpyrazine as connector and preparation method of two-nuclear magnetic resonance imaging contrast agent |
| CN102584869A (en) * | 2011-12-28 | 2012-07-18 | 中国科学院长春应用化学研究所 | 2-nuclear magnetic resonance imaging contrast agent taking 2, 3-biquinoxaline as connecting body and preparation method thereof |
| CN102584869B (en) * | 2011-12-28 | 2014-01-08 | 中国科学院长春应用化学研究所 | 2-nuclear magnetic resonance imaging contrast agent taking 2, 3-biquinoxaline as connecting body and preparation method thereof |
| CN102614531A (en) * | 2012-04-06 | 2012-08-01 | 中国科学院长春应用化学研究所 | Multi-core non-ion type magnetic resonance imaging contrast agent using diacetyl benzene or triacetyl benzene as linker |
| CN102614531B (en) * | 2012-04-06 | 2013-06-05 | 中国科学院长春应用化学研究所 | Multi-core non-ion type magnetic resonance imaging contrast agent using diacetyl benzene or triacetyl benzene as linker |
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Application publication date: 20110921 |