WO1998032469A2 - Polymeres - Google Patents

Polymeres Download PDF

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Publication number
WO1998032469A2
WO1998032469A2 PCT/GB1998/000270 GB9800270W WO9832469A2 WO 1998032469 A2 WO1998032469 A2 WO 1998032469A2 GB 9800270 W GB9800270 W GB 9800270W WO 9832469 A2 WO9832469 A2 WO 9832469A2
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WO
WIPO (PCT)
Prior art keywords
compound
polymer backbone
reporter
moiety
amino acid
Prior art date
Application number
PCT/GB1998/000270
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English (en)
Other versions
WO1998032469A3 (fr
Inventor
Henry Wolfe
Kenneth Kellar
Original Assignee
Nycomed Imaging As
Golding, Louise
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
Priority claimed from GBGB9701813.9A external-priority patent/GB9701813D0/en
Application filed by Nycomed Imaging As, Golding, Louise filed Critical Nycomed Imaging As
Priority to AU58717/98A priority Critical patent/AU5871798A/en
Priority to CA002278200A priority patent/CA2278200A1/fr
Priority to JP53176198A priority patent/JP2001509796A/ja
Priority to EP98902085A priority patent/EP1011736A2/fr
Publication of WO1998032469A2 publication Critical patent/WO1998032469A2/fr
Publication of WO1998032469A3 publication Critical patent/WO1998032469A3/fr
Priority to NO993662A priority patent/NO993662L/no
Priority to US10/057,943 priority patent/US20020076378A1/en

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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
    • A61K49/04—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
    • A61K49/06—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
    • A61K49/12—Macromolecular compounds
    • A61K49/124—Macromolecular compounds dendrimers, dendrons, hyperbranched compounds
    • 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
    • A61K49/0442—Polymeric X-ray contrast-enhancing agent comprising a halogenated group
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link

Definitions

  • the present invention relates to polymers useful as therapeutic and diagnostic agents and to processes for their preparation.
  • the invention relates to amino acid based biodegradable polymers for use in targeting of diagnostic imaging and therapeutic agents.
  • the polymers in accordance with the invention are suitable for use in a variety of applications where specific delivery is desirable, and are particularly suited for the delivery of biologically active agents.
  • a preferred use of the polymers of the invention is in the enhancement of images of selected mammalian organs, tissues and cells in vivo using MR, X-ray, ultrasound, light and nuclear imaging techniques by virtue of their enhanced imaging properties and site specificity.
  • the polymers are especially suited for use as intravascular contrast agents and blood pool agents in such imaging techniques . As such they may be used in imaging blood vessels, e.g. in magnetic resonance angiography, in the measurement of blood flow and volume, in the identification and characterization of lesions by virtue of differences in vascularity from normal tissue, in the imaging of the lungs for the evaluation of pulmonary disease and in blood perfusion studies .
  • Imaging techniques such as MRI and X-ray
  • Some imaging of internal parts relies on inherent attributes of those parts, such as bones, to be differentiated from surrounding tissue in a particular type of imaging, such as X-ray.
  • Other organs and anatomical components are only visible when specifically highlighted by particular imaging techniques .
  • biotargeting image-enhancing metals One such technique with the potential to provide images of a wide variety of anatomical components involves biotargeting image-enhancing metals. Such a procedure has the possibility of creating or enhancing images of specific organs and/or tumors or other such localized sites within the body, while reducing the background and potential interference created by simultaneous highlighting of non-desired sites.
  • metal chelates to tissue or organ targeting molecules, e.g. biomolecules such as proteins
  • tissue or organ targeting molecules e.g. biomolecules such as proteins
  • Many such bifunctional chelating agents i.e. agents which by virtue of the chelant moiety are capable of strongly binding a therapeutically or diagnostically useful metal ion and by virtue of the site-specific molecular component are capable of selective delivery of the chelated metal ion to the body site of interest, are known or have been proposed.
  • drawbacks of conjugating metal chelates to protein carriers for use in MR imaging include inappropriate biodistribution, toxicity and short blood half-life. Their use in MR imaging is therefore limited.
  • proteins provide a defined structure not subject to wide synthetic variation.
  • Site-specific uses of various imaging techniques are enhanced by the use of a multiplicity of the appropriate metal ion conjugated to a site-directed macromolecule and numerous attempts have been made to produce bifunctional polychelants with increased numbers of chelant moieties per site-specific macromolecule.
