WO2007128873A1 - Procédé de préparation de dérivés maléimido de réactifs de marquage de biomolécules et leurs conjugués dérivés - Google Patents

Procédé de préparation de dérivés maléimido de réactifs de marquage de biomolécules et leurs conjugués dérivés Download PDF

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Publication number
WO2007128873A1
WO2007128873A1 PCT/FI2007/050247 FI2007050247W WO2007128873A1 WO 2007128873 A1 WO2007128873 A1 WO 2007128873A1 FI 2007050247 W FI2007050247 W FI 2007050247W WO 2007128873 A1 WO2007128873 A1 WO 2007128873A1
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Prior art keywords
chelate
chelating agent
compound
formula
lanthanide
Prior art date
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PCT/FI2007/050247
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English (en)
Inventor
Jari Hovinen
Original Assignee
Wallac Oy
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Priority claimed from FI20065291A external-priority patent/FI20065291A0/fi
Application filed by Wallac Oy filed Critical Wallac Oy
Publication of WO2007128873A1 publication Critical patent/WO2007128873A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/13—Labelling of peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials

Definitions

  • This invention relates to chelating agents or metal chelates, such as lanthanide(III) chelates tethered to a maleimido function and biomolecule conjugates derived thereof.
  • Time-resolved fluorometry exploits the unique fluorescence properties of lanthanide ⁇ i) chelates.
  • the long fluorescence decay after excitation of these molecules allows time-delayed signal detection. This eliminates background signal originating e.g. from microplates or buffer components.
  • the large Stokes shift i.e. the difference in the chelate's excitation and emission lines, in turn, results in a high signal-to-background ratio.
  • Thiols are know to react with haloacetamides, maleimides, disulfides and their analogues, mercurials, vinyl sulfones, aryl halides, aziridines and oxiranes [Brocklehurst, K. 1979, Int. J. Biochem., 10, 258].
  • the reactions of haloacetamides, maleimides and disulfides are the most commonly employed [Aslam, M., Dent, A., Bioconjugation, Macmillan Reference Ltd, London, 1998]. From them, the haloacetyl derivatives display a wide range of other reactivities, while disulfides are practically completely specific to thiols.
  • maleimides The reactivity of maleimides is between them.
  • the problem of the use of disulfides is the lability of the bioconjugate in the presence of reducing agents which are often present in the conjugation reaction.
  • reducing agents which are often present in the conjugation reaction.
  • Various mercapto selective biomolecule labeling reactants are currently commercially available.
  • the known mercapto selective luminescent lanthanide(III) chelates are haloacetamido or maleimido [Takalo, H., Mukkala, V.-M., Mikola, H., Liitti, P., Hemmila, L, 1994, Bioconjugate Chem., 5, 278; Chen, J., Selvin, P.R., 1999, Bioconjugate Chem. 10, 311] derivatives.
  • the labeling reaction is often performed in the presence of a reducing agent, most commonly tris-carboxyethyl phosphine (TCEP).
  • TCEP tris-carboxyethyl phosphine
  • the reducing agent reacts with the haloacetamido chelate reducing markedly the yield of the desired biomolecule conjugate.
  • TCEP also reduces disulfide derivatized labeling reactants, such as pyridylthioates.
  • maleimido group is stable under the reaction conditions required in solid phase oligopeptide synthesis [Machan, V., 2006, Chemiedozententagung, A26]. Furthermore, maleim ⁇ de reacts faster at neutral pH with mercaptans than haloacetamides, which became exploitable at considerably higher pH values [Schelte, P., Boeckler, C, Frisch. B., Schuber, F., 2000, Bioconjugate Chem., 11, 118].
  • Lanthanide(i ⁇ ) chelates are most commonly prepared by treatment of the free ligands with a slight excess of lanthanide chloride at pH 6-7. When the chelation is completed, the excess of lanthanide is removed by increasing pH of the reaction mixture to ca 11 where the uncomplexed lanthanide precipitates as lanthanide(III) hydroxide.
