EP0692979A1 - Bifunktionelle chelatbildner und ihre anwendung in der radiopharmazeutik - Google Patents

Bifunktionelle chelatbildner und ihre anwendung in der radiopharmazeutik

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Publication number
EP0692979A1
EP0692979A1 EP94912439A EP94912439A EP0692979A1 EP 0692979 A1 EP0692979 A1 EP 0692979A1 EP 94912439 A EP94912439 A EP 94912439A EP 94912439 A EP94912439 A EP 94912439A EP 0692979 A1 EP0692979 A1 EP 0692979A1
Authority
EP
European Patent Office
Prior art keywords
group
cys
ile
leu
asp
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP94912439A
Other languages
German (de)
English (en)
French (fr)
Inventor
Sebastian Erber
Ludger Dinkelborg
Gerhard Rohlfs
Paul-Eberhard Schulze
Bernhard Noll
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Institut fuer Diagnostikforschung GmbH
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Publication date
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Publication of EP0692979A1 publication Critical patent/EP0692979A1/de
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Classifications

    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57536—Endothelin, vasoactive intestinal contractor [VIC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new technetium and rhenium chelate compounds, processes for their preparation and radiopharmaceutical compositions containing these compounds, and conjugates of these compounds with selectively enriching themselves in diseased tissue
  • Substances especially peptides and proteins.
  • the invention further relates to the production of compositions containing these compounds and their use for radiodiagnostic examinations.
  • Radioactive metal ions have long been used in medical diagnostics and therapy.
  • gamma-ray emitters such as the isotope Tc-99m are used for tumor detection.
  • ß-emitters such as the isotopes Re-186, Re-188 and Re-189 are found in the
  • Radionuclide for nuclear medicine questions is technetium-99m, which due to its favorable physical properties (no corpuscular radiation, 6 h physical half-life, 140 keV gamma radiation) and the resulting low radiation exposure are particularly good as radioisotopes for which is suitable for in vivo diagnostics.
  • Technetium-99m can easily be obtained from nuclide generators as pertechnetate and can be used directly in this form for the production of kits for routine clinical needs.
  • radionuclides in in vivo diagnostics as well as therapy depends on the specificity and the selectivity of the labeled chelates to the target cell. These properties can be improved by coupling the chelates to biomolecules according to the "drug targeting" principle. Antibodies, their fragments, hormones, growth factors and substrates of receptors and enzymes are suitable biomolecules.
  • the British patent application GB 2,109,407 describes the use of radioactively labeled monoclonal antibodies against tumor-associated antigens for in vivo tumor diagnosis.
  • donor groups amino, amide, thiol, etc.
  • the known MAG3 even requires a temperature influence of 90-100 ° C for 10 minutes (Bannister, KM et al., - J. Nucl. Med. 1990, 31, 1568-1573) in order to have a radiochemical sufficient for clinical use Purity. These conditions are unsatisfactory for routine clinical operation.
  • N 2 S 2 and N 3 S systems as described by G. Bormans et al. (Nucl. Med. Biol. 1990, 17, 499-506) and described in European patent EP 0 173 424 and EP 0 250 013 meet the requirement for sufficient stability of the corresponding technetium-99m complexes, but are excreted from the organism too quickly and without specific enrichment, so that these find use only in the clinic as kidney function diagnostics and are therefore of limited use, in particular because the demand for substances that specifically accumulate in diseased tissues has increased.
  • the object of the invention is therefore to make these compounds and conjugates available, to create the simplest possible process for their preparation and to provide a kit formulation of these compounds / conjugates according to the invention for their clinical use. This object is achieved by the present invention.
