WO2002043775A2 - Paramagnetic metal ion-based macrocyclic contrast agents - Google Patents
Paramagnetic metal ion-based macrocyclic contrast agents Download PDFInfo
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- WO2002043775A2 WO2002043775A2 PCT/US2001/046151 US0146151W WO0243775A2 WO 2002043775 A2 WO2002043775 A2 WO 2002043775A2 US 0146151 W US0146151 W US 0146151W WO 0243775 A2 WO0243775 A2 WO 0243775A2
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- magnetic resonance
- contrast agent
- carbon atoms
- general formula
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- 0 CCC(CCCC(C)(C1)C(*)C1CC*(*)(*)CC1)C(CC)CC*1(C)N Chemical compound CCC(CCCC(C)(C1)C(*)C1CC*(*)(*)CC1)C(CC)CC*1(C)N 0.000 description 2
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention is directed to contrast agents and methods of using contrast agents for altering the magnetic resonance signal of samples, and more particularly, to paramagnetic metal ion-macrocylic complexes as contrast agents and methods of using such agents for producing image contrast based on a magnetization transfer mechanism.
- Contrast agents are widely used to enhance magnetic resonance imaging (RI) contrast.
- the administration of Extrinsic CAs such as gadolinium (Gd) containing CAs, are thought to achieve contrast by the paramagnetic relaxation effect of a metal-ion to shorten the bulk water relaxation time via rapid exchange of the metal ion's inner-sphere water molecules with bulk solvent.
- Gd gadolinium
- the ability to turn CAs on or off raises the possibility of using such CAs to measure changes in physiological status of tissue samples. For example some CAs exclude Gd from the inner sphere while inactive, and then on activation expose bulk water to a rapidly exchanging water site on the Gd.
- CAs having a slow rate of water exchange are disfavored because this hampers the metal-ion's ability to shorten the bulk water relaxation time and thus enhance contrast.
- Chemical exchange saturation transfer is an alternative technique to enhance MRI contrast. Contrary to the above described CAs, CEST favors CAs having a slow rate of water exchange. For example, intrinsic metabolites with slowly exchangeable NH or OH sites may be saturated to produce a direct intensity decrease in the bulk water signal by Magnetization Transfer (MT) .
- MT Magnetization Transfer
- a magnetic resonance system comprising: a magnetic resonance (MR) contrast agent, wherein the MR agent tetraazacyclododecane ligand has the above described general formula, wherein pendent arms R, R' , R' ' and R' ' ' comprise organic substituents and the tetraazacyclododecane ligand further includes a paramagnetic metal ion coordinated to the tetraazacyclododecane ligand and a water molecule associated with the tetraazacyclododecane ligand, wherein the MR contrast agent produces a magnetization transfer signal when subjected to a radio frequency pulse; and a magnetic resonance apparatus.
- MR magnetic resonance
- FIGURE 7 illustrates an exemplary 1 H NMR spectrum of the Yb(l) 3+ complex produced according to the present invention in the absence of a saturating pulse, and a MT profile for the complex;
- FIGURE 8 illustrates exemplary MR images of a sample contained the Eu(l) 3+ complex (inner cylinder) produced according to the present invention in the absence and presence of a saturating pulse at ⁇ for bound water, and corresponding difference images;
- FIGURE 9 illustrates exemplary MR images of a sample contained the Nd(l) 3+ complex (inner cylinder) produced according to the present invention in the absence and presence of a saturating pulse at ⁇ for bound water, and corresponding difference images;
- FIGURE 10 illustrates an exemplary relationship of the MT effect versus saturation duration time for the Eu(l) 3+ complex
- FIGURE 11 illustrates an exemplary relationship of the MT effect versus saturation power for the Eu(l) 3+ complex
- FIGURE 12 illustrates exemplary MR images of a sample containing the Nd(l) 3+ complex (inner cylinder) produced according to the present invention in the absence and presence of a saturating pulse at ⁇ for bound water with different saturation powers, and corresponding difference images;
- FIGURE 13 illustrates an exemplary 1 H NMR spectrum of the Eu(2) ' complex produced according to the present invention in the absence of a saturating pulse
- FIGURE 14 illustrates an exemplary relationship the pH dependence of the ⁇ M 298 for the bound water molecule of the Eu(2) ' complex of the present invention
