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
• • 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
  • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
  • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
  • A61K51/048—DTPA (diethylenetriamine tetraacetic acid)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2123/00—Preparations for testing in vivo

Definitions

• This invention relates to contrast agents for medical magnetic resonance imaging (MRI) .
• MRI magnetic resonance imaging
• a contrast agent is an exogenous substance that either augments or suppresses the normal in vivo MRI signal, thereby yielding additional diagnostic information.
• the theory (1,2) and applications of various types of contrast agents has been described in the literature (1,2) .
• the Arabic numbers in parentheses in this section refer to the articles cited in this section.
• the applications of a given MRI contrast agent are determined by its distribution in vivo.
• the mechanisms controlling the initial biodistribution can be classed as physico-chemical, i.e., dependent only upon such properties as molecular size, charge, lipophilicity, surface properties, etc., or receptor-mediated—dependent upon the binding of a substrate to a specific receptor in or on cells.
• Different organs may handle the same contrast agent by different mechanisms. For example, the molecular size of the agent may result in its filtration by the kidneys (or confinement to the vascular space) while it is cleared
• Contrast agents exhibiting a physico-chemical distribution mechanism include the gadolinium (III) complex of diethylenetriaminepentaacetic acid (Gd-DTPA) , which distributes in plasma and extracellular fluid, and albumin- (Gd-DTPA) n , which remains largely intravascular (1,2) .
• Gd-DTPA diethylenetriaminepentaacetic acid
• albumin- (Gd-DTPA) n which remains largely intravascular (1,2) .
• the former is used to demonstrate blood-brain barrier lesions or to reveal renal anatomy and function (3) , while the latter has been used experimentally to delineate the vasculature (4) and determine brain blood volume (5,6).
• Iron-dextran although a colloid, has a sufficiently long plasma half-life (12 hr) to be used as an intravascular T2 contrast agent (7) , as do some superparamagnetic iron oxide particle preparations (8,9) . Because of its role in the removal of exogenous compounds from general circulation, the liver is able to actively take up and concentrate soluble, as well as particulate, contrast agents. The pathways followed by solutes from plasma to bile have been reviewed (10-11) and are diagrammed in Figure 4. Passage into the hepatocyte across the cell membrane can take place by pinocytosis, passive diffusion, and/or by carrier-mediated systems that transport bile acids, bilirubin, organic anions, organic cations, neutral organic compounds, or inorganic ions.
• the substrate specificity of different carrier systems can partially overlap (e.g., organic anions and bile acids).
• the substrate may be metabolized intracellularly and/or conjugated with glucuronic acid or glutathione, for example.
• excretion into bile canaliculi again involves passage through a cell membrane. The mechanism of biliary excretion for a given compound may differ from that operative for its uptake.
• the liver has provided the first example of receptor- mediated localization of an MR contrast agent — Fe-EHPG (EHPG is Ethylene-bis(hydroxyphenylglycine) ) (12).
• EHPG is Ethylene-bis(hydroxyphenylglycine)
• Other iron (13-15) , manganese (16-17) , and gadolinium (18) chelates have since been described that have either potential for, or have demonstrated receptor-mediated hepatocyte uptake.
• Gd-BOPTA produced a larger signal enhancement (48%) in liver than Gd-DTPA (16%) in Tl- weighted spin-echo images at 0.5 Tesla.
• organs and tissues may posses receptors with affinity for certain classes of substrates, e.g., amino acids, peptides or catechol amines (19-24).
• OU TM 7UTESHEET These receptors may also bind molecules that resemble the substrate, e.g., a derivative of an amino acid that is present in a peptide substrate (22) or an amide derivative of a naturally occurring catechol amine such as dopamine.
• the contrast agents of this invention may in part localize by such a mechanism. Furthermore, the localization of the catechol containing contrast agents of the present invention may depend in part on their respective reduction- oxidation properties. To date, magnetic resonance imaging (MRI) has played a minor role in imaging of the liver and abdomen of a human being because of degradation of image quality by motion artifacts, and by the lack of suitable contrast agents.
• MRI magnetic resonance imaging
• the present invention relates to a magnetic resonance imaging contrast agent, comprising the complex: L-M wherein M is a metal (II) or (III) ion independently selected from the group consisting of metals of atomic number 21 to 31, metals of atomic number 39 to
• the lanthanide metals having an atomic number from 57 to 71, and metals of atomic number 72 to 82, and
• L is a polydentate organic chelating moiety of structure Ia:
• the present invention relates to a polydentate organic chelating compound of structure I:
• R 1 , R 2 and R 3 when present in A in each of Q, J, X, X', Y and Z are independently selected from hydrogen, alkyl having from 1-7 carbon atoms, phenyl or benzyl; and is selected from 0, 1, 2 or 3, and n is selected from 0 or 1, or the pharmaceutically acceptable salt(s) thereof.