  • R * - ** and R 5 are identical or different, denote a hydrogen atom or a methyl or an ethyl group and
  • R 4 represents a hydrogen atom, a branched or unbranched alkyl group having 1-4 carbon atoms, the C atoms of which may optionally contain amino groups, N (R a R t) ) groups (where R a and R * ° are the same or different - which are and represent branched or unbranched alkyl or acyl radicals having 1-20 carbon atoms, the C atoms of which are optionally substituted by a hydroxyl, a carboxy or an amino group), hydroxyl groups, thiol groups, halogens, carboxy groups, alkoxycarbonyl groups 1-20 carbon atoms, acyloxy groups with 1-12 carbon atoms, aminocarbonyl groups, sulfonyl groups, aminosulfonyl groups or phosphoric acid residues are substituted,
  • R 2 and R 9 are the same or different and have the same meaning as R 4 ,
  • k, 1 and m are the same or different and the numbers mean 0, 1, 2, 3 or 4 and
  • X is a hydrogen atom, a carboxy group, an alkoxy group with 1-20 carbon atoms, an alkoxycarbonyl group with 1-20 carbon atoms, an acyloxy group with 1-20 carbon atoms, an aminocarbonyl group, a sulfonyl group, an amino sulfonyl group, a phosphoric acid residue, a carboxymethylaminocarbonyl - Group, a p-aminophenyl group, a p-hydroxyphenyl group, a halogen atom, a hydroxy group, an amino group, an N (R a R * °) group (where R a and R ** - 5 are the same or different are and represent branched or unbranched alkyl or acyl radicals having 1-20 carbon atoms, the C atoms of which are optionally substituted by a hydroxyl, a carboxy or an amino group), a hydrazine group, a hydrazide group, one
  • Q is a -NH- or -0-
  • Z 1 has the same meaning as Z
  • Y 1 has the same meaning as Y and i have the same meaning as m
  • Q 1 is a -NH-, -C0- or -0-
  • NfR ⁇ ** - 5 " ) group (where R a and R * ° are the same or different and stand for branched or unbranched alkyl or acyl radicals having 1-20 carbon atoms, the C atoms of which may be with a hydroxy, a carboxy - or an amino group), is a bio or macromolecule, means and
  • Y is an unsaturated, at least one double and / or triple bond-containing, unbranched or branched chain with up to 12 carbon atoms, which optionally, one or more times and at any point in the chain with hydroxyl, carboxy, alkoxy, amino or substituted amido groups with 1-20 carbon atoms in the alkyl and / or aryl radical means
  • Z is a hydrogen atom, a halogen atom, a carboxy group, a hydroxy group, an alkoxycarbonyl group with 1-20 carbon atoms, an acyloxy group with 1-20 carbon atoms, an alkoxy group with 1-20 carbon atoms, a cholesteryloxycarbonylmethylaminocarbonyl group, a cholesteryloxycarbonyl group, one Cholesteryloxycarbonylmethyloxycarbonyl group, another steroid or a derivative of an ethine or ethene steroid, a substituent of the formula
  • Q 1 is a -NH-, -CO- or -0-
  • N (R a R * °) group (where R a and R * ° are the same or different and represent branched or unbranched alkyl or acyl radicals having 1-20 carbon atoms, the C atoms of which may be hydroxyl or carboxy - or an amino group), is a bio or macromolecule, means
  • M represents an element of atomic number 43 or 75
  • R 1 the. has the same meaning as R 4 ,
  • R 6 , R 7 and R 8 are the same or different and are for a hydrogen atom, an alkyl group with 1-4 carbon atoms, the C atoms of which are optionally substituted with hydroxyl, carboxy or amino groups or for are a group of the formula -CH 2 -X, in which X has the meaning given above
  • Preferred compounds of the general formula (I) according to the invention are characterized in that the radical Z is a hydrogen atom, a steroid, an ethynyl steroid or an ethenyl steroid.
  • radical Z is a hydrogen atom, a steroid, an ethynyl steroid or an ethenyl steroid and the radical X is a hydrogen atom, a halogen atom, a carboxy group, an amino group or a Amido group with 1-20 carbon atoms in the alkyl and / or aryl radical means.
  • radical Z is a hydrogen atom, a steroid, an ethynyl steroid or an ethenyl steroid
  • radical X is a hydrogen atom, a halogen atom, a carboxy group, an amino group or an amido group with 1-20 carbon atoms in the alkyl and / or aryl radical
  • Y is an ethinylidene group and the radicals R 1 , R 3 , R 6 , R 7 and R 8 each represent hydrogen atoms and k, 1 and m each represent the number 0 .
  • radical Z is a hydrogen atom and the radical X is a cholesteryloxycarbonylmethylaminocarbonyl group, a cholesteryloxycarbonyl group, a Cholesteryloxycarbonylmethyloxycarbonyl distr, another steroid or a derivative of an ethine or ethene steroid means.
  • radical Z is a hydrogen atom
  • radical X is a cholesteryloxycarbonylmethylaminocarbonyl group, a cholesteryloxycarbonyl group, a cholesteryloxycarbonylmethyloxycarbonyl group, another steroid or a derivative of an ethyne or ethene steroid which means
  • the radical Y represents an ethinylidene group and the radicals R 1 , R 3 , R 6 , R 7 and R 8 each represent hydrogen atoms and k, 1 and m each represent the number 0.