- FIGURE 15 illustrates an exemplary relationship the pH dependence of the ⁇ M 298 for protons associated with the amides in the pendent arms of the Eu(2) ⁇ complex of the present invention
- FIGURE 16 illustrates the pH dependence of the MT effect obtained when saturating the bound water molecule of the Eu(2) ⁇ complex of the present invention
- FIGURE 17 illustrates the relationship between the MT effect obtained when saturating the bound water molecule of the Eu(2) ⁇ and the bound water lifetime, ⁇ M 298 , or the exchange limiting regime, ⁇ « ⁇ M ;
- FIGURE 18 illustrates an exemplary 1 H NMR spectrum of the
- Eu(2) ⁇ complex produced according to the present invention in the absence of a saturating pulse, and a MT profile for the complex produced at three different levels of saturating power;
- FIGURE 20 illustrates exemplary MR images of a sample containing the Eu(2) " complex (inner cylinder) produced according to the present invention in the absence and presence of a saturating pulse at ⁇ for amide protons, and corresponding difference images,-
- FIGURE 21 illustrates exemplary MR images of a sample containing the Eu(2) ⁇ complex (inner cylinder) produced according to the present invention in the absence and presence of a saturating pulse at ⁇ for bound water with different saturation powers, and corresponding difference images;
- FIGURE 22 illustrates exemplary MR images of a sample containing the Eu(2) ⁇ complex (inner cylinder) produced according to the present invention in the presence of a saturating pulse at ⁇ for amides protons, and corresponding difference images;
- FIGURE 23 illustrates an exemplary 1 H NMR spectrum of the Yb(9) 3+ complex produced according to the present invention in the absence of a saturating pulse
- FIGURE 24 illustrates an exemplary 1 H NMR spectra of the Yb(9) 3+ complex produced according to the present invention in the absence of a saturating pulse and at different sample pH;
- FIGURE 25 illustrates an exemplary relationship of the pH dependence of the ⁇ M 298 for protons H a and H b associated with the amides in the pendent arms of the Yb(9) 3+ complex of the present invention
- FIGURE 26 illustrates an exemplary a series of bulk water 1 H NMR spectra obtained for an aqueous solution of Yb(9) 3+ complex of the present invention obtained while applying a saturating pulse of different duration and centered between the resonance signal of the H a and H b associated with the amides in the pendent arms of the complex;
- FIGURE 27 illustrates an exemplary relationship between the MT effect obtained for different concentrations of the Yb(9) 3+ complex of the present invention
- FIGURE 29 illustrates an exemplary pH dependence of the
- FIGURE 30 illustrates exemplary ⁇ NMR spectra and MR images of a sample containing the Yb(9) 3+ complex (inner cylinder) produced according to the present invention in the presence of a saturating pulse at ⁇ for amides protons, H a and Hb / associated with the amides in the pendent arms of the complex at two different pHs .
- ri is the relaxivity (mM ⁇ s -1 ) of the CA, originating from both inner- and outer-sphere paramagnetic contributions. See e. g. , Lauffer R.B., 87 CHEM. REV. 901 (1987), incorporated herein by reference.
- the system ideally should be in an exchange limiting regime, defined as ⁇ * ⁇ M ⁇ 1.
- the difference in frequency between the MR frequency of the exchanging sites and the MR frequency of bulk water is defined as ⁇ .
- the life-time of the exchanging site is defined as ⁇ M .
- ⁇ corresponds to about ⁇ 6 ppm to about ⁇ 500 ppm, and preferably about ⁇ 16 ppm to ⁇ 500 ppm. It is therefore possible to saturate the exchanging site while minimizing off-resonance saturation (i.e., direct saturation) of bulk water, and resulting non-specific, detrimental decreased MR signal intensity.
- the CA of the present invention includes a tetraazacyclododecane ligand having a general formula as follows :
- the CA may further include a water molecule, referred to as a bound water molecule, as the exchanging group.
- the bound water molecule is associated with the tetraazacyclododecane ligand and paramagnetic metal ion such that the bound water molecule has a ⁇ » ⁇ M > 1.
- the bound water has a ⁇ > 6 ppm.
- the bound water molecule has the ⁇ M ⁇ 1 ⁇ s .
- the CA further comprises a paramagnetic metal ion coordinated to the tetraazacyclododecane ligand.
