WO1997030734A1 - Agents utilises en resonance magnetique sur le pool sanguin - Google Patents

Agents utilises en resonance magnetique sur le pool sanguin Download PDF

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Publication number
WO1997030734A1
WO1997030734A1 PCT/US1997/002399 US9702399W WO9730734A1 WO 1997030734 A1 WO1997030734 A1 WO 1997030734A1 US 9702399 W US9702399 W US 9702399W WO 9730734 A1 WO9730734 A1 WO 9730734A1
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WO
WIPO (PCT)
Prior art keywords
disulfide
thiol
moiety
composition
contrast agent
Prior art date
Application number
PCT/US1997/002399
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English (en)
Original Assignee
Mallinckrodt Medical, Inc.
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 Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Publication of WO1997030734A1 publication Critical patent/WO1997030734A1/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

Definitions

  • the invention is in the field of imaging.
  • the invention is in the magnetic resonance imaging (MRI) field.
  • the invention is in the field of MRI of the blood pool .
  • contrast agents in diagnostic medicine is rapidly growing.
  • MRI proton magnetic resonance imaging
  • increased contrast of internal organs and tissues may be obtained by administering compositions containing paramagnetic metal species which increase the relaxivity of water protons surrounding the tissue.
  • the technique of MRI encompasses the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to X-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail. As currently used, the images produced constitute a map of the proton density distribution, in organs and tissues.
  • the technique of MRI is advantageously non-invasive as it avoids the use of ionizing radiation.
  • the nuclei under study in a sample e.g. protons
  • RF radio- frequency
  • nuclei with appropriate spin when placed in an applied magnetic field (B, expressed generally in units of gauss or Tesla [10 4 gauss]) align in the direction of the field.
  • B expressed generally in units of gauss or Tesla [10 4 gauss]
  • these nuclei precess at a frequency, f, of 42.6 MHz, at a field strength of 1 Tesla.
  • f a frequency
  • an RF pulse of radiation will excite the nuclei and can be considered to tip the net magnetization out of the field direction, the extent of this rotation being determined by the pulse duration and energy.
  • the nuclei "relax" or return to equilibrium with the magnetic field, emitting radiation at the resonant frequency.
  • the decay of the emitted radiation is characterized by two relaxation times, i.e., Ti, the spin-lattice relaxation time or longitudinal relaxation time, that is, the time taken by the nuclei to return to equilibrium along the direction of the externally applied magnetic field, and T 2 , the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins.
  • T 2 the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins.
  • scanning planes and slice thicknesses can be selected.
  • T 2 proton density, pulse sequence and flow
  • T 2 proton density, pulse sequence and flow
  • MRI may be capable of differentiating different tissue types and in detecting diseases which induce physicochemical changes that may not be detected by X-ray or CT which are only sensitive to differences in the electron density of tissue.
  • these relaxation times are influenced by the environment of the nuclei, (e.g., viscosity, temperature, and mechanisms whereby the initially imparted radio-frequency energy is dissipated to the surrounding environment.
  • the rate of this energy loss or relaxation can be influenced by certain other nuclei which are paramagnetic.
  • Chemical compounds incorporating these paramagnetic nuclei may substantially alter the Ti and T 2 values for nearby protons. The extent of the paramagnetic effect of a given chemical compound is a function of the environment.
  • paramagnetic ions have been administered in the form of complexes with organic complexing agents.
  • Such complexes provide the paramagnetic ions in a soluble, non-toxic forms, and facilitate their rapid clearance from the body following the imaging procedure.
  • Gries, et al. U.S. Patent 4,647,447, disclose complexes of various paramagnetic ions with conventional aminocarboxylic acid complexing agents.
  • a preferred complex disclosed by Gries, et al . is the complex of gadolinium (III) with diethylenetriamine-pentaacetic acid (“DTPA”) .
  • the present invention provides compositions comprising a contrast agent capable of reversibly binding to thiol groups of blood-borne proteins.
  • the compositions of the invention provide increased residence time of the contrast agent in the vasculature, thus providing effective blood pool contrast agents.
  • the invention also provides methods for imaging a patient comprising administering a composition of the invention and obtaining an image. DETAILED DESCRIPTION OF INVENTION
  • Any thiol or disulfide capable of reacting with a disulfide or thiol of a blood-borne protein can be used with the desired contrast agent.