  • Bifunctional polychelants in which the chelant moieties are residues of open chain PAPCAs, such as EDTA and DTPA, and in which the backbone molecule is a polyamine such as polylysine or polyethyleneimine have been produced.
  • WO-A-90/12050 describes techniques for producing polychelants comprising macrocyclic chelating moieties, such as polylysine-polyDOTA, and for the preparation of corresponding bifunctional polychelants.
  • macrocyclic chelating moieties such as polylysine-polyDOTA
  • This document also suggests the use of starburst dendrimers, such as a sixth generation PAMAM starburst dendrimer as the skeleton for such polychelants.
  • WO-A-93/06868 similarly describes polychelants comprising dendrimeric backbone molecules linked to a plurality of macrocyclic chelant moieties, e.g. DOTA residues. These in turn may be conjugated to a site-directed molecule, e.g. a protein.
  • starburst dendrimers have found little use in imaging.
  • the present invention lies in the recognition that co-polymers of amino acids carrying or attached to one or more reporter groups, e.g. chelating moieties, fluors, or absorbers, are particularly suitable for diagnostic and therapeutic use by virtue both of their structures and of their substantial uniformity in terms of molecular weight distribution. Moreover, by virtue of their relatively high molecular weights such compounds can function as effective blood pool agents without requiring attachment to site-directed biomolecules .
  • reporter groups e.g. chelating moieties, fluors, or absorbers
  • the invention provides a compound comprising a linear, branched or dendrimeric polymer backbone with linked thereto at least one reporter moiety, said polymer backbone comprising a plurality of amine-containing acids, e.g. amino acid residues or similar non-native amine-containing acids; with the proviso that when the polymer backbone is linear, the reporter moiety comprises an iodinated contrast agent, an ultrasound contrast agent, a light- based reporter or a metal chelator other than DOTA, DTPA or similar polyaminopolycarboxylic acids.
  • the reporter moiety preferably comprises an iodinated contrast agent or TMT.
  • reporter moiety is intended to define any atom, ion or molecule which may be linked to the polymer backbone to produce an effect which is detectable by any chemical, physical or biological examination.
  • a reporter moiety may thus be either a therapeutic or diagnostic agent, e.g. a contrast agent or pharmacologic agent.
  • two or more reporter moieties are attached to a given polymer backbone, these may be identical or different. Thus, these may comprise any combination of diagnostic and/or therapeutic agents.
  • the number of attached reporter moieties depends on the structure of the polymer backbone, in particular the degree of any branching, but generally will be in the range of from 3 to 200, preferably up to 100, e.g. up to 50.
  • Dendrimeric (or cascade) polymers are preferred as the backbone moiety. These are formed from monomers which act as branching sites and with each successive branching a new "generation" is formed.
  • the dendrimeric backbone molecule preferably comprises a multiplicity of native or non-native, preferably native amino acid residues arranged to extend radially outwards from a central core moiety. These amino acid residues may be terminally bonded directly, or optionally via a linking group, to one or more reporter groups. Alternatively, these may be terminally branched by the addition of further amino acid residues .
  • a backbone molecule wherein a central branched core has itself been terminally branched once is termed a first-generation backbone molecule .
  • first-generation backbone molecules provides second, third, fourth etc. generation backbones.
  • branching from this may extend radially in one or more directions, resulting in either radially asymmetrical or symmetrical dendrimers.
  • the dendrimer backbone molecules are radially asymmetrical.
  • Dendrimeric polymers comprising a plurality of native or non-native, preferably native amino acid residues form a further aspect of the invention. Conveniently, these comprise from 3 to 200 amino acid residues, e.g. from 3 to 100 amino acid residues extending radially from a central core moiety.
  • the core moiety may itself comprise one or more amino acid residues, other core moieties are contemplated.
  • the core moiety may be any molecule to which a multiplicity of successive amino acid residues may be attached and may itself comprise a reporter moiety.
  • Suitable core moieties include H 2 NCOCH 2 CH 2 CONH 2 , and
  • Y represents hydrogen or an alkyl or aryl group, e.g. a C ⁇ g alkyl group
  • X represents a -C0 2 H, -S0 2 C1 or -CH 2 Br group, as well as modifications thereto and derivatives thereof .
  • the dendrimer core may itself comprise a reporter moiety.