  • a third group of preferred compounds of the general formula (I) according to the invention is characterized in that the radical Z represents a hydrogen atom and the radical X represents a hydrogen atom, a carboxy group or a substituent of the formula
  • Q 1 is a -NH-, -CO- or -O-,
  • V represents a hydrogen atom, a hydroxyl group, an N ⁇ '-'- R- ** -') group (where R and R * ° are identical or different and represent branched or unbranched alkyl or acyl radicals having 1-20 carbon atoms, whose C atoms are optionally with a hydroxy, a carboxy or an amino group), is a bio or macromolecule.
  • radical Z represents a hydrogen atom
  • radical X represents a hydrogen atom, a carboxy group or a substituent of the formula
  • Q 1 is a -NH-, -C0- or -0-
  • V is a hydrogen atom, a hydroxyl group, an N (R a R * °) group (where R a and R- b are the same or different and represent branched or unbranched alkyl or acyl radicals having 1-20 carbon atoms, the carbon atoms of which optionally substituted with a hydroxyl, a carboxy or an amino group), is a bio or macromolecule, the radical Y is an ethinylidene group and the radicals R 1 , R 3 , R 6 , R 7 and R 8 each represent hydrogen atoms and k, 1 and each represent the number 0.
  • radical Z represents a hydrogen atom
  • radical X represents a hydrogen atom, a carboxy group, an alkoxy group with 1-20 carbon atoms, an alkoxycarbonyl group with 1-20 carbon atoms
  • compounds of the general formula (I) according to the invention are characterized in that the radical Z denotes a hydrogen atom, the radical X denotes a hydrogen atom, a carboxy group, an alkoxy group with 1-20 carbon atoms, an alkoxycarbonyl group with 1-20 carbon atoms, an acyloxy group with 1-20 carbon atoms, an aminocarbonyl group, a sulfonyl group, an aminosulfonyl group, a phosphoric acid residue, a carboxymethylaminocarbonyl group, a p-aminophenyl group, a p-hydroxyphenyl group, a halogen atom, a hydroxy group, an amino group, an N (R a R * °) group (where R a and R * ° are identical or different and stand for branched or unbranched alkyl or acyl radicals having 1-20 carbon atoms, the C atoms of which may be substituted with a hydroxyl,
  • a 1 , A 2 , A 3 , R 1 , R 6 , R 7 , R 8 , Y and Z have the meaning given above and in which T is a hydrogen atom, an acetate group, a benzoate group, a p-methoxybenzyl group, a Represents acetamidomethyl group, a benzamidomethyl group, a trimethylacetamidomethyl group, a hydroxyacetyl group or another suitable sulfur protecting group.
  • the present invention furthermore relates to conjugates of compounds according to the invention of the general formulas I and II with substances which selectively accumulate in tissues.
  • the fragments are linked depending on the type of substances to be connected in an amidic, imidic or ester-like manner. If the substances accumulating in the tissues are peptides, proteins, antibodies or fragments of these, the linkage is amidic via their amino groups; if the substances accumulating in tissues contain hydroxyl groups, the linkage is ester-like; if the substances accumulating in the tissues contain aldehyde groups, the linkage is imidic. Preference is given to substances which accumulate in tissues and which accumulate in diseased tissues, in particular in those tissues in which atherosclerotic plaques are present.
  • conjugates which are characterized in that the substances accumulating in the diseased tissue mean peptides and proteins, in particular endotheline, partial sequences of endothelin, endothelin analogues, endothelin derivatives or endothelin antagonists.
  • the reaction is preferably carried out in an aqueous medium at room temperature.
  • Protecting group takes place in situ or according to the literature methods known to the person skilled in the art, for example by basic hydrolysis, reductive cleavage, etc. (see for example "Protective Groups in Organic Synthesis", T.W. Greene, John Wiley and Sons 1981).
  • the present invention furthermore relates to processes for the preparation of the compounds of the general formula (II) according to the invention characterized in that one is known per se
  • a 1 and T have the meaning given in claim 11 and W has the meaning of a leaving group which enables A 1 to react with free amino groups
  • N-haloacetylamides required as starting substances are prepared by methods known from the literature by acylation of an amino function with haloacetic acid halides (JACS, 1969, 90, 4508; Chem. Pharm. Bull. 1981, 29 (1), 128).
  • N-protected .alpha.- and .beta.-amino acids are processed according to the methods known to those skilled in the art, for example via an addition / elimination reaction of an amine (primary or secondary) with a Carbonyl compound (for example acid chloride, mixed anhydride, activated ester) coupled to N-unprotected organic molecules.
