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
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations

Definitions

• This invention relates to magnetic resonance imaging (MRI) and, more particularly, to methods and compositions for enhancing MRI.
• the recently developed technique of magnetic resonance imaging 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 and/or their relaxation times m organs and tissues.
• CT computed tomography
• the technique of MR imaging 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., T 1 , 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 1 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 the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins.
• MR imaging In MR imaging, scanning planes and slice thicknesses can be selected. This selection permits high quality transverse, coronal and sagittal images to be obtained directly. The absence of any moving parts in MR imaging equipment promotes a high reliability. It is believed that MR imaging has a greater potential than CT for the selective examination of tissue characteristics in view of the fact that in CT, x-ray attenuation coefficients alone determine image contrast, whereas at least five separate variables ( T 1 , T 2 , proton density, pulse sequence and flow) may contribute to the MR signal.
• 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 1 and T 2 two of the principal imaging parameters are the relaxation times, T 1 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 radiofrequency 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 1 and T 2 values for nearby protons.
• the extent of the paramagnetic effect of a given chemical compound is a function of the environment within which it finds itself.
• paramagnetic divalent or trivalent ions of elements with an atomic number of 21 to 29, 42 to 44 and 58 to 70 have been found effective as MRI image contrasting agents.
• Suitable such ions 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). Because of their very strong magnetic moments, gadolinium (III), terbium (III), dysprosium (III), holmium (III) and erbium (III) are preferred. Gadolinium (III) ions have been particularly preferred as MR image contrasting agents.
• the divalent and trivalent paramagnetic ions have been administered in the form of complexes with organic complexing agents.
• complexes provide the paramagnetic ions in a soluble, non-toxic form, and facilitate their rapid clearance from the body following the imaging procedure.
• Paramagnetic ions such as gadolinium (III) have been found to form strong complexes with DTPA. These complexes do not dissociate substantially in physiological aqueous fluids.
• the complexes have a net charge of -2, and generally are administered as soluble salts. Typical such salts are the sodium and N- methylglucamine salts.
• ionizable salts are attended by certain disadvantages. These salts can raise the in vivo ion concentration and cause localized disturbances in osmolality, which in turn, can lead to edema and other undesirable reactions.
• hydrophilic complexes tend to concentrate in the interstitial fluids, whereas lipophilic complexes tend to associate with cells. Thus, differences in hydrophilicity can lead to different applications of the compounds. See, for example, Weinmann et al., AJR, 142, 679 (Mar. 1984) and Brasch et al., AJR, 142, 625 (Mar. 1984).
• the present invention provides novel complexing agents and complexes of complexing agents with paramagnetic ions.
• the complexes are represented by the following formula 1:
• A is -CHR 2 -CHR 3 or -CHR 2 CHR 3 M 2+ is a paramagnetic ion of an element with an atomic number 21-29, 42-44, or 58-70 and a valence, z, of 2+ or 3+;
• the R 1 groups may be the same or different selected from a group consisting of -O-
• the R 2 , R 3 , R 4 , R 5 and R 7 groups may be the same or different selected from a group consisting of hydrogen, alkyl -such as for example methyl or ethyl wherein methyl is preferable to reduce lipophilicity, acyl -such as for example acetyl, aryl -such as for example phenyl, benzoyl, mono- or poly- hydroxyalkyl -such as for example hydroxymethyl or dihydroxypropyl wherein dihydroxypropyl is preferable to enhance water solubility, mono- or polyalkoxyalkyl -such as
• R 6 groups may be the same or different selected from the group
• R 8 , R 9 and R 10 groups have the same definition as R 2 , R 3 , R 4 , R 5 and R 7 of formula 1;
• the carbon-containing R groups preferably contain 1 to 6 carbon atoms; and m and n ranges preferably from 1 to 6.
• a diagnostic composition and a method of performing a MRI diagnostic procedure which involves administering to a warm-blooded animal an effective amount of the above-described complex and then exposing the warm-blooded animal to a MRI procedure, thereby imaging at least a portion of the body of the warm-blooded animal.
• the complexing agents employed in this invention are derivatives of well-known polyaminocarboxylic acid chelating agents, such as DOTA, DTPA, EDTA and cyclohexyldiaminotetraacetic acid.
• polyaminocarboxylic acid chelating agents such as DOTA, DTPA, EDTA and cyclohexyldiaminotetraacetic acid.
• some carboxylic acid groups of the polyaminocarboxylic acid are converted to N-alkoxyamide groups, such as those of the formula,
• the paramagnetic ion is trivalent and the chelating agent is DTPA, two of the carboxylic acid groups will be derivatized to the N-alkoxyamide form.
• the paramagnetic ion is divalent, three of the carboxylic acid groups of DTPA or two of the carboxylic acid groups of EDTA may be derivatized to the N-alkoxyamide form.
• the resulting complexes could be substantially non-ionic as evidenced by very low electrical conductivity.
• N-alkoxyamide derivatives of the chelating agents are prepared in a conventional manner. In general, they are prepared by reacting a stoichiometric amount of an unsubstituted or substituted hydroxylamine compound of the formula,
• a reactive derivative of the polyaminocarboxylic acid chelating agent under amide forming conditions.
• Such reactive derivatives include, for example, anhydrides, mixed anhydrides and acid chlorides.