  • this procedure cannot be used with activated chelates due to the lability of the activating groups under basic conditions. This problem can be solved by using an ion transfer loaded with the desired metal ion as the ion source [Stavrianpoulous, US 4,767,609].
  • the main object of the present invention is to provide a method for the preparation chelating agents and metal chelates thereof tethered to maleimido function, useful for labeling of mercapto functions of biomolecules for use as probes in time resolved fluorescence spectroscopy, magnetic resonance imaging (MRT) or positron emission tomography (PET) and single positron emission computed tomography (SPECT).
  • MRT magnetic resonance imaging
  • PET positron emission tomography
  • SPECT single positron emission computed tomography
  • the major advantages of the present invention are: (i) The maleimido function can be coupled to the protected Hgand giving rise to hydrophobic, stable conjugates which can be synthesized in large scale and purified on classical column chromatography.
  • the protection groups can be removed with acid, and the free ligand can be converted to the corresponding lanthanide(IH) chelate by treatment with ion exchange resin loaded with lanthanide ions.
  • the invention concerns a method for the preparation of a chelating agent or metal chelate of formula (I),
  • X is a chelating agent able to bind a metal ion or a metal chelate
  • L is a linker
  • L 1 and L are linkers or are missing, A 1 and A 2 are reactive groups, and G is a chelating agent comprising a chelating part having carboxylic acid or phosphonic acid groups which are protected, and optionally a chromophoric moiety, optionally in the presence of an activator or a catalyst, to form a compound of formula (IT)
  • the invention concerns a labeling reactant, which is a chelating agent or a lanthanide chelate of formula (I),
  • L is a linker and X is a luminescent or non-luminescent lanthanide chelate, or a chelating agent able to chelate a metal to create said lanthanide chelate, wherein said chelating agent comprises a chelating part and optionally a chromophoric moiety comprising of one or more noncondensed aromatic units, wherein said aromatic units optionally are substituted.
  • the invention concerns a compound of formula (II)
  • L is a linker and G is a chelating agent comprising a chelating part having carboxylic acid or phosphonic acid groups which are protected, and optionally a chromophoric moiety.
  • the invention concerns a biospecific binding reactant conjugated with the labeling reactant according to this invention.
  • the reactive groups A 1 and A 2 can be any groups able to react with each other and form a covalent bond in the presence or absence of an activator or a catalyst.
  • the reactive groups are preferably selected from the group consisting of carboxyl, carbonyl, active ester, acid halide, aromatic halide, aminooxy, thioester, amino, alkynyl, azido, hydroxyl, and a group with pKg ⁇ 14.
  • the nature of the activator and the catalyst is dependent on the coupling reaction.
  • a coupling reaction between the maleimido derivative tethered to a carboxylic acid group and the amino derivative of the protected chelating agent in the presence of an activator is those commonly used in the formation of peptide bonds, including DCC, HOBT and HATU.
  • the maleimido derivative has to be preactivated in situ prior to the addition of the addition of the protected chelating agent, and the reaction is performed in the presence of an organic base, most commonly DIPEA.
  • the most suitable solvents are DMF, acetonitrile, THF and chlorinated hydrocarbons.
  • the protected chelating agents tethered to the maleimido group of formula (II) are hydrophopic, stable organic molecules, they can be purified by means of chromatography.
  • chromatographic methods are column chromatography on silica gel and aluminum oxide.
  • the reactive groups required for the reactions disclosed in (i)-(xii) can be directly attached to maleimide or to the protected chelating agent, or via linkers L 1 and lA After completed reaction the linker L is formed.
  • the protected chelating agent G is able to chelate a metal ion after it is deprotected and treated to the said metal ion, and comprises an optional chromophoric moiety and at least three protected carboxylic acid or phosphonic acid groups.