- a paramagnetic metal ion is within the scope of the invention, although certain metal ions of the lanthanide group are preferred.
- the preferred metal ion includes one of Eu 3+ , Tb 3+ , Dy 3+ or Ho 3+ .
- the metal ion may also include Pr 3+ , Nd 3+ , Sm 3+ , Er 3+ or Tm 3+ .
- R 2 does not have a proton exchangeable group and is not hydrogen.
- R 2 may comprise alkyl groups having 20 carbon atoms or less, cycloalkyl groups having 20 carbon atoms or less, alkyloxy groups having 20 carbon atoms or less, alkyl ethers having 10 oxygen atoms or less and 20 carbon atoms or less, or polyols having 20 carbon atoms or less.
- Ri may comprise H, alkyl groups having 20 carbon atoms or less, cycloalkyl groups having 20 carbon atoms or less, alkyloxy groups having 20 carbon atoms or less, alkyl ethers having 10 oxygen atoms or less and 20 carbon atoms or less, or polyols having 20 carbon atoms or less.
- FIGURE 1 Another embodiment of the present invention is a method 100 of using a magnetic resonance (MR) contrast agent.
- the method comprises subjecting 110 a contrast agent contained within a sample to a radio frequency (RF) pulse.
- the contrast agent (CA) is a tetraazacyclododecane ligand having the general formula as presented below:
- pendent arms R, R' , R' ' and R' ' ' comprise organic substituents and the tetraazacyclododecane ligand further includes a paramagnetic metal ion (M 3+ ) coordinated to the tetraazacyclododecane ligand and a water molecule (bound H 2 0) associated with the tetraazacyclododecane ligand.
- the method 100 further comprises obtaining 120 a magnetization transfer (MT) signal by applying 130 a radio frequency pulse at a resonance frequency of the water molecule.
- MT magnetization transfer
- the water molecule referred to as a bound water molecule, has a ⁇ « ⁇ M > 1.
- method 100 may further include producing a magnetization transfer MR image 140 from the magnetization transfer signal.
- Method 100 may optionally further include applying a saturating pulse radio 150 frequency pulse to produce the magnetization transfer signal.
- a saturating pulse radio 150 frequency pulse to produce the magnetization transfer signal.
- the CA has at least one, and preferably four, pendent arms containing an amide group.
- Such embodiments of method 100 include obtaining the magnetization transfer signal 120 by applying a radio frequency pulse 160 at a resonance frequency of the protons associated with the amide.
- the radio frequency pulse may be applied at the resonance frequency of one or all of the exchangeable protons associated with the amide to produce a magnetization transfer signal that is sensitive to pH.
- the relationship between pH and the magnetization signal may be further be preferably expressed as a ratio of the MT signal obtained while applying the radio frequency pulse one exchangeable amide proton relative to the MT signal obtained while applying the radio frequency pulse to a second or all of the exchangeable amide protons.
- the pendent arms of the CA each contain an amide group
- the pendent arms are identical and have the general formula: -CHR1-CO-NR2-R3, wherein R 1# R 2 and R 3 comprise organic substituents.
- the Ri and R 2 are H
- the R 3 has the general formula: -
- the CA has pendent arms R and R' ' that are identical, the pendent arms R' and R' ' ' are identical, and the pendent arms R' and R' ' ' are not equal to the pendent arms R and R' ' .
- the pendent arms R and R' ' have the general formula: -CHR ⁇ -CO-NH-R 2 ; and the pendent arms R' and R' ' ' have the general formula: -CHR 3 -CO-NH-R where Ri, R 2 , R 3 , and R comprise organic substituents, and the R2 is not equal to the R 4 .
- the system 200 comprises a magnetic resonance (MR) contrast agent (CA) 210, wherein the MR agent contains a tetraazacyclododecane ligand having the same general formula described for method 100.
- the CA 210 includes pendent arms R, R' , R' ' and R' ' ' that comprise organic substituents.
- CA 210 further includes a paramagnetic metal ion coordinated to a water molecule, referred to as a bound water molecule, associated with the tetraazacyclododecane ligand, where the MR contrast agent produces a magnetization transfer signal when subjected to a radio frequency pulse.
- the CA includes at least one and up to twenty tetraazacyclododecane ligands.