  • the invention provides a compound comprising a dendrimeric polymer backbone extending radially from a reporter moiety, said polymer backbone comprising a plurality of amino acid residues.
  • biodegradable linking groups serve to link the reporter moieties to the polymer backbone.
  • biodegradation of the compound at the targeted site results in release of the reporter moieties, e.g. an ionic or non-ionic contrast agent at the site of interest.
  • suitable linking groups include amide, ether, thioether, guanidyl , acetal, ketal and phosphoester groups .
  • Linkage between the backbone and the reporter groups is preferably via an amide bond, the amide nitrogen deriving from the backbone molecule and the amide carbonyl deriving from a carboxyl or carboxyl derivative on the reporter group.
  • biodegradable polymer The advantage of a biodegradable polymer is that it will not accumulate at the injection site, e.g. during lymphographic procedures, or in tissues, e.g. the liver during angiographic procedures provided its degradation rate is tuned to the required imaging time.
  • Biodegradability of the compounds of the invention can be adjusted by selection of particular linker and peptide cluster compounds.
  • the biodegradability of the linkers and polymer backbones can be optimised in vi tro using purified enzymes and/or biological fluids/tissues. The use of amino acid monomers which themselves are rapidly cleared may further aid clearance after imaging.
  • Preferred polymer backbones are those comprising from 3 to 200 amino acid residues, preferably from 3 to 100 amino acid residues and having a molecular weight of from 300 to 20,000 daltons. These are preferably bonded via peptide bonds, thereby ensuring the biodegradability of the polymer and subsequent elimination from the body.
  • the polyamino acid may be a polymer of a single species or at least two different species of amino acids, or may be a block copolymer.
  • the polyamino acid is poly-1-aspartic acid.
  • Particularly preferred compounds in accordance with the invention are those of formula I :
  • n is an integer of from 1 to 100; and R represents a reporter group or a biodegradable linker- reporter adduct .
  • the reporter moieties are chelating agents. These are capable of chelating metal ions with a high level of stability, and may be metallated with the appropriate metal ion(s), e.g. to enhance images in MRI , gamma scintigraphy or X-ray or to deliver cytotoxic doses of radioactivity to kill undesirable cells such as tumors.
  • the chelating agents are contrast agents comprising at least one paramagnetic metal ion.
  • the chelating agents may be used in their unmetallated or undermetallated state for absorption of available metal ions in vivo, e.g. in metal detoxification.
  • the reporter moieties may also comprise therapeutic agents, e.g. antibiotic, analgesic, anti-inflammatory or other bioactive agents. Prolonged circulation in the blood of polymers carrying such agents substantially prolongs their therapeutic effect. Proteolysis of the linking groups provides a release of therapeutic agent. Selection of a particular linking group thus provides the potential for a timed release of therapeutic agent at the desired site of interest.
  • therapeutic agents e.g. antibiotic, analgesic, anti-inflammatory or other bioactive agents.
  • the compounds in accordance with the invention can be attached by well-known methods to one or more site-directed molecules or targeting agents, e.g. a protein, to form bifunctional polymers which can enhance images and/or deliver cytotoxic doses of radioactivity to the targeted cells, tissues, organs, and/or body ducts.
  • site-directed molecules or targeting agents e.g. a protein
  • targeting agents e.g. a protein
  • Targeting of contrast agents to the site of interest in this way increases the effectiveness of the imaging method.
  • Such agents accumulate at the site of interest which is dependent upon the specificity of the targeting agent.
  • the polymers may be used as blood pool agents without being coupled to site directed molecules.
  • any terminal amino acid residues may thus be bonded either directly or via a biodegradable linking group to either a reporter or a targeting agent.
  • a biodegradable linking group to either a reporter or a targeting agent.
  • each terminal amino acid residue is bound via a biodegradable linking group to a targeting agent.
  • the number of targeting agents will be from 1 to 128, preferably from 1 to 16, e.g. from 1 to 4.
  • those compounds comprising a dendrimeric polymer backbone may comprise a targeting agent or site-directed macromolecule as the core moiety.
  • the resulting peptide cluster may in turn be linked to one or more reporter moieties.
  • the invention thus provides a compound comprising a dendrimeric polymer backbone extending radially from a targeting agent, said polymer backbone comprising a plurality of amino acid residues with linked thereto at least one reporter moiety.