  • amino protecting group After the amino protecting group has been cleaved off using known literature methods, for example by acidic or basic hydrolysis, hydrogenolysis, reductive cleavage with alkali metals in liquid ammonia, the remaining amino function is again reacted with an N-protected a- and ß-amino acid derivatized according to known literature methods (for example carbodiimide method).
  • known literature methods for example carbodiimide method.
  • the amino protective group is split off according to the literature methods mentioned above.
  • carboxylic acid (s) corresponding carboxylic acids are converted by the methods known to the person skilled in the art by converting the carboxylic acid (s) corresponding carboxylic acids, for example by the carbodiimide method (Fieser, Reagents for Organic Synthesis 10, 142), over a mixed or cyclic anhydride (Org. Prep. Proc Int. 1975, 7, 215) or via an activated ester (Adv. Org. Chem. Part B, 472).
  • the compounds according to the invention have the desired properties to a high degree. They contain the radioisotopes required for their use in a stable bound form in the complex.
  • the coupling possibilities of the chelate complexing agents according to the invention are of particular importance since they are to be regarded as trifunctional and, in addition to metal complexation, enable coupling via the multiple bond as well as via a carboxy or amino group in A 1 , A 2 or A 3 .
  • Linking the chelating agents via the multiple bond with steroids is of great advantage, it being possible either to couple to a -CH 2 group of the steroid or to link to the 17-ethynyl or 17-ethenyl group of steroids.
  • Steroid hormone receptor The technetium complex of 3,17ß-dihydroxy-17o; - (5- [2-benzoylthioacetylglycyl-glycyl] -aminopent-1- (E) -en-3-in) -1,3,5-estratriene ( Example 13b) in the in vitro cytosol test (Carlson, KE et al. 1989, 32, 345-355) a receptor affinity which corresponds to that of 17ß-estradiol. As a result, these compounds are outstandingly suitable for receptor imaging with technetium-99m and for tumor diagnosis / therapy of steroid hormone-dependent tumors.
  • Another advantage of the present invention is that the optional linkage via the carboxy or multiple bond offers the possibility of solubility and pharmacokinetics of these complexes by chemical substitution at the grain level. control plexer. Biodegradable groups or linkers in X are of particular importance here.
  • bio- and macromolecules eg monoclonal antibodies, steroids, ...) in X or Z
  • suitable bio- and macromolecules eg monoclonal antibodies, steroids, ...) in X or Z
  • complexes according to the invention are obtained which have a surprisingly high tissue and organ specificity and are therefore excellent for solving a number of diagnostic and therapeutic Problems can contribute.
  • the complex-forming ligands of the general formula (II) in which Z denotes a hydrogen atom and / or ligands of the general formula (II) in which an ethynyl function is contained can be obtained by the processes known to the person skilled in the art (for example R. Rossi et al., Tetrahedron 1983, 39, 287) can be coupled to iodine vinyl steroids.
  • the iodine vinyl steroids required are synthesized using methods known from the literature (for example H. Hofmeister et al., Tetrahedron 1986, 42, 3575).
  • the conversion of carboxy groups on compounds of the general formula (II) can be carried out, for example, by the carbodiimide method (Fieser, Reagents for Organic Synthesis 10, 142), via a mixed or cyclic anhydride (Org. Prep. Proc. Int. 1975, 7 , 215) or above an activated ester (Adv. Org. Chem. Part B, 472) can be carried out.
  • the coupling of the chelating agents to bio or macromolecules takes place according to the methods known to the person skilled in the art by converting the carboxy group (s) on the chelating agent, for example according to the carbodiimide method (Fieser, Reagents for Organic Synthesis 10, 142), via a mixed one or cyclic anhydride (Org. Prep. Proc. Int. 1975, 7, 215) or via an activated ester
  • the chelating agents obtained in this way can also be linked to bio or macromolecules which are known to accumulate particularly in the organ, organ part or tissue to be examined.
  • bio or macromolecules which are known to accumulate particularly in the organ, organ part or tissue to be examined.
  • Such molecules are, for example, enzymes, hormones, polysaccharides such as dextrans or starches, porphyrins, bleomycins, insulin, prostaglandins, steroid hormones, amino sugars, amino acids, peptides such as polylysine, proteins (such as immunoglobulins, monoclonal antibodies) , Lectins), lipids (also in the form of liposomes) and nucleotides of the DNA or RNA type.
  • conjugates with albumins such as human serum albumin
  • antibodies such as monoclonal antibodies or antimyosin, specific for tumor-associated antigens.
  • suitable synthetic polymers such as polyethyleneimines, polyamides, ect. be tied up.
  • the pharmaceutical agents formed therefrom are suitable, for example, for use in tumor diagnosis and tumor therapy, atherosclerosis diagnosis. stik or receptor imaging.