• the ring can be saturated or unsaturated and substituted or unsubstituted. If the heterocyclic ring is substituted, the total number of substituents typically is 1 to 3.
• the reactions for preparing the N-alkoxyamide derivatives of the present invention are conducted in an organic solvent at an elevated temperature.
• Suitable solvents include those in which the reactants are sufficiently soluble and which are substantially unreactive with the reactants and products.
• Lower aliphatic alcohols, ketones, ethers, esters, chlorinated hydrocarbons, benzene, toluene, xylene, lower aliphatic hydrocarbons, and the like may advantageously be used as reaction solvents.
• solvents examples include methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, acetone, methylethyl ketone, diethylketone, methyl acetate, ethyl acetate, chloroform, methylene chloride, dichloroethane, hexane, heptane, octane, decane, and the like.
• the reaction solvent advantageously is one which does not contain reactive functional groups, such as hydroxyl groups, as these solvents can react with the acid chlorides, thus producing unwanted by-products.
• reaction temperature may vary widely, depending upon the starting materials employed, the nature, of the reaction solvent and other reaction conditions. Such reaction temperatures may range, for example, from about 20°C to about 85oC, preferably from about 25oC to about 50°C.
• any remaining anhydride or acid chloride groups can be hydrolyzed to the carboxylate groups by adding a stoichiometric excess of water to the reaction mixture and heating for a short time.
• the resulting N-alkoxyamide is recovered from the reaction mixture by conventional procedures.
• the product may be precipitated by adding a precipitating solvent to the reaction mixture, and recovered by filtration or centrifugation.
• the paramagnetic ion is combined with the N- alkoxyamide derivative under complex-forming conditions.
• any of the paramagnetic ions referred to above can be employed in making the complexes of this invention.
• the complexes can conveniently be prepared by mixing a suitable oxide or salt of the paramagnetic ion with the complexing agent in aqueous solution. To assure complete complex formation, a slight stoichiometric excess of the complexing agent may be used.
• an elevated temperature e.g., ranging from about 20°C to about 100oC, preferably from about 40oC to about 80oC, may be employed to insure complete complex formation.
• complete complex formation will occur within a period from a few minutes to a few hours after mixing.
• the complex may be recovered by precipitation using a precipitating solvent such as acetone, and further purified by crystallization, if desired.
• novel complexes of this 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 1.0M of a paramagnetic ion complex according to this invention.
• Preferred parenteral formulations have a concentration of paramagnetic ion complex of 0.1M to 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 0.001 to about 15 mole % excess, of a complexing agent associated with one or more physiologically acceptable, non-toxic cation.
• physiologically acceptable, non-toxic cations include sodium ions, calcium ions, magnesium ions, copper ions, zinc ions and the like and mixtures thereof. Calcium ions are preferred.
• a typical single dosage formulation for parenteral administration has the following composition:
• Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration.
• 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 equipment being used, etc.
• 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 0.005 to about 0.5 MMol 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 20 MMol of paramagnetic ion complex per kg of patient body weight.
• the novel MR image contrasting agents of this invention are expected to possess a unique combination of desirable features.
• the paramagnetic ion complexes should exhibit high solubility in physiological fluids, notwithstanding their substantially non-ionic character. This high solubility should allow the preparation of concentrated solutions, thus minimizing the amount of fluid required to be administered.
• the non-ionic character of the complexes also should reduce the osmolality of the diagnostic compositions, thus preventing undesired edema and other side effects.
• compositions of this invention are used in the conventional manner.
• the compositions may be administered to a warm-blooded animal either systemically or locally to the organ or tissue to be imaged, and the animal then subjected to the MR imaging procedure.
• the compositions have been found to enhance the magnetic resonance images obtained by these procedures.
• the complexing agents of this invention may also be employed for delivery of radiopharmaceuticals and complexing heavy metals for x-ray contrast applications.
• Example 1 The invention is further illustrated by the following examples, which are not intended to be limiting.
• Example 1 The invention is further illustrated by the following examples, which are not intended to be limiting.
• a stirred suspension of methoxylamine hydrochloride (13.36g, 0.16 mol) in anhydrous isopropyl alcohol (100 ml) was treated with 35g of methanolic sodium methoxide (Aldrich, 25% w/w). The mixture was stirred at room temperature for 10 minutes and filtered to remove sodium chloride. The filtrate was added to a suspension of DTPA-dianhydride (14.28g, 0.04 mol) in anhydrous isopropyl alcohol (50 ml). The entire mixture was stirred at 50-55oC for two hours. The gummy suspension was treated with methanol (150 ml) and filtered to remove undissolved impurities.

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• 1991
  • 1991-11-12 WO PCT/US1991/008431 patent/WO1992009884A1/en not_active Application Discontinuation
  • 1991-11-12 EP EP92902010A patent/EP0660925A1/de not_active Withdrawn
  • 1991-11-12 CA CA002096543A patent/CA2096543A1/en not_active Abandoned
  • 1991-11-12 JP JP4501072A patent/JPH06502858A/ja active Pending
  • 1991-11-12 AU AU90810/91A patent/AU656355B2/en not_active Ceased

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