  • the thiol or disulfide to thiol or disulfide linkage could be effected either in vivo, by injecting the thiol or disulfide containing contrast agent, or alternatively, in vitro, by reaction of a blood-borne protein with the thiol or disulfide bearing the contrast agent followed by injection of the resulting derivatized protein.
  • Prototypica Gd complex incorporating the disulfide moiety.
  • Suitable moieties containing thiols for use with the invention include mercaptoacetyl, 2-mercaptoaminoethyl, mercaptobenzoyl, 3-mercaptopropionyl and thiosalicyl.
  • Suitable disulfides containing moieties for use with the invention include dithiodiacetyl, dithiodiacetocarbamoyl, 2,2'- dithiodiaminoethyl, dithiodibenzoyl, 3, 3 ' -dithiodiproprionyl and dithiodisalicyl.
  • Thiols and disulfides for use with the invention are typically readily available from sources such as Aldrich (Milwaukee, Wisconsin) .
  • An article by J. P. Mahieu et al., Int. J. Biol. Macromol., 1993, Vol. 15, pp 233-240, incorporated herein by reference, provides numerous disulfide and thiol moieties one can use with the invention.
  • HSA Human serum album
  • the source of cysteine is a mixed disulfide, HSA-cysteine, which forms from HSA (thiol) and dissolved cystine (cys-S-S-cys) present in the blood plasma.
  • HSA-cysteine a mixed disulfide
  • cys-S-S-cys dissolved cystine
  • Dimeric disulfide complexes and mixed disulfide complexes can react directly with HSA-SH in the plasma to produce the high reJaxrvity contrast agent, Gd-L-S-S-HSA, in vivo.
  • Thiol-Gd complexes can undergo exchange with mixed HSA-d ⁇ sulf ⁇ des to produce the active contrast agent
  • the cornplex may be eliminated as a tow molecular weight thiol, or disulfide, by the reaction of Gd-L-S-S-HSA with endogenous thiols. R-SH. It is believed the invention aids in retarding glomerular filtration of the lower-molecular contrast agents. Also, due to the reversible binding of the contrast agent to the blood- borne protein, the contrast agent can be released back into the bloodstream and eliminated by renal excretion.
  • paramagnetic species such as ions of elements with atomic numbers of 22 to 29, 42 to 44 and 58 to 70 have been found effective as MRI image contrasting agents.
  • suitable ions include chromium (III) , manganese (II) , manganese
  • Gadolinium (III) ions have been particularly preferred as MRI contrasting agents.
  • compositions of the invention can be formulated into diagnostic compositions for enteral or parenteral administration.
  • These compositions contain an effective amount of the paramagnetic ion complex along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated.
  • parenteral formulations advantageously contain a sterile aqueous solution or suspension of from about 0.05 to about 1.0M of a paramagnetic ion complex according to this invention.
  • Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration.
  • Preferred parenteral formulations have a concentration of paramagnetic ion complex of about 0.1M to about 0.5M.
  • Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride.
  • compositions may advantageously contain a slight excess (e.g., from about 0.01 to about 15.0 mole % excess) of a complexing agent or its complex with a physiologically acceptable, non-toxic cation.
  • physiologically acceptable, non-toxic cations include calcium ions, magnesium ions, copper ions, zinc ions, salts of n-methylglucamine and diethanolamine, and the like. Generally, calcium ions are preferred.
  • Formulations for enteral administration may vary widely, as is well-known in the art. In general, such formulations are liquids which include an effective amount of the paramagnetic ion complex in aqueous solution or suspension. Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like. Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities.
  • the diagnostic compositions are administered in doses effective to achieve the desired enhancement of the NMR image.
  • doses may vary widely, depending upon the particular paramagnetic ion complex employed, the organs or tissues which are the subject of the imaging procedure, the NMR imaging procedure, the NMR imaging equipment being used, and the like.
  • parenteral dosages will range from about 0.001 to about 1.0 MMol of paramagnetic ion complex per kg of patient body weight.
  • Preferred parenteral dosages range from about 0.01 to about 0.5MMol of paramagnetic ion complex per kg of patient body weight.
  • Enteral dosages generally range from about 0.5 to about 100 MMol, preferably from about 1.0 to about 10 MMol, preferably from about 1.0 to about 20.0 MMol of paramagnetic ion complex per kg of patient body weight.
  • compositions of the invention are used in the conventional manner.
  • the compositions may be administered to a patient, typically a warm-blooded animal, either systemically or locally to the organ or tissue to be imaged, and the patient then subjected to the NMR imaging procedure.
  • Protocols for imaging and instrument procedures are found in texts such as Stark, D.D.; Bradley, W.G. Magnetic Resonance Imaging; Mosby Year Book: St. Louis, MO, 1992.