  • the binding affinity and binding specificity of the pharmaceutical agents formed to the target organ, target organ part or target tissue must not be affected or only slightly impaired by the conjugate formation.
  • radiopharmaceutical compositions according to the invention are likewise prepared in a manner known per se by dissolving or suspending the complexing agents according to the invention and their conjugates - optionally with the addition of the additives customary in galenicals - in an aqueous medium and then optionally lyophilizing the solution or suspension .
  • Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), additives of auxiliary ligands (such as sodium citrate or sodium tartrate), reducing agents (such as tin (II) chloride) or - if necessary - electrolytes such as sodium chloride or - if necessary - (an) auxiliary (s) customary in galenics (for example lactose, mannitol) and / or surfactant (s) (for example lecithins, Tween ⁇ R ⁇ , Myrj (R ).
  • physiologically acceptable buffers such as tromethamine
  • additives of auxiliary ligands such as sodium citrate or sodium tartrate
  • reducing agents such as tin (II) chloride
  • reducing agents such as tin (II) chloride
  • electrolytes such as sodium chloride or - if necessary - electrolytes
  • sodium chloride for example lactose, mannitol
  • the invention further relates to a kit for the production of radiopharmaceuticals, consisting of a compound of the general formula (II), a reducing agent and, if appropriate, an auxiliary ligand, which are present in the dry state or in solution, an instruction for use with a reaction instruction for implementing the described Compounds with Techne ⁇ tium-99m or rhenium in the form of a pertechnetate solution or perrhenate solution.
  • the radiopharmaceutical compositions according to the invention are administered to a patient in an amount of 0.1 mCi to 50 mCi, preferably in an amount of 0.5 mCi to 30 mCi per 70 kg of body weight.
  • the complex compounds / conjugates according to the invention are used for radio diagnostics and radiotherapy in the form of their complexes with the radioisotopes of the elements with the atomic number 43 or 75.
  • radiopharmaceutical compositions according to the invention meet the diverse requirements for suitability as radiopharmaceuticals for radio diagnostics and radiotherapy. So they are ideally suited to Enrich application in target tissues and thus enable a non-invasive
  • the water-solubility of the radiopharmaceutical compositions according to the invention is ensured by the auxiliaries customary in galenics, as described above. Furthermore, the radiopharmaceutical agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that the radionuclide bound in the complex is not released or is not clinically relevant or is not exchanged.
  • Preferred radiopharmaceutical compositions according to the invention are further characterized in that they contain the compounds of the general formula I or II according to the invention in the form of liposomes and that if appropriate, the compound of the general formula (I) according to the invention is prepared in a kit with technetium or rhenium in the form of the permetallates.
  • the radiopharmaceutical agents according to the invention can also be used in radioimmunotherapy or radiation therapy. These differ from radio diagnostics only in the amount and type of radioisotope used. The goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range. Suitable ß-emitting isotopes are, for example, rhenium-186 and rhenium-188.
  • the radiopharmaceutical compositions according to the invention are suitable for the non-invasive in vivo presentation of tissues containing steroid receptors, for example steroid hormone-dependent tumors.
  • radiopharmaceutical agents according to the invention are suitable for the non-invasive in vivo imaging of atherosclerotic vessel changes, for example of plaques.
  • a solution of 0.5 mg (1.44 ⁇ mol) S-benzoylthioacetylglycylglycylpropargylamide [la] in 50 ⁇ l 1 N sodium hydroxide solution is mixed with 250 ⁇ l phosphate buffer (Na 2 HP0 4 , 0.5 mol / 1, pH 8.5) diluted. Then 50 ⁇ l of a 0.15 molar trisodium citrate dihydrate solution and 2.5 ⁇ l of a 0.2 molar tin (II) chloride dihydrate solution are added.
  • the reaction mixture is mixed with a pertechnetate solution (0.4-0.9 mCi) from a Mo-99 / Tc-99m generator, incubated for 10 minutes at room temperature and then filtered (0.2 ⁇ m filter).
  • the analysis of the marking is carried out by means of HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min; Eluent A: phosphate buffer (Na 2 HP0; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na HP0 4 ; 0.01 mol; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • the analysis of the marking is carried out by means of HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min; Eluent A: phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • a solution of 0.5 mg (1.40 ⁇ mol) of S-acetyl-thioacetyl-glutaminylglycylpropargylamide [3b] in 50 ⁇ l of 0.1 N sodium hydroxide solution is mixed with 250 ⁇ l of phosphate buffer (Na 2 HP0 4 , 0.5 mol / 1, pH 8.5) diluted. Then 50 ⁇ l of a 0.15-molar trisodium citrate dihydrate solution and 2.5 ⁇ l of a 0.2-molar tin (II) chloride dihydrate solution are added.
