WO1997014443A1 - Substances chimiotactiques marquees magnetiquement comme agents de contraste pour l'imagerie par rmn de tissus vivants cibles - Google Patents

Substances chimiotactiques marquees magnetiquement comme agents de contraste pour l'imagerie par rmn de tissus vivants cibles Download PDF

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Publication number
WO1997014443A1
WO1997014443A1 PCT/IB1996/001103 IB9601103W WO9714443A1 WO 1997014443 A1 WO1997014443 A1 WO 1997014443A1 IB 9601103 W IB9601103 W IB 9601103W WO 9714443 A1 WO9714443 A1 WO 9714443A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
tetraazacyclododecane
peptides
do3a
glycyl
Prior art date
Application number
PCT/IB1996/001103
Other languages
English (en)
Inventor
Michael F. Tweedle
Krishan Kumar
Stephen Eaton
Original Assignee
Bracco International B.V.
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 Bracco International B.V. filed Critical Bracco International B.V.
Priority to EP96932764A priority Critical patent/EP0814849A1/fr
Priority to JP9515662A priority patent/JPH10511701A/ja
Publication of WO1997014443A1 publication Critical patent/WO1997014443A1/fr

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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
    • A61K49/14—Peptides, e.g. proteins
    • 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
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • 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
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
    • A61K49/1839—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule the small organic molecule being a lipid, a fatty acid having 8 or more carbon atoms in the main chain, or a phospholipid
    • 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
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1866—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
    • 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
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1896—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes not provided for elsewhere, e.g. cells, viruses, ghosts, red blood cells, virus capsides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins

Definitions

  • N(X)-Y-Leu-Phe-Z-W where X is a protective formyl, acetyl or t-Boc group; Y is methionine or norleucine; W is a label, e.g. an EDTA or DTPA chelate of a radioactive or paramagnetic isotope covalently attached to the peptide, and Z is a bond or a linker, e.g. Lys or Nle-Tyr-Lys.
  • the reference also describes the injection of the radioactive labeled chemotactic peptides into experimental rats previously infected in the thighs with strains of E . col i , and the subsequent localization of the infection sites by hourly serial ⁇ -camera images.
  • the chelates or chelatant molecules are suitably derivatized to carry groups to effect bonding in the preparation of the magnetically labeled chemoattractants of the invention.
  • DO3A can be successively converted to its p-aminophenyl- and p-iothiocyanatophenyl-acetamido derivatives according to the following scheme:
  • Example 5b A solution of LiOH (110 mg, 2.62 mmol) in dioxane-water (5 mL, 4:1) was added to the product in Example 5b (0.70 g, 0.75 mmol) and stirred at room temperature for 4 h.
  • the reaction mixture was diluted to ⁇ 10 mL with water and pH of the solution adjusted to ⁇ 4.00 with KHSO 4 solution.
  • the solution was evaporated under vacuum to afford a foamy solid.
  • the soild was then subjected to preparative reversed-phase HPLC purification using water-acetonitrile (0.1% TFA) as eluant to separate diastereoisomers resulting from the D- and L-forms of phenylalanine.
  • Trimethyl-N-formyl-L-methionyl-L-leucyl-L-phenylalanyl-L-iso-leucinyl)-N-(4-aminophenyl)acetamido]-1,4,7,10-tetra-azacyclododecane-1,4,7-triacetate) (0.35 g, 0.33 mmol) was added to a solution of LiOH (50 mg, 1.2010 mmol) in dioxane-water (3:1) (15 mL). The reaction mixture was stirred at room temperature for 3 h. Water (20 mL) was added to the reaction mixture and the pH of the solution was adjusted to 4.00 by the addition of KHSO 4 solution.
  • the isothicyanate DTPA derivative, (ITC-DTPA, Structure I) is synthesized according to M.W. Brechbiel et al. in Inorg. Chem. 25 (1986), 2772 or Bioconj. Chem. 2 (1991), 187.
  • the Gd(III) complex of ITC-DTPA is prepared in situ by mixing equimolecular quantities of the ligand and GdC13 in a suitable solvent ad raising the pH of the mixture slowly.
  • the conjugation of the chelate and the chemotactic peptide (see the previous Examples), and its final purification, is achieved according to the method given in the next Example for the conjugation of Gd(IPA-DO3A).
  • ITC-DTPA is made by usual means from the corresponding aniline (Structure II)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nanotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Hematology (AREA)
  • Virology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des substances chimiotactiques marquées magnétiquement, par exemple, des peptides chimiotactiques, pour effectuer des investigations et des diagnostics sur des sites ou des organes malades ou atteints chez des humains ou chez des animaux. Les peptides chimiotactiques ont la formule générale N(X)-Y-Leu-Phe-Z-A-W. Dans cette formule, (X) est H ou un groupe protecteur tel que le formyle, acétyle, t-Boc et similaire; Y est Nle ou Met; Z est une liaison chimique, un acide aminé ou un oligopeptide, tel que (N(η))Lys, Ile, Asp, Nle-Tyr-Lys ou (Gly)n, n étant compris entre 1 et 4; A est un groupe de liaison; et W est un chélate macrocyclique paramagnétique modifié chimiquement de manière appropriée ou une particule magnétique. L'invention concerne également des compositions administrables et acceptables sur le plan physiologique, contenant les substances chimiotactiques marquées, des procédés pour préparer ces substances, des formulations les contenant et des procédés d'utilisation de ces formulations pour détecter, localiser et diagnostiquer, dans l'organisme, des sites infectés ou atteints d'une inflammation, ou d'autres traumatismes.
PCT/IB1996/001103 1995-10-19 1996-10-18 Substances chimiotactiques marquees magnetiquement comme agents de contraste pour l'imagerie par rmn de tissus vivants cibles WO1997014443A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP96932764A EP0814849A1 (fr) 1995-10-19 1996-10-18 Substances chimiotactiques marquees magnetiquement comme agents de contraste pour l'imagerie par rmn de tissus vivants cibles
JP9515662A JPH10511701A (ja) 1995-10-19 1996-10-18 生体組織のｎｍｒイメージングにおける標的コントラスト剤としての磁気標識化学誘引剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US566995P 1995-10-19 1995-10-19
US60/005,669 1995-10-19