  • the protected chelating agent G is selected from a group consisting of wherein Z is independently selected from ftiryl, thienyl, phenyl or phenylethynyl, where phenyl is substituted or unsubstitued, or Z is not present, wherein G is a radical of any of the aforementioned structures and tethered to L, and R" an alkyl ester of an allyl ester.
  • Z is substituted phenyl, said phenyl is preferably trialkoxysubstituted, more preferably trimethoxysubstituted.
  • this invention concerns the method for the conversion of the said protected chelating agent tethered to the maleimido function (II) to the corresponding metal chelate of formula (I), and comprises (i) removal of the said ester protecting groups; (ii) and treatment of the resulting deprotected ligand with the appropriate metal salt.
  • acid labile protecting groups are the most suitable protecting groups.
  • Particularly preferable protecting group is /-butyl group.
  • the preferable method for the conversion of the said deprotected chelating agent to the corresponding metal chelate is by treatment with ion exchange resin loaded with the corresponding metal ions.
  • the most preferable ion exchange resin is Dowex-50.
  • this invention concerns chelating agents or lanthanide( ⁇ i) chelates of formula (I)
  • Ln is lanthanide, or is not present .
  • the most preferable lanthanides are europium, terbium, samarium, dysprosium, gadolinium and holmium.
  • the chelating agent or the chelate is preferably one of the following structures
  • Z is independently selected from furyl, thienyl, phenyl or phenylethynyl, where phenyl is substituted or unsubstitued, or Z is not present, wherein X is a radical of any of the aforementioned structures and tethered to the linker L and Ln is lanthanide.
  • Ln 3+ is missing.
  • Z is substituted phenyl, said phenyl is preferably trialkoxysubstituted. more preferably trimethoxysubstituted.
  • Lanthanide is most preferably selected from the group consisting of europium, terbium, samarium, dysprosium, gadolinium, and holmium.
  • the target i.e the biospecific binding reactant
  • the target can be a oligopeptide, protein or any bioactive molecule containing one or more mercapto groups.
  • the invention is further elucidated by the following non-restricting examples.
  • the structures and synthetic routes employed in the experimental part are depicted in Schemes 1 and 2.
  • Experimental details are given in Examples 1-4.
  • Scheme 1 illustrates synthesis of luminescent lanthanide(i ⁇ ) chelates tethered to a maleimido group.
  • Experimental details are given in Examples 1-5.
  • Scheme 2 illustrates the reaction between the conjugate molecule and a model peptide containing a single cysteine residue in its structure. Experimental details are given in Example 5.
  • Adsorption column chromatography was performed on columns packed with silica gel 60 (Merck).
  • the cation exchange resin (Dowex 50 X 8, 20-50 mesh, H + form) was converted to the Ln 3+ form by treatment with the appropriate lanthanide(i ⁇ ) chloride followed by washing with water until pH of the eluent was neutral.
  • 6-(2,5- dioxo-2H-pyrrol-l(5H)-yl)hexanoic acid, and the model peptide (CVEIDK) were purchased from Fluka and Sigma-Genosys, respectively.
  • NMR spectra were recorded on a Bracker 600 spectrometer operating at 600.13 MHz for H. The signal of TMS was used as an internal ( 1 H) reference.
  • Example 1 The synthesis of tetra(tert-butyl) 2,2',2",2'" ⁇ 4-(4-(6-(2,5-dioxo-2H- pyrrol- 1 (5H)-yl)hexylcarboxamido)phenylethynyl]pyridine-2,6-diyl]bis- (methylenenitrilo) ⁇ tetrakis(acetate), 1.