• the present invention also relates to a method of preparing a chelate compound of structure
• R is an organic structure comprising an alkyl, aromatic or a heteroaromatic group
• R 1 is selected from hydrogen, alkyl having from 1-7 carbon atoms, phenyl or benzyl, and m is selected from 0, 1, 2 or 3, and n is selected from 0 or 1, in an anhydrous polar aprotic solvent at between about 50 and 150° for between about 2 and 10 hr; and (b) removing the solvent and recovering the compound of structure I.
• FIGS. IA, IB, 1C and ID are each a representation of the structures of the compounds BOPTA, BSP, DPDP and DTPA, respectively.
• Figures 2A, 2B, 2C and 2D are each a representation of the structures of the chelates EDTA, EDTP, EHPG and HBED, respectively.
• Figure 3 is a representation of a species of the general reaction to produce a bis amino acid substituted chelate.
• Figure 4 is a cross-sectional representation of the cells, components and pathways found in the hepatobiliary region.
• Figure 5A is a photograph of T-l weighted magnetic resonance images of a rat at various times (indicated in minutes) after injection of the Gd-DTPA-(bisphenylalanine) . Approximately 0.1 mmol/kg dose.
• Figure 6A is a photograph of T-l weighted magnetic resonance images at various times (indicated in min) obtained as in Figure 5A and Figure 5B for the Gd-DTPA-bis (phenylalanine ethyl ester) .
• Figs. 5B and 6B are photographic enlargements of the pre- and 0-min post injection images of Fig. 5A & 6A, resp.
• Figure 7 is a photograph of the T-l weighted magnetic resonance images of two mice side-by-side at various times (indicated in min) after simultaneous injection of Gd-DTPA- bisphenyl-alanine (bis acid) described in Example 8 below, at approximately 0.1 mmol/kg dose.
• the images are 2 mm thick slices in a coronal plane at the level of the heart. The heart, liver and intestines are evident.
• Figure 8 is a photograph of T-l weighted magnetic resonance images as obtained for Figure 6 except that a different preparation of Gd-DTPA bis-(phenylalanine ethyl ester) was employed.
• Figures 9-13 are each a graphic representation of MRI imaging in heart, lung, kidney, liver and skeletal muscle tissue, respectively, showing % enhancement versus time (min) for Gd(III)-DTPA-(3HTA) 2 and for Gd(III)-DTPA-(DMPE) 2>
• Figure 14A is a photograph of T-l weighted MRI images of a rat as obtained (as indicated in min) for Figure 5 using Gd(III)-DTPA-(3HTA) 2 .
• Figure 14B is a photograph of a second coronal plane at the level of the kidneys, as shown in Figure 14A.
• Figure 15A is a photograph of T-l weighted MRI images of a rat as obtained (as indicated in min) for Figure 5 using Gd(III)-DTPA-(DMPE) 2 .
• Figure 15B is a photograph of a second coronal plane at the level of the kidneys, as shown in Figure 15A.
• Figures 16-20 are each a graphic representation of MRI imaging in heart, lung, kidney, liver and skeletal muscle tissue, respectively, showing % enhancement versus time (min) for Gd(III)-DTPA-(L-PheOEt) 2 and for Gd(III)-DTPA-(D- PheOEt) 2 .
• Figures 21A and 2IB are each T-l weighted MRI photographic images of a rat as obtained for Figures 14 and 15 using Gd(III)-DTPA-(L-PheOEt) 2 and for Gd(III)-DTPA-(D- PheOEt)2 « However, the dose level was 0.05 mmol/kg.
• Alkylene refers to methylene, ethylene, propylene, and the like up to six carbon units.
• Amino acid refers generally to the type of ⁇ -amino acids found in living subjects or mammals. However, synthetic ⁇ -amino acids which are not found in nature are also useful. Further these D- and L- amino acids as separate chiral isomers are independently useful. Mixtures of the D- and L- isomers are also contemplated in this invention.
• Metal of atomic number 21 to 29 refers to scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc and gallium respectively.
• Paramagnetic ions are especially preferred. Iron, manganese, nickel, chromium, cobalt are preferred.