- ligands may be covalently or noncovalently bonded to a carrier, such as a protein or polymer, comprising a portion of the CA. Collecting several such ligands, and associated metal ions and bound water molecules, allows effective MT contrast to be achieved at lower concentrations of CA.
- the system 200 further comprises a magnetic resonance apparatus 220.
- the MR apparatus may include all the hardware and software components necessary to produce magnetic resonance spectra or images .
- the system 200 may further comprise a sample 230 that contains the CA 220 within it.
- the sample includes living subject including animal, for example human, species, or a portion of fluid or tissue withdrawn from the subject.
- the sample 230 containing the CA 220 may be an inanimate object, or contain other non-living material.
- the magnetic resonance apparatus 210 produces a magnetization transfer image 240 of the sample 230 from the magnetization transfer signal.
- Such a system 200 may preferably produce the image by applying the radio frequency pulse at a resonance frequency of the bound water molecule 250.
- the radio frequency signal may be applied at the resonance frequency of protons associated with an amide included in one or more of the pendent arms of the CA 260.
- the magnetic resonance apparatus produces a magnetization transfer difference signal 255 by applying the radio frequency pulse at a ⁇ of the bound water molecule, acquiring the magnetization transfer signal and subtracting the signal from a MR signal obtained by applying a radio frequency pulse at - ⁇ .
- a difference signal may be produced in analogous fashion, by applying the radio frequency pulse at a ⁇ of the protons associated with amides 265 in the pendent arms of the CA 210 and subtracting the signal from a MR signal obtained by applying a radio frequency pulse at - ⁇ .
- either difference signals 255, 265 may be further processed by the apparatus 220 to produce a difference image.
- the magnetic resonance system 200 may further include in the apparatus 220 hardware that produces a saturating pulse 270.
- the saturating pulse is preferably sufficiently frequency specific to saturate only the exchangeable protons, for example the bound water or the protons associated with the amides contained within the pendent arms of the CA 210.
- the saturating pulse preferably ranges from about 1 to about 3 seconds .
- the CA 210 used in the MR system 200 may include any of the embodiments of CA discussed above in the method 100.
- the exchangeable proton within the CA 210, for example bound water preferably has a ⁇ « ⁇ M ⁇ 1. In certain embodiments of the MR system 200, the ⁇ > 6 ppm. In other preferred embodiments of the MR system 200, the ⁇ M > 1 ⁇ s .
- CAs prepared according to the present invention are presented below for illustrative purposes and do not limit the scope of the claimed invention.
- the synthesis of polyazamacrocyles having pendent arms comprising organic substitutants has been described in: U.S. Patent 5,428,155, to Sherry A.D. and van estrenen, J.; Kovacs and Sherry, pH- Controlled Selective Protection of Polyaza Macrocycles, SYNTHESIS, 761-63, (July 1997); Zhang S., Winter P., Wu. K. & Sherry A.D., A Novel Europium (III) -Based Contrast Agent, 123 J.AM.CHEM.SOC. 1517-18 (2001); Zhang S., Wu. K.
- a first experiment examined the life times at 298°K, ⁇ M 298 , of water molecules bound to various lanthanide-macrocylic complexes of the present invention, and having the general formula, Ln(l) 3+ , where the four pendent arms R, R' , R' ' and
- R' are all ethyl -acetamidoacetate ( i . e . , LnDOTA-4AmC ⁇ 3+ ⁇ as
- ⁇ M 298 is strongly dependent on the radius of the central lanthanide ion.
- the plot shows the ⁇ M 298 measured for a series of Ln(l) 3+ complexes in acetonitrile plus 2-4% water versus the Ln 3+ ionic radii.
- Individual ⁇ M 298 values were obtained by fitting the temperature dependent 17 0 NMR bound water line widths according to standard exchange theory. In a separate series of experiments, it was found that ⁇ M 298 was about 2-fold shorter when pure water was the solvent.
- FIGURE 9 shows analogous images for a phantom with no saturation (left, nosat) , saturation at -6400 Hz (middle, Satp) the resonance frequency of Nd 3+ -bound water, saturation at +6400 (right, satn) , and the corresponding difference images.
- the inner vial contains 62.5 mM Nd(l) 3+ at neutral pH, while the outer vial is pure water.
- the irradiation duration time was 2 s, with a power of 41 db by using a 2.5 cm surface coil.