  • 6-(2,5-dioxo-2H-pyrrol-l(5H)-yl)hexanoic acid 60 mg, 0.28 mmol
  • O-(7- azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate 100 mg, 0.28 mmol
  • ⁇ N-diisopropylethylamine 73 ⁇ L, 0.56 mmol
  • Tetra(t ⁇ rt-butyl) 2,2 ',2 ",2 ' ' '-[[4-[(4-aminophenyl)ethynyl]pyridine-2,6- diyl]bis(methylenenitrilo)]tetrakisacetate (100 mg, 0.18 mmol), synthesized as disclosed in Takalo, H., Hanninen, E., Kankare, J., 1993, HeIv. Chim. Acta, 76, 877, was added and the reaction was allowed to proceed overnight at RT. The reaction mixture was diluted with dichloromethane (50 mL) and washed with 10% citric acid. The organic layer was dried over Na 2 SO 4 and concentrated.
  • Example 2 The synthesis of tetra(tert-butyl) 2,2',2",2'"- ⁇ 6,6'- ⁇ 4"-2-[4-(6-(2,5- dioxo-2H-pyrrol-l (5H)-yl)hexyl)carboxamido ⁇ henyl)ethyl]pyrazole-l ",3 "- diyl ⁇ bis(pyridine)-2,2 r -diyl ⁇ bis(methylenenitrilo) ⁇ tetrakis(acetate) 2.
  • Example 3 The synthesis of 2,2'.2" 5 2'" ⁇ 4-(4-(6-(2,5-dioxo-2-H-pyrrol-l(5H)- yl)hexylcarboxamido)phenylethynyl]pyridine-2,6-diyl]bis- (methylenenitrilo) ⁇ tetrakis(acetic acid) euro ⁇ ium(HI) 3.
  • Example 4 The synthesis of 2,2 ⁇ 2 ",2'"- ⁇ ⁇ 6,6 '- ⁇ 4 ' '-2-[4-(6-(2,5-dioxo-2H-pyrrol- 1 (5H)-yl)hexyl)carboxamidophenyl)ethyl]pyrazole-l ",3 ' '-diyl ⁇ bis(pyridine)-2,2 '- diyl ⁇ bis(methylenenitrilo) ⁇ tetrakis(acetic acid) terbium( ⁇ i) s 4.
  • Example 5 Labeling of the oligopeptide with the europium chelate 3.
  • the model peptide (AC-CVEIDK-CONH 2 ) (1 mg) was dissolved in Tris HCl buffer (1 mL; pH 7).
  • Compound 3 (1 equiv.) was added, and the reaction was allowed to proceed for 1 h at RT. Purification on HPLC yielded the desired oligopeptide conjugate. t R 18.14 min.

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Abstract

La présente invention concerne un nouveau procédé destiné à la préparation d'agents chélateurs ou de chélates métalliques, en particulier de chélates de lanthanides (III), reliés à une fonction maléimido, ainsi que de nouveaux produits finaux et des intermédiaires produits à l'aide de ce procédé. L'invention concerne également des biomolécules conjuguées dérivées de ces agents chélateurs.
PCT/FI2007/050247 2006-05-05 2007-05-04 Procédé de préparation de dérivés maléimido de réactifs de marquage de biomolécules et leurs conjugués dérivés WO2007128873A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US79767406P 2006-05-05 2006-05-05
FI20065291 2006-05-05
US60/797,674 2006-05-05
FI20065291A FI20065291A0 (fi) 2006-05-05 2006-05-05 Biomolekyylien leimausreagenssien maleimidojohdannaisia ja niistä johdettuja konjugaatteja
US84203606P 2006-09-05 2006-09-05
US60/842,036 2006-09-05

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102732246A (zh) * 2012-06-15 2012-10-17 大连理工大学 一种具有细胞膜通透性的铕配合物单线态氧荧光探针及其应用
WO2013054046A1 (fr) * 2011-10-12 2013-04-18 Centre National De La Recherche Scientifique Sondes luminescentes pour le marquage biologique et l'imagerie, leur procede de preparation
US10137209B2 (en) 2015-06-04 2018-11-27 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US11814369B2 (en) 2016-11-28 2023-11-14 Bayer Pharma Aktiengesellschaft High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging
US11944690B2 (en) 2018-11-23 2024-04-02 Bayer Aktiengesellschaft Formulation of contrast media and process of preparation thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4767609A (en) * 1984-01-30 1988-08-30 Enzo Biochem, Inc. Therapeutic and diagnostic processes using isotope transfer to chelator-target recognition molecule conjugate