Publications (1)

Publication Number Publication Date
WO1997014443A1 true WO1997014443A1 (fr) 1997-04-24

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Country Status (3)

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EP (1) EP0814849A1 (fr)
JP (1) JPH10511701A (fr)
WO (1) WO1997014443A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033947A1 (fr) * 1997-12-24 1999-07-08 Henkel Kommanditgesellschaft Auf Aktien Utilisation de complexes de metaux de transition avec des ligands dendrimeres pour renforcer l'effet de blanchiment de composes peroxygene
WO2004029080A1 (fr) * 2002-09-27 2004-04-08 Nihon Medi-Physics Co., Ltd. Compose se liant aux leucocytes, et composition medicale renfermant le compose a l'etat marque comme principe actif
US6872536B1 (en) * 1998-11-10 2005-03-29 Bracco Imaging S.P.A. Chemotactic peptide antagonists for imaging sites of inflammation
US8414926B1 (en) 2006-09-12 2013-04-09 University Of South Florida Nanoparticles with covalently bound surfactant for drug delivery
WO2015123654A1 (fr) 2014-02-17 2015-08-20 The Cleveland Clinic Foundation Nanoparticules amine-passivées pour le traitement et l'imagerie du cancer
WO2018017985A1 (fr) 2016-07-21 2018-01-25 Case Western Reserve University Structures de particules de virus végétal ou de type viral
US10086095B2 (en) 2012-10-09 2018-10-02 Case Western Reserve University Rod-shaped plant virus nanoparticles as imaging agent platforms
WO2021195716A1 (fr) * 2020-04-02 2021-10-07 Monash University Conjugués antibiotiques
US11193111B2 (en) 2013-01-17 2021-12-07 Case Western Reserve University Viral nanoparticle multimers

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4511075B2 (ja) * 2001-04-23 2010-07-28 レンゴー株式会社 含硫ウレタン系デンドリマー及びその製造方法
US8175678B2 (en) 2005-09-13 2012-05-08 Koninklijke Philips Electronics N.V. Multiple contrast agent injection for imaging
ES2432393T3 (es) * 2006-08-30 2013-12-03 Ge Healthcare As Procedimiento de polarización nuclear dinámica (PND), y compuestos y composiciones para su uso en el procedimiento