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Abstract
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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AU2002241576A AU2002241576A1 (en) | 2000-11-20 | 2001-11-20 | Paramagnetic metal ion-based macrocyclic contrast agents |
EP01988253A EP1390079A2 (en) | 2000-11-20 | 2001-11-20 | Paramagnetic metal ion-based macrocylic contrast agents |
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US25226900P | 2000-11-20 | 2000-11-20 | |
US60/252,269 | 2000-11-20 |
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WO2002043775A2 true WO2002043775A2 (en) | 2002-06-06 |
WO2002043775A3 WO2002043775A3 (en) | 2003-12-18 |
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PCT/US2001/046151 WO2002043775A2 (en) | 2000-11-20 | 2001-11-20 | Paramagnetic metal ion-based macrocyclic contrast agents |
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US (1) | US6875419B2 (en) |
EP (1) | EP1390079A2 (en) |
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WO (1) | WO2002043775A2 (en) |
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WO2003063912A1 (en) * | 2002-01-29 | 2003-08-07 | Bracco Imaging S.P.A. | Responsive paramagnetic mri contrast agents |
EP1466629A1 (en) * | 2003-04-11 | 2004-10-13 | BRACCO IMAGING S.p.A. | Adducts between magnetic resonance shift reagents and substrates containing exchangeable protons for "CEST" applications |
WO2006114765A2 (en) | 2005-04-26 | 2006-11-02 | Koninklijke Philips Electronics N.V. | Mri involving contrast agent with time modulated contrast enhancement |
WO2006121889A2 (en) * | 2005-05-06 | 2006-11-16 | Epix Pharmaceuticals, Inc. | Chemical exchange saturation transfer contrast agents |
WO2006032705A3 (en) * | 2004-09-23 | 2006-12-21 | Guerbet Sa | Contrast agents encapsulating systems for cest imaging |
WO2006114738A3 (en) * | 2005-04-26 | 2007-06-21 | Koninkl Philips Electronics Nv | Mri contrast agents comprising cest active paramagnetic complex |
WO2012059576A1 (en) * | 2010-11-05 | 2012-05-10 | Bracco Imaging Spa | Cest systems exhibiting a concentration independent responsiveness |
US9050378B2 (en) | 2003-12-10 | 2015-06-09 | Board Of Regents, The University Of Texas System | N2S2 chelate-targeting ligand conjugates |
US10207013B2 (en) | 2014-03-17 | 2019-02-19 | The Board Of Regents Of The University Of Texas Systems | Gadolinium-based contrast agents for sensitive detection of Zn2+ with MRI |
US10814013B2 (en) | 2006-10-05 | 2020-10-27 | The Board Of Regents Of The University Of Texas System | Efficient synthesis of chelators for nuclear imaging and radiotherapy: compositions and applications |
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EP1178837A2 (en) * | 1999-04-21 | 2002-02-13 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Method for enhancing contrast produced by mri |
AU2002241576A1 (en) * | 2000-11-20 | 2002-06-11 | Board Of Regents University Of Texas System | Paramagnetic metal ion-based macrocyclic contrast agents |
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US7330028B2 (en) * | 2005-09-26 | 2008-02-12 | General Electric Company | Apparatus and method of simultaneous fat suppression, magnetization transfer contrast, and spatial saturation for 3D time-of-flight imaging |
US8003078B2 (en) * | 2006-03-29 | 2011-08-23 | Barnes-Jewish Hospital | Targeted MR imaging agents |
CA2650574A1 (en) * | 2006-04-27 | 2007-11-08 | Barnes-Jewish Hospital | Detection and imaging of target tissue |
US20090142273A1 (en) * | 2006-06-08 | 2009-06-04 | Case Western Reserve University | Activatable cest MRI agent |
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US11246949B2 (en) * | 2011-05-11 | 2022-02-15 | The Research Foundation For The State University Of New York | Imaging contrast agents and uses thereof |
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- 2001-11-20 US US10/001,858 patent/US6875419B2/en not_active Expired - Fee Related
- 2001-11-20 EP EP01988253A patent/EP1390079A2/en not_active Withdrawn
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US6875419B2 (en) | 2005-04-05 |
AU2002241576A1 (en) | 2002-06-11 |
EP1390079A2 (en) | 2004-02-25 |
US20020127182A1 (en) | 2002-09-12 |
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