WO1988008422A1 (fr) * 1987-04-22 1988-11-03 Schering Aktiengesellschaft Complexants cyliques substitues, complexes et sels de complexes, leur procede de production et substances pharmaceutiques les contenant
US5053503A (en) * 1989-02-17 1991-10-01 Centocor Chelating agents
JPH06135932A (ja) * 1992-10-30 1994-05-17 Doujin Kagaku Kenkyusho:Kk 新規なエチレンジアミン四酢酸誘導体
EP1419786A1 (fr) * 2002-11-13 2004-05-19 Bracco Imaging S.p.A. Méthode pour sélectivement et quantitativement fonctionnaliser des fragments Fab d'immunoglobuline, molécules conjuguées utilisant ceux-ci et ses compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4767609A (en) * 1984-01-30 1988-08-30 Enzo Biochem, Inc. Therapeutic and diagnostic processes using isotope transfer to chelator-target recognition molecule conjugate
WO1988008422A1 (fr) * 1987-04-22 1988-11-03 Schering Aktiengesellschaft Complexants cyliques substitues, complexes et sels de complexes, leur procede de production et substances pharmaceutiques les contenant
US5053503A (en) * 1989-02-17 1991-10-01 Centocor Chelating agents
JPH06135932A (ja) * 1992-10-30 1994-05-17 Doujin Kagaku Kenkyusho:Kk 新規なエチレンジアミン四酢酸誘導体
EP1419786A1 (fr) * 2002-11-13 2004-05-19 Bracco Imaging S.p.A. Méthode pour sélectivement et quantitativement fonctionnaliser des fragments Fab d'immunoglobuline, molécules conjuguées utilisant ceux-ci et ses compositions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ARANO Y. ET AL.: "Reassessment of Diethylenetriaminepentaacetic Acid (DTPA) as a Chelating Agent for Indium-111 Labeling of Polypeptides Using a Newly Synthesized Monoreactive DTPA Derivative", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, 1996, pages 3451 - 3460, XP000197344 *
ARANO Y. ET AL.: "Stability of a Metabolizable Ester Bond in Radioimmunoconjugates", NUCLEAR MEDICINE & BIOLOGY, vol. 23, 1996, pages 129 - 136 *
OKABAYASHI Y. ET AL.: "High-Performance Liquid Chromatography for Amino Compounds and Thiol Compounds Derivatized with Europium Chelate", ANALYTICAL CHEMISTRY, vol. 66, no. 9, 1994, pages 1448 - 1453 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013054046A1 (fr) * 2011-10-12 2013-04-18 Centre National De La Recherche Scientifique Sondes luminescentes pour le marquage biologique et l'imagerie, leur procede de preparation
FR2981349A1 (fr) * 2011-10-12 2013-04-19 Centre Nat Rech Scient Sondes luminescentes pour le marquage biologique et l'imagerie, leur procede de preparation
US9388202B2 (en) 2011-10-12 2016-07-12 Centre National De La Rechrche Scientifique Luminescent probes for biological labeling and imaging, method for preparing same
CN102732246A (zh) * 2012-06-15 2012-10-17 大连理工大学 一种具有细胞膜通透性的铕配合物单线态氧荧光探针及其应用
US10137209B2 (en) 2015-06-04 2018-11-27 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US10722601B2 (en) 2015-06-04 2020-07-28 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US11491245B2 (en) 2015-06-04 2022-11-08 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US11814369B2 (en) 2016-11-28 2023-11-14 Bayer Pharma Aktiengesellschaft High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging
US11944690B2 (en) 2018-11-23 2024-04-02 Bayer Aktiengesellschaft Formulation of contrast media and process of preparation thereof

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