Landscapes

  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Compositions renfermant un agent de contraste capable de se lier de manière réversible à des groupes thiol de protéines véhiculées par le sang. Ces compositions apportent une longévité accrue de l'agent de contraste dans le système vasculaire, conférant ainsi leur efficacité à des agents de contraste sur le pool sanguin. L'invention porte également sur des méthodes de visualisation d'un patient prévoyant l'administration d'une composition visée par l'invention et l'obtention d'une image.
PCT/US1997/002399 1996-02-21 1997-02-18 Agents utilises en resonance magnetique sur le pool sanguin WO1997030734A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60428596A 1996-02-21 1996-02-21
US08/604,285 1996-02-21

Publications (1)

Publication Number Publication Date
WO1997030734A1 true WO1997030734A1 (fr) 1997-08-28

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PCT/US1997/002399 WO1997030734A1 (fr) 1996-02-21 1997-02-18 Agents utilises en resonance magnetique sur le pool sanguin

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WO (1) WO1997030734A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016474A1 (fr) * 1997-09-26 1999-04-08 Schering Aktiengesellschaft Complexes metalliques lipophiles pour necroses et imagerie de l'infarctus
US6495118B1 (en) 1997-09-26 2002-12-17 Schering Aktiengesellschaft Lipophilic metal complexes for necrosis and infarction imaging
US7041790B2 (en) 2002-03-26 2006-05-09 Dyax Corp. Fibrinogen binding moieties

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091514A (en) * 1987-03-26 1992-02-25 Neorx Corporation Metal-radionuclide-labeled proteins and glycoproteins for diagnosis and therapy
US5095111A (en) * 1989-03-17 1992-03-10 The John Hopkins University Thiolactone bifunctional chelating agents for diagnostic and therapeutic products

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091514A (en) * 1987-03-26 1992-02-25 Neorx Corporation Metal-radionuclide-labeled proteins and glycoproteins for diagnosis and therapy
US5095111A (en) * 1989-03-17 1992-03-10 The John Hopkins University Thiolactone bifunctional chelating agents for diagnostic and therapeutic products

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EUROPEAN JOURNAL OF NUCLEAR MEDICINE, June 1993, Vol. 20, No. 6, VERBEKE et al., "Technitium-99m Mercaptoalbumin as a Potential Substitute for Technetium-99m Labelled Red Blood Cells", pages 473-482. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016474A1 (fr) * 1997-09-26 1999-04-08 Schering Aktiengesellschaft Complexes metalliques lipophiles pour necroses et imagerie de l'infarctus
US6495118B1 (en) 1997-09-26 2002-12-17 Schering Aktiengesellschaft Lipophilic metal complexes for necrosis and infarction imaging
US7041790B2 (en) 2002-03-26 2006-05-09 Dyax Corp. Fibrinogen binding moieties

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