Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/48—NMR imaging systems
  • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
  • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
  • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/04—X-ray contrast preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/04—X-ray contrast preparations
  • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
  • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
• • 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
  • A61K49/189—Host-guest complexes, e.g. cyclodextrins
• • 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
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
  • A61K51/1268—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules host-guest, closed hollow molecules, inclusion complexes, e.g. with cyclodextrins, clathrates, cavitates, fullerenes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
  • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2604/00—Fullerenes, e.g. C60 buckminsterfullerene or C70

Definitions

• the invention relates to magnetic resonance imaging
• MRI magnetic resonance imaging
• x-ray imaging x-ray imaging
• radiopharmaceuticals More particularly the invention relates to methods and compositions for enhancing MRI, x-ray imaging and radiopharmaceuticals.
• the technique of MRI encompasses the detection of certain atomic nuclei (those possessing magnetic dipole moments) 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.
• CT X-ray computed tomography
• the technique of MRI is advantageously non- invasive as it avoids the use of ionizing radiation.
• the hydrogen atom having a nucleus consisting of a single unpaired proton, has the strongest magnetic dipole moment of any nucleus. Since hydrogen occurs in both water and lipids, it is abundant in the human body. Therefore, MRI is most commonly used to produce images based upon the distribution density of protons and/or the relaxation times of protons in organs and tissues. Other nuclei having a net magnetic dipole moment also exhibit a nuclear magnetic resonance phenomenon which may be used in MRI, MRS, and MRSI applications.
• Such nuclei include carbon-13 (six protons and seven neutrons) , fluorine-19 (9 protons and 10 neutrons) , sodium-23 (11 protons and 12 neutrons) , and phosphorus-31 (15 protons and 16 neutrons) . While the phenomenon of NMR was discovered in 1945, it is only relatively recently that it has found application as a means of mapping the internal structure of the body as a result of the original suggestion of Lauterbur (Nature , 242. 190-191 (1973)) . The fundamental lack of any known hazard associated with the level of the magnetic and radio- frequency fields that are employed renders it possible to make repeated scans on vulnerable individuals. Additionally, any scan plane can readily be selected, including transverse, coronal, and sagittal sections.
• the nuclei under study in a sample e.g. protons, 19 F, etc.
• a sample e.g. protons, 19 F, etc.
• RF radio-frequency
• nuclei with appropriate spin when placed in an applied magnetic field align in the direction of the field.
• 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 extend 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, T_ L and T 2 .
• T___ is 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.
• T 2 is the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins.
• T 1 and T 2 relaxation in tissues are generally longer by about a factor of two (2) in excised specimens of neoplastic tissue compared with the host tissue.
• 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.
• T and T 2 two of the principal imaging parameters are the relaxation times, T and T 2 .
• these relaxation times are influenced by the environment of the nuclei (e.g., viscosity, temperature, and the like) .
• These two relaxation phenomena are essentially 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 T j. and T 2 values for nearby nuclei having a magnetic dipole moment .
• the extent of the paramagnetic effect of the given chemical compound is a function of the environment within which it finds itself.
• the present invention provides methods and compositions for improved magnetic resonance imaging, spectroscopy, and radiopharmaceuticals.
• the compositions are of the general formula:
• compositions and methods of performing diagnostic procedures which involve administering to a warm-blooded animal (including humans) a diagnostically effective amount of the compositions of the invention and then exposing the warm-blooded animal to an imaging procedure.
• Stable C 60 closed carbon shells have recently been isolated from vaporized graphite.
• the highly stable C 60 compound is marked by an icosahedral-cage structure, a polygon with -60 equivalent vertices, 32 faces, 12 of which are pentagonal and 20 hexagonal.
• the icosahedral structure is typified by a soccer ball.
• the C 60 structure has been given the name “buckminsterfullerene” due to its similarity to the geodesic domes of Buckminster Fuller.
• the class of closed cage, carbon clusters is commonly referred to as “fullerenes. " C 60 is the prototypical fullerene. A number of methods for the formation and purification of C 60 have been developed and are known in the art.
• pure graphitic carbon is vaporized in an inert atmosphere, and C 60 is extracted from the deposited soot with benzene, toluene, carbon disulfide, or carbon tetrachloride.
• the extract consists primarily of C 60 and C 70 .
• Other stable low molecular weight fullerenes have also been identified, such as C 24 , C 28 , C 32 , and C 50 .
• the existence of high molecular weight fullerenes, such as C 240 and C 540 is theoretically predicted.
• C 60 exhibits extended aromaticity and has been found to be a sensitizer.