• Metal (lanthanides) having an atomic number from 57 to 71 refers to lanthanide, cerium, praseodymium etc. to lutentium, respectively. Paramagnetic gadolinium (III) or dysprosium (III) are preferred.
• the contrast agents of this invention localize in several organ systems, e.g., in the kidney, urinary tract, and urinary bladder; in the liver, biliary tree, and intestinal lumen; and in the myocardium. This localization results in increased MRI signal and image contrast.
• the resulting images show both improved anatomic detail and allow the functional state of certain organ systems, e.g., the urinary and biliary systems, to be ascertained.
• This localization probably involves a combination of physico-chemical and receptor-based mechanisms. For example, binding to blood components results in enhancement of the blood pool and may contribute to heart enhancement. Localization in the liver may result from recognition and
• the precursor can be DTPA-bis anhydride (or a similar structure, e.g. EDTA-bis anhydride) which contacted with an amino acid of the structure of the known natural or synthetic amino acids, e.g. D, L, or mixtures thereof.
• an amino acid of the structure of the known natural or synthetic amino acids e.g. D, L, or mixtures thereof.
• only one amino acid residue is added to one or more of the locations designated by Q, J, X, X', Y or Z, i.e., polypeptide bonds are usually not formed.
• the bis-anhydride if a limited amount (e.g. 0.5 equivalent) of the amino acid is used, production of the mono amino acid derivative is favored. If two equivalents of amino acid is used, then the bis-amino acid derivative is produced. For DTPA or higher analogs of polycarboxylic acids, forcing conditions, such as using a coupling reagent and a large excess of the amino acid or protected amino acid may be required.
• Any anhydrous dipolar aprotic solvent can be used for the synthesis.
• Dimethylformamide (DMF) dimethylacetamide, acetonitrile or the like are useful. DMF is preferred.
• the reaction mixture is heated at 70 to 100°C for between about 2-12 hr, preferably between 90 and 100°C for 4-5 hr, especially 6 hr.
• the reaction mixture is cooled and the solvent is removed using a conventional rotary evaporator or its equivalent.
• the present invention relates to a novel preparation of the compounds of structure I. 14
• Metal chelates are typically prepared by the reaction of a metal salt or oxide with the chelating ligand in a suitable aqueous or organic solvent in the appropriate stoichiometric ratio. Elevated temperatures are sometimes required. The pH of the reaction mixture is then adjusted with a base to obtain the corresponding chelate salt. Alternatively, acid can often be used to obtain the protonated chelate.
• R group preferred as independently selected from an aromatic group, an alkylene aromatic group, a substituted aromatic group or a heteroaromatic group.
• aryl aromatic groups shown below:
• X, X', Y and Z is independently selected from H (the acid), alkyl having from 1 to 7 carbon atoms (the mono, di, tri, etc. acid ester) cyclic groups such as cyclohexyl, phenyl, benzyl or 1- or 2-naphthyl.
• Paramagnetic metal ions are preferred, especially iron (II) and (III) and gadolinium (III) .
• the amides and related structures are produced by starting with the appropriate amino acid amide (usually as the hydrochloride) .
• the amino acid amide is then contacted with the corresponding dianhydride as is described above for the amino acid ester. If a less than equivalent amount of amino acid amide is used and at high dilution in the solvent the mono amino acid amide is favored. If a stoichiometric excess of the amino acid amide is used the diamino acid amide structure is obtained.
• Amide structures are also described in Examples 12 to 22.
• the amide structures are useful in MRI, because they have good contrast properties for specific tissue and have a longer useful half-life in a mammalian system.
• the present invention relates to substituted alkylenearyl derivatives, (e.g. methylene catechols) of EDTA and DTPA-type structures.
• substituted alkylenearyl derivatives e.g. methylene catechols
• the aryl and substituted aryl groups are defined as part of group R 4 .
• the NH 2 CH 2 CH 2 -substituted aryl is
• the present invention also concerns the preparation of a chelating ligand that bears one or more catecholamide groups, making a stable chelate of this ligand with a useful metal ion, and using the chelate for diagnostic imaging or spectroscopy. If the metal ion is paramagnetic, e.g., Gd(III) or Dy(III) , the chelate can produce contrast enhancement in an MRI, or cause shifts, broadening, or other changes in a magnetic resonance spectrum.