  • the heat stable STa enterotoxin from E.coli as described in WO-A-95/11694 is particularly suitable as a core targeting agent.
  • Attached Figure 1 illustrates a compound of the invention in which the STa peptide is linked to a poly-1-aspartic acid cluster (Asp3) which in turn is linked to a plurality of TMT reporter molecules.
  • the polymers in accordance with the invention are in and of themselves useful entities in medical diagnosis and therapy, due in part to their unique localization in the body.
  • the size of the polymer typically 200 to 100,000 daltons, particularly 200 to 50,000 daltons, especially 10,000 to 40,000 daltons, radically alters its biodistribution.
  • Selection of particular linking groups and/or variations in the polyamino acid sequence also affects the biodistribution of the polymers and the attached reporter or targeting agents .
  • the compounds of the invention generally have extended intravascular residence times, e.g. of the order of hours, although this can be specifically tailored according to the desired use of the compounds by selection of appropriate linking agents and/or modification of the polyamino acid sequence of the backbone polymer.
  • ECF extracellular fluid
  • the compounds will eventually clear into the extracellular fluid (ECF) space and undergo renal excretion. Since the compounds remain primarily in the intravascular system for a diagnostically useful residence time, they are suitable for a range of uses from blood pool and cardiac perfusion imaging, CNS tumour detection and volume determination to thrombus detection and angiography.
  • blood pool agents they are particularly suited to use in studies of blood flow or volume, especially in relation to lesion detection and myocardial perfusion studies.
  • the conventional monomeric MRI contrast agents which rapidly disperse into the extracellular/extravascular space cannot readily be used for these purposes.
  • the polymers according to the invention can be administered at significantly reduced dosages relative to current monomeric MRI contrast agents such as GdDTPA and GdDOTA, thus providing a significantly improved safety margin in their use.
  • the invention thus provides compounds which are able to provide MR contrast enhancement of the blood pool for long periods of time, which have a specificity towards accumulation in various body tissues, which provide relatively large amounts of metal and whose molecular weight can be synthetically tailored to produce an agent of desired composition, molecular weight and size.
  • chelates according to the invention may be produced which are capable of functioning as X-ray agents, e.g. by choosing tungsten, and also as MR contrast agents by choosing an appropriate metal ion e.g. a lanthanide ion.
  • the site-directed molecule is preferably an antibody, antibody fragment, other protein or other macromolecule which will travel in vivo to that site to deliver the chelated metals.
  • the capacity of this site-directed macromolecule to travel and/or bind to its target is not compromised by the addition of the chelated metals.
  • the number of chelates per molecule is sufficient to enhance the image of that particular target.
  • Suitable chelating agents for attachment to the polymer backbone include both linear and macrocyclic PAPCAs.
  • suitable PAPCAs include ethylenediamine tetraacetic acid (EDTA) , diethylenetriamine pentaacetic acid (DTPA), 1,4,7,10- tetraazacyclododecanetetraacetic acid (DOTA), 1,4,7,10- tetraazacyclododecane-1, 4 , 7-triacetic acid (D03A) , 1- oxa-4 , 7 , 10-triazacyclododecanetriacetic acid (DOXA) , 1, 4 , 7-triazacyclononanetriacetic acid (NOTA) and 1,4,8, 11-tetraazacyclotetradecanetetraacetic acid (TETA) .
  • EDTA ethylenediamine tetraacetic acid
  • DTPA diethylenetriamine pentaacetic acid
  • DDA 1,4,7,10- t
  • chelating agents suitable for attachment to the polymer backbone include terpyridines such as described in US-A-5367080 , e.g. 4 ' - (3-amino-4-methoxy- phenyl) -6,6" -bis (N' ,N' -dicarboxymethyl-N- methylhydrazino) -2,2' : 6 ' , 2 " -terpyridine (THT) and 4 ' - (3-amino-4-methoxy-phenyl) -6,6" -bis [N,N- di (carboxymethyl) aminomethyl] -2,2' : 6 ' , 2 " -terpyridine (TMT) .
  • terpyridines such as described in US-A-5367080 , e.g. 4 ' - (3-amino-4-methoxy- phenyl) -6,6" -bis (N' ,N' -dicarboxymethyl-N-
  • Metals that can be incorporated, through chelation include lanthanides and other metal ions, including isotopes and radioisotopes thereof, such as, for example, Mg, Ca, Sc, Ti, B, V, Cr, Mn, Fe, Co, Ni , Cu, Zn, Ga, Sr, Y, Zr, Tc, Ru, In, Hf , W, Re, Os, Pb and Bi .