• Chemical modification of the C 60 structure is necessary to prepare compositions suitable for in vivo applications. Hydrogenation of fullerenes is achieved using known techniques, such as catalytic hydrogenation or dissolving metal reduction. The partially hydrogenated compounds, C 60 H 36 and C 60 H 18/ are readily formed. Complete hydrogenation to C 60 H 60 by catalytic hydrogenation may be accomplished using higher pressures of H 2 and variation of catalyst.
• fluorinated, heterocyclic, and other functionalized derivatives of the C 60 structure have been prepared.
• paramagnetic metal species as used herein includes within its scope both paramagnetic atoms and ions. Also, the presence of a paramagnetic metal species may enhance MRI, MRS, and MRSI. It is also believed that incorporating a paramagnetic metal species into the center of the fullerene cage will increase the dipole moment of the entire cage. This may render the cluster water soluble and reduce in vivo toxicity of the paramagnetic metal species.
• Fullerenes in particular C 60 , have much higher reactivity than might be expected based on their inherent stability resulting from an aromatic-type structure consisting of twenty 6-membered rings fused to twelve 5- membered rings.
• Buckyball (C so ) is insoluble in water and most organic solvents except for benzene (1.44 mg/mL) , toluene (2.15 mg/mL) , and carbon disulfide (5.16 mg/mL) ; reduced fullerenes are highly soluble in THF, however.
• C 60 undergoes examples of some types of reactions that C 60 undergoes are: nucleophilic and electrophilic and radical additions, Friedel-Crafts, Diels-Alder, electrocyclic, hydroboration, cycloaddition, electrophilic aromatic substitution, reductive alkylation, and halogenation.
• C 60 has been shown to react with organometallic transition metal complexes (Balch, A. J., et al . -Tnorg. Che . 1991, 30, 3980 and Fagan, P. J., et al . Ace. Chem. Res. 1992, 25, 134) .
• the resulting C 60 derivatives are water soluble or can be derivatized to be such; moreover, by boiling an aqueous solution of ⁇ - cyclodextrin with a solid mixture of C 60 and C 70 , researchers have been able to extract C 60 from the mixture into the aqueous solution (Andersson, T., et al . ) .
• nucleophilic groups include amines, alkoxides, thiolates, and carbanions derived from carbonyl compounds.
• attachment of chelators to C 60 could be effected through a linker group.
• C 60 with a linker group e.g., sodium diethyl malonate, followed by decarboxylation and esterification
• a chelator bearing a suitable pendant nucleophilic group e.g., primary amine
• fuzzyball Reaction of fuzzyball with a paramagnetic metal, such as those mentioned in this document, affords a compound with a potentially large (6-14) number of paramagnetic metal ions .
• High relaxivity results not only because of the large number of paramagnetic metal ions, but also because of the exceptionally slow tumbling of fuzzyball.
• Minimal osmolarity results from combination of free complexes into a single particle in solution.
• MRI applications include use as a contrast agent for extracellular fluid or the blood pool, or for attachment to targeting groups (especially monoclonal antibodies) .
• targeting groups especially monoclonal antibodies
• exceptionally high relaxivity is critical to successful contrast enhancement at a practical loading of the MAb with the contrast agent.
• Fuzzyball with Gd(III) might also find application as a non- conventional X-ray contrast agent.
• paramagnetic ions of elements with an atomic number of 21 to 29, 42 to 44, and 58 to 70 have been found effective as MRI contrasting agents.
• suitable paramagnetic ions for use with the invention include chromium(III) , manganese (II) , manganese (III) , iron(III) , iron(II), cobalt (II), nickel (II), copper(II) , praseodymium(III) , neodymium(III) , samarium(III) and ytterbium(III) .
• gadolinium(III) , terbium(III) , dysprosium(III) , holmium(III) and erbium(III) are preferred.
• Gadolinium(III) ions have been particularly preferred as MRI contrasting agents.
• nucleophilic groups work well . Examples of nucleophilic groups include amines, amides, alcohols, phenols, thiols and hydrazines. The more linkers used generally increases the chances of getting a larger number of chelators attached, and therefore a greater number of metals bound. With radiopharmaceuticals, however, only one bound metal is generally necessary.
• Linkers are chosen for their reactivity with the carbon cage. One site of the linker generally reacts with the carbon cage and another site of the linker generally reacts with the site of the chelator.
• Suitable chelators for use with the invention include diethylenetriamine pentaacetic acid (DTPA) , ethylene diamine tetraacetic acid (EDTA) , 1, 4, 7, 10-tetraazacyclododecane tetraacetic acid (DOTA) , mercaptoacetylglycyl glycylglycine (MAG3) , 1, 4, 8, 11 tetraaza-cyclotetradecane (cyclam) , N, N'-bis(OJ- hydroxybenzyl) ethylene diamine N,N' -diacetic acid (HBED) , and 2, 9, 9-tetramethyl-4, 7-diaza-l, 10-decanedithiol .