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0125995A2 (fr) * 1983-05-12 1984-11-21 Advanced Magnetics, Inc. Particules magnétiques pour l'utilisation dans des séparations
WO1988000060A1 (fr) * 1986-07-03 1988-01-14 Advanced Magnetics, Inc. Materiau super paramagnetique biodegradable utilise dans des applications cliniques
EP0398143A1 (fr) * 1989-05-09 1990-11-22 The General Hospital Corporation Peptides chimiotactiques marqués pour visualiser des sites d'inflammation ou d'infection
EP0403961A2 (fr) * 1989-06-19 1990-12-27 BEHRINGWERKE Aktiengesellschaft Conjungués protéiques magnétiques, procédé pour les synthétiser et leur emploi
EP0565930A1 (fr) * 1992-03-27 1993-10-20 Nihon Medi-Physics Co., Ltd. Dérivés des acides tétraacétiques de tétraazacyclododécane et leur utilisation comme agent diagnostique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0125995A2 (fr) * 1983-05-12 1984-11-21 Advanced Magnetics, Inc. Particules magnétiques pour l'utilisation dans des séparations
WO1988000060A1 (fr) * 1986-07-03 1988-01-14 Advanced Magnetics, Inc. Materiau super paramagnetique biodegradable utilise dans des applications cliniques
EP0398143A1 (fr) * 1989-05-09 1990-11-22 The General Hospital Corporation Peptides chimiotactiques marqués pour visualiser des sites d'inflammation ou d'infection
EP0403961A2 (fr) * 1989-06-19 1990-12-27 BEHRINGWERKE Aktiengesellschaft Conjungués protéiques magnétiques, procédé pour les synthétiser et leur emploi
EP0565930A1 (fr) * 1992-03-27 1993-10-20 Nihon Medi-Physics Co., Ltd. Dérivés des acides tétraacétiques de tétraazacyclododécane et leur utilisation comme agent diagnostique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
E.C.WIENER E.A.: "Dendrimer-based metal chelates: a new class of MRI contrast agents", MAGNETIC RESONANCE IN MEDICINE, vol. 31, no. 1, January 1994 (1994-01-01), BALTIMORE, pages 1 - 8, XP000423671 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033947A1 (fr) * 1997-12-24 1999-07-08 Henkel Kommanditgesellschaft Auf Aktien Utilisation de complexes de metaux de transition avec des ligands dendrimeres pour renforcer l'effet de blanchiment de composes peroxygene
US6872536B1 (en) * 1998-11-10 2005-03-29 Bracco Imaging S.P.A. Chemotactic peptide antagonists for imaging sites of inflammation
WO2004029080A1 (fr) * 2002-09-27 2004-04-08 Nihon Medi-Physics Co., Ltd. Compose se liant aux leucocytes, et composition medicale renfermant le compose a l'etat marque comme principe actif
US7220827B2 (en) 2002-09-27 2007-05-22 Nihon Medi-Physics Co., Ltd. Compound binding to leukocytes and medicinal composition containing the compound in labeled state as the active ingredient
KR100900178B1 (ko) * 2002-09-27 2009-06-02 니혼 메디피직스 가부시키가이샤 백혈구 결합성 화합물 및 그 표지 화합물을 유효 성분으로하는 의약 조성물
US8414926B1 (en) 2006-09-12 2013-04-09 University Of South Florida Nanoparticles with covalently bound surfactant for drug delivery
US10086095B2 (en) 2012-10-09 2018-10-02 Case Western Reserve University Rod-shaped plant virus nanoparticles as imaging agent platforms
US11020497B2 (en) 2012-10-09 2021-06-01 Case Western Reserve University Rod-shaped plant virus nanoparticles as imaging agent platforms
US11193111B2 (en) 2013-01-17 2021-12-07 Case Western Reserve University Viral nanoparticle multimers
WO2015123654A1 (fr) 2014-02-17 2015-08-20 The Cleveland Clinic Foundation Nanoparticules amine-passivées pour le traitement et l'imagerie du cancer
WO2018017985A1 (fr) 2016-07-21 2018-01-25 Case Western Reserve University Structures de particules de virus végétal ou de type viral
WO2021195716A1 (fr) * 2020-04-02 2021-10-07 Monash University Conjugués antibiotiques

Also Published As

Publication number Publication date
JPH10511701A (ja) 1998-11-10
EP0814849A1 (fr) 1998-01-07

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