  • isotopes and radioisotopes thereof such as, for example, Mg, Ca, Sc, Ti, B, V, Cr, Mn, Fe, Co, Ni , Cu, Zn, Ga, Sr, Y, Zr, Tc, Ru, In, Hf , W, Re, Os, Pb and Bi .
  • the choice of metal ion for chelation will depend upon the desired therapeutic or diagnostic application.
  • the reporter moiety may comprise an ionic or non-ionic iodinated monocyclic or bis-cyclic X-ray contrast agent.
  • mono and bis-cyclic is meant that the contrast agents contain either one or two iodinated rings.
  • the iodinated rings will be di- or tri-iodinated, e.g. tri- iodinated aryl rings, in particular phenyl rings.
  • iodinated contrast agents for use in accordance with the invention include iohexol , iopentol, iopamidol and iodixanol .
  • one or more iodinated contrast agents may be conjugated to form an alternating co-polymer which in turn can be attached to the polymer backbone.
  • An example of the synthesis of such a co-polymer from iodixanol is shown below:
  • the bifunctional agents in accordance with the invention involve coupling the compounds to a site- directed molecule.
  • the site-directed molecules may be any of the molecules that naturally concentrate in a selected target organ, tissue, cell or group of cells, or other location in a mammalian body, in vivo. These can include amino acids, oligopeptides (e.g. hexapeptides) , molecular recognition units (MRU's), single chain antibodies (SCA's), proteins, non-peptide organic molecules, Fab fragments, and antibodies.
  • site-directed molecules include polysaccharides (e.g.
  • CCK and hexapeptides CCK and hexapeptides
  • proteins such as lectins, asialofetuin, polyclonal IgG, blood clotting proteins (e.g. hirudin) , lipoproteins and glycoproteins) , hormones, growth factors, and clotting factors (such as PF4) .
  • Exemplary site-directed proteins include E.coli heat stable enterotoxin STa and its analogues, polymerized fibrin fragments (e.g., E : ) , serum amyloid precursor (SAP) proteins, low density lipoprotein (LDL) precursors, serum albumin, surface proteins of intact red blood cells, receptor binding molecules such as estrogens, liver-specific proteins/polymers such as galactosyl-neoglycoalbumin (NGA) (see Vera et al . in Radiology 151: 191 (1984)) N- (2 -hydroxy-propyl) methacrylamide (HMPA) copolymers with varying numbers of bound galactosamines (see Duncan et al., Biochim. Biophys . Acta 880:62 (1986)), and allyl and 6-aminohexyl glycosides (see Wong et al . , Carbo . Res. 170:27 (1987)), and fibrinogen.
  • SAP
  • the site-directed protein can also be an antibody.
  • the choice of antibody, particularly the antigen specificity of the antibody, will depend on the desired use of the conjugate. Monoclonal antibodies are preferred over polyclonal antibodies.
  • HSA Human serum albumin
  • HSA Human serum albumin
  • Preparation of antibodies that react with a desired antigen is well known.
  • Antibody preparations are available commercially from a variety of sources.
  • Fibrin fragment E ⁇ can be prepared as described by Olexa et al. in J. Biol . Chem. 2_5_4:4925 (1979).
  • Preparation of LDL precursors and SAP proteins is described by de Beer et al . in J. Immunol. Methods 5_0:17 (1982). The above described articles are incorporated herein by reference in their entirety.
  • the compounds in accordance with the invention are conveniently prepared by conjugation of a linear, branched or dendrimeric backbone comprising a plurality of amino acid residues to one or more reporter groups in a non-reactive solvent.
  • Linkage of the reporter groups to the backbone molecule may be effected through any reactive group and standard coupling techniques are known in the art.
  • Preferred reaction conditions, e.g. temperature, solvents etc. depend primarily on the particular reactants and can be readily determined by those skilled in the art.
  • Metals can be incorporated into a chelant moiety by any one of three general methods: direct incorporation, template synthesis and/or transmetallation. Direct incorporation is preferred.
  • the polymer backbone itself may be synthesised in accordance with conventional peptide synthesis techniques. Suitable methods for forming the amino acid units are described in, for example, "Synthesis of Optically Active -Amino Acids" by Robert M. Williams (Pergamon Press, 1989).