  • a pertechnetate solution (0.4-0.9 mCi) from a Mo-99 / Tc-99m generator is added to the reaction mixture, incubated for 10 minutes at room temperature and then filtered (0.2 ⁇ m filter) .
  • the analysis of the marking is carried out by means of HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min, eluent A: phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • ⁇ 1.60-1.88 (m; 2H, -CHCH 2 CH 2 COOH) 2.30 (S; 3H, -C0CH 3 ) 2.28 (t; 2H, -CHCH 2 CH 2 COOH) 3, 04 (t; 1H, -C ⁇ CH) 3.68 (S; 2H, -NH (CH 2 ) C0-) 3.70 - 3.77 (m; 1H, -CHCH 2 CH 2 COOH) 3.88 (dd; 2H, -NH (CH 2 ) -C ⁇ CH) 4.19 (s; 2H, -SCH 2 CO-) 8.11 (m; 1H, -NH-) 8.23 (m; 1H, -NH-) 8.35 (m; 1H, -NH-)
  • the analysis of the marking is carried out by means of HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min; Eluent A: phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • the residue is taken up in 50 ⁇ l of 1 N sodium hydroxide solution and diluted with 250 ⁇ l of phosphate buffer (Na 2 HP0 4 , 0.5 mol / 1, pH 7.5). Then 50 ⁇ l of a 0.15 molar trisodium citrate dihydrate solution and 2.5 ⁇ l of a 0.2 molar tin (II) chloride dihydrate solution are added.
  • phosphate buffer Na 2 HP0 4 , 0.5 mol / 1, pH 7.5
  • the reaction mixture is with a pertechnetate solution
  • Eluent B acetonitrile / phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • a solution of 0.5 mg (0.7 ⁇ mol) of N- [2-acetylthio-3-cholesteryloxycarbonylpropionyl] glycylglycylpropagylamide [6a] in 300 ⁇ l of DMSO is mixed with 30 ⁇ l of 1 N sodium hydroxide solution. Then 50 ⁇ l of a 0.15 molar trisodium citrate dihydrate solution and 0.4-0.9 mCi of a pertechnetate solution from a Mo-99 / Tc-99m generator are added. The reaction mixture is added in portions with 10 ul of a 0.2 molar tin (II) chloride dihydrate solution, incubated for 10 minutes at room temperature and then filtered (0.2 micron filter).
  • II 0.2 molar tin
  • the analysis of the label is carried out using HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 30 min; Eluent A: acetonitrile / water 50:50 (v / v), eluent B: acetonitrile; Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • a solution of 0.5 mg (0.65 ⁇ mol) cholesterol [N- (2-acetylthiosuccinylglycylglycylpropargylamid-4-yl) -gly- an] ester [7a] in 300 ⁇ l DMSO is mixed with 30 ⁇ l 0.1 N sodium hydroxide solution. Then 50 ⁇ l of a 0.15 molar trisodium citrate dihydrate solution and 0.4-0.9 mCi of a pertechnetate solution from a Mo-99 / Tc-99m generator are added.
  • a solution of 0.5 mg (0.9 ⁇ mol) of N-dodecanoyl-cysteineylglyeylglycylpropargylamide [8a] in liquid HF is stirred for 15 min at 0 ° C. After the solvent has been evaporated off at room temperature, the residue is dissolved in 300 ⁇ l of DMSO and 30 ⁇ l of 1N sodium hydroxide solution are added. Subsequently, 50 ⁇ l of a 0.15 molar trisodium citrate dihydrate solution and 0.4-0.9 mCi of a pertechnetate solution from a Mo-99 / Tc-99m generator are added. The reaction mixture is mixed in portions with 10 ⁇ l of a 0.2 molar tin (II) chloride dihydrate solution, incubated for 10 minutes at room temperature and then filtered (0.2 ⁇ m filter).
  • II 0.2 molar tin
  • the analysis of the marking is carried out by means of HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min, eluent A: phosphate buffer (Na 2 HP0; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • the reaction mixture is mixed in portions with 10 ul of a 0.2 molar tin (II) chloride dihydrate solution, incubated for 10 minutes at room temperature and then filtered (0.2 micron filter).