• the metal ion is paramagnetic, e.g., Gd(III) or Dy(III)
• Figure 5 is a photograph of T-l weighted magnetic resonance images of a rat obtained before, and at 0, 5, 10,
• the images are 60 mm x 60 mm x 3 mm thick slices in the coronal plane. The region covered extends from just above the heart to somewhat below the liver. Enlargements of the pre- and 0-min post images are shown in Figure 5B. Imaging parameters are indicated along the left of the Figure and include the repetition time (3000000 microseconds) , echo time (6000 microseconds, number of signal averages (4) , and the image matrix size (128 x 256) . The increase in signal intensity, particularly in the heart and liver, are readily apparent. Increase in signal intensity of the intestinal lumen is particularly apparent in the 25 min and later images, and suggests that contrast agent has been excreted into that organ.
• Figure 6A and 6B are photographs of T-l weighted magnetic resonance images obtained as described in Fig. 5A and 5B, except that Gd-DTPA-bis(phenylalanine ethyl ester) was used as the contrast agent. Note that this compound results in different apparent enhancement in the liver and heart as compared to that shown in Fig. 5A and 5B. These results suggest that the two compounds have significantly different biodistributions and pharmacokinetics.
• Any physician can determine the best mode of administration of the contrast agent. Generally, injection into a vein is used.
• contrast agents described herein are useful for the magnetic resonance imaging of the heart, liver, biliary tree, bladder and intestine of a subject, e.g. an animal, a mammal, especially a human being.
• MAGNETIC RESONANCE IMAGING OF A RAT USING Gd-DTPA-BIS(PHENYLGLYCINE) A 300 g male Sprague-Dawley rat was anesthetized with a intraperitoneal injection of a mixture of ketamine and diazepam, and a catheter was inserted into a lateral tail vein. The rat then was placed in a 5-cm inside diameter (i.d.) imaging coil in the bore of a 2-Tesla imager- spectrometer system (GE CSI; General Electric Co., Fremont, California) .
• GE CSI 2-Tesla imager- spectrometer system
• DTPA-bis(anhydride) 2.85 g (8.0 mmol), 10 mL of di- methylformamide (DMF), and 4.2 mL (24 mmol) of diisopropyl- ethylamine (DIPEA) (Sigma Chemical Co., St. Louis, MO) were combined in a 50 mL round-bottom flask equipped with a magnetic stirrer.
• DIPEA diisopropyl- ethylamine
• reaction mixture was concentrated in vacuo to yield a viscous residue.
• This material was triturated with 100 mL of acetone, and the volatile components of the resulting mixture were removed in vacuo.
• the solid residue was recrystallized from a mixture of 125 mL of 60/40 water/ethanol.
• the white, crystalline product was washed with two 25-mL portions of cold ethanol, and the washed solid was dried in vacuo at 40°C for 1 hr to obtain 3.0 g (50% of theory).
• Analytically pure product was obtained by dissolving 1 g of the above crystals in 75 mL of ethanol at 80-85°C, treating the resulting solution with decolorizing charcoal, removing the latter by filtration, and cooling the filtrate in an ice bath. Seed crystals were then added, and after 45 min, 0.6 g of recrystallized solid was isolated by filtration.
• DTPA-bis(phenylalanine benzyl ester) was similarly prepared (according to Example 4) from L-phenylalanine benzyl ester p-toluene-sulfonic acid salt, 4.28 g (10 mmol; Sigma Chemical Co., St. Louis, MO) . Ethyl acetate was used in place of ethanol for recrystallization. The yield was 2.6 g (75% of theory).
• a 300 g male Sprague-Dawley rat was anesthetized with a intraperitoneal injection of a mixture of ketamine and diazepam, and a catheter was inserted into a lateral tail vein.
• the rat then was placed in a 5-cm inside diameter (i.d.) imaging coil in the bore of a 2-Tesla imager- spectrometer system (GE CSI; General Electric Co., Fremont, California) .
• GE CSI 2-Tesla imager- spectrometer system
• Example 7 0.6 g of the Gd-DTPA-bis(phenylalanine) solution described in Example 7 was injected via the catheter. A series of post-injection images were obtained. The images displayed an initial enhancement in the liver and heart. As this enhancement decreased somewhat with time, increased intensity in the rat's small intestine then was observed, indicating hepatobiliary transport of the contrast agent. Intensity data are summarized below. The intensity values show some fluctuations due to breathing motion and other small artifacts.
• COMPARATIVE MRI DATA IN MICE Figure 8 is a photograph of T-l weighted magnetic resonance images obtained as in Figure 6, except that a different preparation of Gd-DTPA-(Phe-Et) 2 was used.