  • the reactive side chain groups present e.g. amino, thiol and/or carboxy, will be protected during the coupling of the individual amino acids, although it is possible to leave some side chain groups unprotected, e.g. hydroxy, primary amide groups, during the entire synthetic procedure.
  • the final step in the synthesis of a compound in accordance with the invention will be the deprotection of a fully protected or partly protected derivative of such a compound and such a process forms part of the invention.
  • the present invention provides a process for producing a compound as hereinbefore described, said process comprising deprotecting a partially or fully protected derivative thereof.
  • the peptide compounds for use in accordance with the invention may be produced in good yield and high purity ( ⁇ 0.1% racemisation per step) by synthesising in the amino to carboxy direction.
  • This method of synthesis has been found to be particularly effective in preparing the dendrimeric polymer backbones. In particular, these have been found to be more stable than those dendrimers derived from the more conventional Michael addition chemistry.
  • synthesising the polymer backbones in the amino to carboxy direction has been found to produce discrete polymers which are substantially non cross-linked and which have particularly low levels of racemic impurities.
  • the invention further provides a process for the preparation of a compound comprising a linear, branched or dendrimeric polymer backbone with linked thereto at least one reporter moiety, said polymer backbone comprising a plurality of amino acid residues, said process comprising: (a) stepwise linking of successive protected amino acid residues in the amino to carboxy direction to form a polymer backbone;
  • the first aspartic acid derivative will have a protected amino group and a free carboxyl group while the other reactant will have either a free or activated ⁇ -amino group and a protected carboxyl group.
  • the intermediate may be purified, e.g. by chromatography, and then selectively deprotected to permit addition of further amino acid residues. This procedure is continued until the required amino acid sequence is completed.
  • Suitable amine protecting groups include carbobenzoxy (Z- or Cbz) , t-butoxycarbonyl (Boc-) and 9- fluorenylmethoxycarbonyl (Fmoc-) .
  • Carboxyl protecting groups which may be used include benzyl (-Bzl) and t- butyl (-tBu) .
  • Amine protecting groups such as Boc and carboxyl protecting groups such as -tBu may be removed simultaneously by acid treatment, e.g. with trifluoroacetic acid.
  • the coupling of free amino and carboxyl groups may, for example, be effected using N,N' -dicyclohexyl carbodiimide (DCC) .
  • DCC N,N' -dicyclohexyl carbodiimide
  • Other coupling agents which may be used include l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and 2- (11-H-benzotriazolyl-l-yl) - 1, 1, 3-tetramethyluranium tetrafluoroborate (TBTU) .
  • the coupling reactions may be effected at ambient temperatures, conveniently in a suitable solvent system, e.g. tetrahydrofuran, dimethylformamide, dimethylsulphoxide or a mixture of these solvents.
  • a suitable solvent system e.g. tetrahydrofuran, dimethylformamide, dimethylsulphoxide or a mixture of these solvents.
  • the compounds of the invention may be administered to patients for imaging in amounts sufficient to yield the desired contrast with the particular imaging technique.
  • dosages of from 0.001 to 5.0 mmoles of chelated imaging metal ion per kilogram of patient bodyweight are effective to achieve adequate contrast enhancements.
  • preferred dosages of imaging metal ion will be in the range of from 0.02 to 1.2 mmoles/kg bodyweight while for X-ray applications dosages of from 0.5 to 1.5 mmoles/kg are generally effective to achieve X-ray attenuation.
  • Preferred dosages for most X-ray applications are from 0.8 to 1.2 mmoles of the lanthanide or heavy metal/kg bodyweight .
  • the dosage of the compounds of the invention for therapeutic use will depend upon the condition being treated, but in general will be of the order of from 1 pmol/kg to 1 mmol/kg bodyweight.
  • the compounds of the present invention may be formulated with conventional pharmaceutical or veterinary aids, for example emulsifiers, fatty acid esters, gelling agents, stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, etc., and may be in a form suitable for parenteral or enteral administration, for example injection or infusion or administration directly into a body cavity having an external escape duct, for example the gastrointestinal tract, the bladder or the uterus.
  • the compounds of the present invention may be in conventional pharmaceutical administration forms such as tablets, capsules, powders, solutions, suspensions, dispersions, syrups, suppositories etc.