  • the analysis of the label is carried out using HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min; Eluent A: phosphate buffer (Na 2 HP0; 0.01 M; pH 2.0); Eluent ' B: acetonitrile / phosphate buffer (Na 2 HP0; 0.01 M, pH 2.0) 50:50 (v / v); flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • a solution of 2.0 g (6.7 mmol) of N-dodecanoyl homocysteine thiolactone in anhydrous THF is mixed with a solution of 1.2 g (7.0 mmol) of glycylglycylpropargylamide in DMF. After the addition of 1 ml of triethylamine, the mixture is heated under reflux for 3 hours. The mixture is then concentrated under reduced pressure, the residue is taken up in CH 2 C1 2 and washed with dilute HCl. The organic phases are washed neutral with water and dried over Mg 2 SO 4 .
  • a solution of 0.5 mg (1.1 ⁇ mol) of N-decanoylhomocysteineylglycylglycylpropargylamide [11a] in 300 ⁇ l DMSO is mixed with 30 ⁇ l 1 N sodium hydroxide solution. Then 50 ⁇ l of a 0.15 molar trisodium citrate dihydrate solution and 0.4-0.9 mCi of a pertechnetate solution from a Mo-99 / Tc-99m generator are added. The reaction mixture is mixed in portions with 10 ul of a 0.2 molar tin (II) chloride dihydrate solution, 10 minutes incubated at room temperature and then filtered
  • the analysis of the label is carried out using HPLC: MERCK Nucleosil column, 125x4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min, eluent A: phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na 2 HP0; 0.01 M, pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • 3rd 11 (t; 1H, -C ⁇ CH) 3.36 - 3.40 (m; 2H, -CHCH 2 CH 2 SH) 3.51 (s; 1H, -SH)
  • a solution of 0.5 mg (1.3 ⁇ mol) N-hexanoylhomocysteineylglycylglycylpropargylamide [12a] in 300 ⁇ l DMSO is mixed with 30 ⁇ l 1 N sodium hydroxide solution. Then 50 ⁇ l of a 0.15 molar trisodium citrate dihydrate solution and 0.4-0.9 mCi of a pertechnetate solution from a Mo-99 / Tc-99m generator are added. The reaction mixture is added in portions with 10 ul of a 0.2 molar tin (II) chloride dihydrate solution, incubated for 10 minutes at room temperature and then filtered (0.2 micron filter).
  • II 0.2 molar tin
  • Eluent B acetonitrile / phosphate buffer (Na 2 HP0 4 ; 0.01 M, pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • Eluent B phosphate buffer (Na 2 HP0 4 ; 0.001 M; pH 7.4); Flow rate: 2.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • a solution of 0.5 mg (1.67 ⁇ mol) S-acetyl-thioacetylsarcosylglycylpropargylamide [15a] in 50 ⁇ l 0.1 N sodium hydroxide solution is mixed with 250 ⁇ l phosphate buffer (Na 2 HP0 4 , 0.5 mol / 1, pH 8.5). Then 50 ⁇ l of a 0.15-molar trisodium citrate dihydrate solution and 2.5 ⁇ l of a 0.2-molar tin (II) chloride dihydrate solution are added.
  • a pertechnetate solution (0.4-0.9 mCi) from a Mo-99 / Tc-99m generator is added to the reaction mixture, incubated for 10 minutes at room temperature and then filtered (0.2 ⁇ m filter) .
  • the analysis of the marking is carried out by means of HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min, eluent A: phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na HP0; 0.01 M; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • a solution of 0.5 mg (1.4 ⁇ mol) 2- (S-acetylthio) succinylsarcosylglycylpropargylamide [16a] in 50 ⁇ l 0.1 N sodium hydroxide solution is mixed with 250 ⁇ l phosphate buffer (Na 2 HP0 4 , 0.5 mol / 1, pH 8.5). Then 50 ⁇ l of a 0.15 molar trisodium citrate dihydrate solution and 2.5 ⁇ l of a 0.2 molar tin (II) chloride dihydrate solution are added.
  • a pertechnetate solution (0.4-0.9 mCi) from a Mo-99 / Tc-99m generator is added to the reaction mixture, incubated for 10 minutes at room temperature and then filtered (0.2 ⁇ m filter).
  • the analysis of the marking is carried out by means of HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min; Eluent A: phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 95%.
  • the filtrate is mixed with a solution of 1 mg Cys-Ser-Cys-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp (Endothelin 1) in anhydrous DMF and stirred for 20 hours at room temperature.
  • the reaction solution is concentrated at room temperature under reduced pressure. After dropwise addition of diethyl ether, a flocculent precipitate is formed, which is centrifuged and purified by preparative HPLC (gradient: acetonitrile / phosphate buffer).