• HPLC HPLC
• Solvent A mobile phase -25 mmolar ammonia formate in water
• Solvent B 50/50 (U/V) acetonitrile/water
• the material used as a contrast agent in Figure 6 was found to have partially hydrolyzed to a mixture of Gd-DTPA- (ca 45%), Gd-DTPA-(Phe-Et) (Phe) (ca 45%), and Gd- 24
• Gd-DTPA-(3-HTAK Solutions of Gd-DTPA-(3-HTA) 2 for imaging experiments were prepared by reacting DTPA-(3-HTA) 2 in aqueous solution with a stoichiometric amount of GdCl 3 dissolved in water. After about 90% of the GdCl 3 had been added, the pH of the reaction mixture was adjusted to between 5 and 6 with aqueous NaOH solution. Xylenol orange indicator (1 drop of a 1 mg/mL aqueous solution) then was added, and GdCl 3 solution was added dropwise until the indicator changed from yellow to violet (at pH ⁇ 6) .
• the pH then was adjusted to between 7 and 8 with aqueous NaOH and, if necessary, aqueous Hcl solution.
• the reaction mixture was passed through a 0.22 ⁇ m sterile filter into a sterile serum vial.
• the final concentration ranged from 0.02 to 0.5 M, depending upon the initial concentrations of the reactants and the volumes of base and acid added for pH adjustment.
• the anesthetized animal was placed in the imaging coil and secured with tape.
• the coil containing the animal then was placed in the magnet bore, and the magnetic field was shimmed. Pre-contrast images were obtained.
• the contrast agent (100 ⁇ mol/kg) then was injected via the tail-vein catheter, and additional images were obtained at various intervals for up to 90 min post injection.
• Contrast agent enhancement was determined by measuring the mean signal intensity (SI) in operator- designated regions of interest (ROI) . These were normalized to the pre-injection value for each ROI according to the following formula:
• % Enhancement 100 X (SI post - SI pre )/SI pre
• Figures 9 - 13 respectively, for each of the contrast agents are illustrated, Gd-DTPA-(3-HTA) 2 also tended to produce higher lung enhancement (186% ⁇ 51% vs. 141% ⁇ 4%) .
• the differences between the effects produced by the two agents was smaller than in heart (cf. Figs. 9 and 10) .
• Example 20 Representative images using each agent are shown in Figures 14A and 14B and 15A and 15B as MRI photographic images.
• Example 20
• the rates of hydrolysis of the esters in rat plasma or pH 7.4 HEPES buffer were determined by addition of 10% by volume of Gd-153 radiolabeled 0.025 M chelate solution and incubation at 0 or 25°C Aliquots were withdrawn at various time intervals and examined by HPLC [PRP-1 column; water-acetonitrile gradient; 25 Mm ammonium formate, pH 7 mobile phase] .
• This may be due to the change in net charge (from 0 to - 1) of the chelate and/or to a change in conformation of the molecule due to coordination of the Gd by the free phenylalanine carboxylate group.
• Changing the stereochemistry of the amino acid portion of the chelate to the unnatural D-enantiomer caused the rate of ester hydrolysis in plasma to greatly decrease.
• Example 22 Determination of Relative Amounts of Urinary and Biliary Excretion
• Male Sprague-Dawley rats were anesthetized with an intraperitoneal injection of mixture of ketamine (90 mg/kg) and diazepam (2 mg/kg) , and fitted with a 23-guage cannula placed in a lateral tail vein.
• ketamine 90 mg/kg
• diazepam 2 mg/kg
• a second piece of tubing was placed in the urinary bladder and secured with a purse-string suture.
• the flap of the abdominal wall was closed, and the incision was covered with gauze.
• Heparinized (1 unit/mL) saline was infused at a rate of 0.075 mL/min via the iv catheter. After a 15 min stabilization period, the infusion was interrupted long enough to deliver a bolus dose (0.1 mmol/kg) of Gd-153 labeled contrast agent, and then resumed. Samples of bile and urine were collected in tared tubes at regular intervals before and after injection of radiolabeled agent. The net weights of these samples were determined. The amount of Gd-153 present in each sample was determined by counting in a chamber gamma counter. The raw counts were corrected for background and normalized to the total amount of Gd-153 injected.
• Gd-DTPA-(L-PheOEt) 2 30.5 ⁇ 7.4 46.9 ⁇ 8.0
• Gd-DTPA-(D-PheOEt) 2 51.3 ⁇ 5.1 39.2 ⁇ 5.5

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