  • solutions, suspensions and dispersions in physiologically acceptable carrier media for example water for injections, will generally be preferred.
  • the compounds according to the invention may therefore be formulated for administration using physiologically acceptable carriers or excipients in a manner fully within the skill of the art.
  • the compounds optionally with the addition of pharmaceutically acceptable excipients, may be suspended or dissolved in an aqueous medium, with the resulting solution or suspension then being sterilized.
  • parenteral e.g., intravenous administration
  • parenterally administrable forms e.g. intravenous solutions
  • Suitable vehicles include aqueous vehicles customarily used for administering parenteral solutions such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection and other solutions such as are described in Remington's Pharmaceutical Sciences, 15th ed. , Easton: Mack Publishing Co., pp. 1405-1412 and 1461-1487 (1975) and The National Formulary XIV, 14th ed. Washington: American Pharmaceutical Association (1975) .
  • the solutions can contain preservatives, antimicrobial agents, buffers and antioxidants conventionally used for parenteral solutions, excipients and other additives which are compatible with the chelates and which will not interfere with the manufacture, storage or use of products.
  • the invention provides a pharmaceutical composition, e.g. an image enhancing or therapeutic composition, comprising a compound of the invention together with at least one pharmaceutical carrier or excipient.
  • a pharmaceutical composition e.g. an image enhancing or therapeutic composition, comprising a compound of the invention together with at least one pharmaceutical carrier or excipient.
  • the invention provides the use of a compound according to the invention or a chelate thereof for the manufacture of an image enhancing contrast medium or a therapeutic composition.
  • the invention provides a method of generating an image of a human or non-human animal, especially mammalian, body which method comprises administering to said body an image enhancing amount of a compound according to the invention and thereafter generating an image e.g. an MR, X-ray, ultrasound or scintigraphic image, of at least a part of said body.
  • an image e.g. an MR, X-ray, ultrasound or scintigraphic image
  • Example 1 Asymmetric peptide cluster
  • Step 1
  • Step 2
  • Step 1
  • Step 2
  • Step 3
  • Step 4
  • Step 1
  • Step 2
  • the product from Step 1 was dissolved in 250 mL THF:DMF (1:1, v/v) with 60 mmoles of triethylamine and 40 mmoles of L-aspartic acid- ( ⁇ , ⁇ - (tButyl) ester . To this solution was added 60 mmoles of TBTU. After 16 hours, an additional 20 mmoles of L-aspartic acid-( , ⁇ - (tButyl) ester was added and the reaction continued overnight .
  • Example 3 X-ray contrast agent
  • Compound I may be coupled to any one of the Asp x clusters described in Examples 1 and 2 to form an iodinated X-ray contrast agent.

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Abstract

La présente invention concerne des composés renfermant un squelette polymère linéaire, ramifié ou dendrimère auquel est liée au moins une fraction reporter, ledit squelette polymère comprenant plusieurs acides contenant des amines. De tels composés peuvent être liés à un ou plusieurs agents de ciblage et sont utiles comme agents thérapeutiques et diagnostiques, en particulier dans les techniques d'imagerie médicale.