• DTPA diethylenetriamine pentaacetic acid
• EDTA ethylene diamine tetraacetic acid
• DOTA 1, 4, 7, 10-tetraazacyclododecane tetraacetic acid
• MAG3 mercapto
• Bio olecule refers to all natural and synthetic molecules that play a role in biological systems.
• Biomolecules include hormones, amino acids, peptides, peptidomimetics, proteins, deoxyribonucleic acid (DNA) ribonucleic acid (RNA) , lipids, albumins, polyclonal antibodies, receptor molecules, receptor binding molecules, monoclonal antibodies and aptamers.
• Specific examples of biomolecules include insulins, prostaglandins, growth factors, liposomes and nucleic acid probes.
• Examples of synthetic polymers include polylysine, arborols, dendrimers, and cyclodextrins.
• biomolecules The advantages of using biomolecules includes enhanced tissue targeting through specificity and delivery.
• the bio olecule can be attached to a variety of places on the molecules of the invention. Coupling of the chelating moieties to biomolecules can be accomplished by several known methods (e.g., Krejcarek and Tucker Biochem. Biophys. Res. Pnmm.. 30, 581 (1977) ; Hnatowich, et al. Science. 220, 613 (1983) .
• a reactive moiety present on the chelating moiety, fuzzyball or linker is coupled with a second reactive group located on the biomolecule.
• a nucleophilic group is reacted with an electrophilic group to form a covalent bond between the biomolecule and the chelate.
• nucleophilic groups examples include amines, anilines, alcohols, phenols, thiols and hydrazines.
• Electrophilic group examples include halides, disulfides, epoxides, maleimides, acid chlorides, anhydrides, mixed anhydrides, activated esters, imidates, isocyanates and isothiocyanates.
• compositions of the invention can also be employed for delivery of either radiopharmaceuticals or heavy metals for x-ray contrast into the body.
• the complexed metal ion For use in diagnostic and therapeutic radiopharmaceuticals the complexed metal ion must be radioactive. Radioisotopes of the elements technetium, rhenium, indium, gallium, copper, yttrium, samarium and holmium are suitable.
• the complexed metal ion must be able to absorb adequate amounts of the x-rays. These metal ions are generally referred to as radioopaque. Suitable elements for use as the radioopaque metal ion include lead, bismuth, gadolinium, dysprosium and praseodymium.
• compositions may further contain physiologically acceptable non-toxic cations in the form of a gluconate, chloride or other suitable organic or inorganic salts, including suitable soluble complexes with a chelate/ligand to enhance safety.
• physiologically acceptable non-toxic cations include sodium ions, calcium ions, magnesium ions, copper ions, zinc ions, and mixtures thereof.
• compositions of the invention can be formulated into diagnostic compositions for enteral or parental administration. These compositions contain an effective amount of the 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 1.0 M of an ion complex.
• Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration.
• Preferred parenteral formulations have a complex concentration 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.
• 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. Such doses may vary widely, depending upon the particular ion complex employed, the organs or tissues which are the subject of the imaging procedure, the imaging procedure, the imaging equipment being used, and the like.
• parenteral dosages will range from about 0.001 to about 1.0 mMol of ion complex per kg of patient body weight.
• Preferred parenteral dosages range from about 0.01 to about 0.5mMol of 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 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 imaging procedure.
• Protocols for imaging and instrument procedures are found in texts such as Stark, D.D.;
• Radiopharmaceutical imaging procedures are found in Fred A. Mettler, Jr., M.D. , M.P.H., Milton J. Guiberteau, M.D., Essentials of Nuclear Medicine Imaging, Grune and Stratton, Inc., New York, NY 1983) and E. Edmund Kim, M.S., M.D. and Thomas P. Haynie, M.D., (MacMillan Publishing Co. Inc., New York, NY 1987) .
• Ethylenediamine is dried via azeotropic distillation with toluene. To 100 mL of this ethylenediamine is added
• the anhydride is cleaved by acid hydrolysis. After removal of the solvent under reduced pressure, a solid results.
• Example 2 To the solid product obtained in substantial accordance with the teaching of Example 2 is added an excess (12 molar equivalents) of GdCl 3 in dimethylacetamide. Following purification on an ion- exchange resin, the major product obtained is of the formula C 60 (ethylenediamine) 10 (DTPA)____,(Gd)_____.
• the C 60 (1,4-diaminobutane) 2 adduct is prepared in substantial accordance with the teaching of Example 4, except that only 2 molar equivalent of the amine is reacted with the C 60 .
• MAG3 eps

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• 1994
  • 1994-09-30 JP JP7510886A patent/JPH09503765A/ja active Pending
  • 1994-09-30 EP EP94930502A patent/EP0722291A1/en not_active Withdrawn
  • 1994-09-30 AU AU79600/94A patent/AU7960094A/en not_active Abandoned
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