  • reaction mixture is mixed with a pertechnetate solution (0.4-0.9 mCi) from a Mo-99 / Tc-99m generator, incubated for 10 minutes at room temperature and then filtered (0.2 ⁇ m filter).
  • the analysis of the marking is carried out by means of HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min, eluent A: phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 80%.
  • a pertechnetate solution (0.4-0.9 mCi) from a Mo-99 / Tc-99m generator is added to the reaction mixture, incubated for 10 minutes at room temperature and then filtered (0.2 ⁇ m filter) .
  • the analysis of the marking is carried out by means of HPLC: MERCK Nucleosil column, 125 x 4 mm, 5 ⁇ m; Gradient from 100% A to 100% B within 7.5 min; Eluent A: phosphate buffer (Na 2 HP0 4 ; 0.01 M; pH 2.0); Eluent B: acetonitrile / phosphate buffer (Na HP0; 0.01 M; pH 2.0) 50:50 (v / v); Flow rate: 1.0 ml / min.
  • the radiochemical purity of the Tc-99m complex is more than 90%.

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EP94912439A 1993-03-31 1994-03-29 Bifunktionelle chelatbildner und ihre anwendung in der radiopharmazeutik Withdrawn EP0692979A1 (de)

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DE4311021A DE4311021A1 (de) 1993-03-31 1993-03-31 Bifunktionelle Chelatbildner, deren Technetium- und Rhenium-Komplexe, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende radiopharmazeutische Mittel
DE4311021 1993-03-31
PCT/DE1994/000369 WO1994022491A1 (de) 1993-03-31 1994-03-29 Bifunktionelle chelatbildner und ihre anwendung in der radiopharmazeutik

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DE4310999C2 (de) * 1993-03-31 1996-07-18 Diagnostikforschung Inst Bifunktionelle chalkogenatom-unterbrochene Chelatbildner vom Typ XN¶1¶S¶1¶X' für radioaktive Isotope und deren Metallkomplexe, Verfahren zu ihrer Herstellung sowie diese enthaltende pharmazeutische Mittel
DE4311022C2 (de) * 1993-03-31 1996-07-11 Diagnostikforschung Inst Bifunktionelle chalkogenatom-unterbrochene Chelatbildner vom Typ S¶3¶N¶2¶ für radioaktive Isotope und deren Metallkomplexe, Verfahren zu ihrer Herstellung sowie diese enthaltende pharmazeutische Mittel
DE4337600A1 (de) * 1993-11-01 1995-05-04 Diagnostikforschung Inst N-Alkyl-Peptidchelatbildner, deren Metallkomplexe mit Radionukliden, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende radiopharmazeutische Zusammesetzungen
US5632969A (en) * 1994-10-13 1997-05-27 Merck & Co., Inc. N3 S2 chelating ligands optionally radiolabelled with Tc or Re, useful for diagnostic or therapeutic applications
EP0826000B1 (en) * 1995-05-10 2002-10-23 Darwin Discovery Limited Peptide compounds which inhibit metalloproteinase and tnf liberation and their therapeutic uses
IL123430A (en) * 1995-10-05 2001-04-30 Darwin Discovery Ltd Theo-converted peptides as inhibitors for metallic proteinases and TNF release
DE19652374A1 (de) * 1996-12-04 1998-06-10 Schering Ag Verwendung von Endothelin-Konjugaten in der Therapie, neue Endothelin-Konjugate, diese enthaltende Mittel, sowie Verfahren zu deren Herstellung
NZ511705A (en) * 2001-05-14 2004-03-26 Horticulture & Food Res Inst Methods and rapid immunoassay device for detecting progesterone and other steroids
EP1469875A1 (en) 2002-01-29 2004-10-27 Wyeth Compositions and methods for modulating connexin hemichannels
CN101648028B (zh) * 2002-05-06 2012-11-21 恩多塞特公司 维生素-定向的显象剂
WO2014007632A1 (en) * 2012-07-06 2014-01-09 Stichting Het Nederlands Kanker Instituut Cysteine protease capturing agents
CN116731101A (zh) 2016-06-01 2023-09-12 雅斯娜 用于治疗多种疾病的n-己酸-l-酪氨酸-l-异亮氨酸-(6)-氨基己酰胺的衍生物

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WO1992019274A1 (en) * 1991-05-08 1992-11-12 Mallinckrodt Medical, Inc. Technetium chelates to be used for determining the renal function
JPH0570484A (ja) * 1991-09-12 1993-03-23 Hitachi Chem Co Ltd ペプチドおよびその塩
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