PCT/GB1998/000270 1997-01-29 1998-01-29 Polymeres WO1998032469A2 (fr)

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AU58717/98A AU5871798A (en) 1997-01-29 1998-01-29 Polymers
CA002278200A CA2278200A1 (fr) 1997-01-29 1998-01-29 Polymeres
JP53176198A JP2001509796A (ja) 1997-01-29 1998-01-29 重合体
EP98902085A EP1011736A2 (fr) 1997-01-29 1998-01-29 Polymeres
NO993662A NO993662L (no) 1997-01-29 1999-07-28 Polymerer
US10/057,943 US20020076378A1 (en) 1997-01-29 2002-01-29 Polymers

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US5707497P 1997-08-27 1997-08-27
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018791A1 (fr) * 1998-09-29 2000-04-06 Statens Serum Institut Ensemble de presentation de ligands (lpa) son procede de preparation et ses utilisations
WO2001002861A1 (fr) * 1999-06-29 2001-01-11 Dako A/S Detection a l'aide de sondes et de marqueurs a dendrimeres
WO2001007469A2 (fr) * 1999-07-23 2001-02-01 Les Laboratoires Servier Dendrimeres polypeptidiques en tant que porteurs unimoleculaires d'agents de contraste d'imagerie diagnostique, de substances bioactives et de medicaments
WO2002033412A1 (fr) * 2000-10-14 2002-04-25 Macrogen Inc. Support biologique et methode de preparation dudit support
WO2020142664A1 (fr) * 2019-01-03 2020-07-09 Ionpath, Inc. Compositions et réactifs pour imagerie par faisceau d'ions
CN113307863A (zh) * 2021-05-25 2021-08-27 华南农业大学 一种聚天冬氨酸及其盐类抗体的制备方法和应用

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1814598B1 (fr) * 2004-11-22 2011-01-12 Ge Healthcare As Agents de contraste pour cibler une matrice extra cellulaire
JP4870941B2 (ja) * 2005-05-09 2012-02-08 公立大学法人大阪府立大学 高分子化合物
KR101334780B1 (ko) * 2010-08-13 2013-12-02 한국생명공학연구원 요오드를 함유한 방사형상의 고분자 화합물, 이의 제조방법 및 이를 포함하는 ｃｔ용 조영제 조성물

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EP0331616A2 (fr) * 1988-02-29 1989-09-06 Schering Aktiengesellschaft Formateur de complexe lié à un polymère, ces complexes, procédé de préparation et milieu pharmaceutique les contenant
EP0481526A1 (fr) * 1989-04-07 1992-04-22 Nycomed Salutar, Inc. Agents de chélation
WO1993006868A1 (fr) * 1991-10-07 1993-04-15 COCKBAIN, Jilian, Roderick, Michaelson Polychelateurs dendrimeres
WO1993010824A1 (fr) * 1991-12-04 1993-06-10 Guerbet S.A. Nouveau compose macromoleculaire polyamine iode, son procede de preparation et son utilisation comme agent de contraste
WO1994005203A1 (fr) * 1992-09-04 1994-03-17 The General Hospital Corporation Polymeres biocompatibles contenant des fractions therapeutiques ou de diagnostic
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EP0331616A2 (fr) * 1988-02-29 1989-09-06 Schering Aktiengesellschaft Formateur de complexe lié à un polymère, ces complexes, procédé de préparation et milieu pharmaceutique les contenant
EP0481526A1 (fr) * 1989-04-07 1992-04-22 Nycomed Salutar, Inc. Agents de chélation
WO1993006868A1 (fr) * 1991-10-07 1993-04-15 COCKBAIN, Jilian, Roderick, Michaelson Polychelateurs dendrimeres
WO1993010824A1 (fr) * 1991-12-04 1993-06-10 Guerbet S.A. Nouveau compose macromoleculaire polyamine iode, son procede de preparation et son utilisation comme agent de contraste
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018791A1 (fr) * 1998-09-29 2000-04-06 Statens Serum Institut Ensemble de presentation de ligands (lpa) son procede de preparation et ses utilisations
WO2001002861A1 (fr) * 1999-06-29 2001-01-11 Dako A/S Detection a l'aide de sondes et de marqueurs a dendrimeres
WO2001007469A2 (fr) * 1999-07-23 2001-02-01 Les Laboratoires Servier Dendrimeres polypeptidiques en tant que porteurs unimoleculaires d'agents de contraste d'imagerie diagnostique, de substances bioactives et de medicaments
WO2001007469A3 (fr) * 1999-07-23 2001-05-10 Antonio Verdini Dendrimeres polypeptidiques en tant que porteurs unimoleculaires d'agents de contraste d'imagerie diagnostique, de substances bioactives et de medicaments
WO2002033412A1 (fr) * 2000-10-14 2002-04-25 Macrogen Inc. Support biologique et methode de preparation dudit support
WO2020142664A1 (fr) * 2019-01-03 2020-07-09 Ionpath, Inc. Compositions et réactifs pour imagerie par faisceau d'ions
CN113307863A (zh) * 2021-05-25 2021-08-27 华南农业大学 一种聚天冬氨酸及其盐类抗体的制备方法和应用

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AU5871798A (en) 1998-08-18
WO1998032469A3 (fr) 1998-11-05
CN1246059A (zh) 2000-03-01
KR20000070544A (ko) 2000-11-25
EP1011736A2 (fr) 2000-06-28
JP2001509796A (ja) 2001-07-24
NO993662D0 (no) 1999-07-28
NO993662L (no) 1999-09-28
CA2278200A1 (fr) 1998-07-30

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