CA2232315A1 - Bifunctional sulfide-containing sulfonamide-chelating agents such as s2 ny for radioactive isotopes - Google Patents

Bifunctional sulfide-containing sulfonamide-chelating agents such as s2 ny for radioactive isotopes Download PDF

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CA2232315A1
CA2232315A1 CA 2232315 CA2232315A CA2232315A1 CA 2232315 A1 CA2232315 A1 CA 2232315A1 CA 2232315 CA2232315 CA 2232315 CA 2232315 A CA2232315 A CA 2232315A CA 2232315 A1 CA2232315 A1 CA 2232315A1
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Ludger Dinkelborg
Christoph Stephan Hilger
Wolfgang Kramp
Johannes Platzek
Bernd Raduchel
Sebastian Erber
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Bayer Pharma AG
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    • 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
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • 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
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B59/001—Acyclic or carbocyclic compounds
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/008—Peptides; Proteins
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/14—Angiotensins: Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Abstract

The invention concerns novel compounds of general formula (I), M-L, in which M stands for a radioisotope of Tc or Re and L stands for a ligand of general formula (II) R1S-CR2R3-(CR4R5)n=1,2-S-CHR6-CHR7-SO2-NH-(CR8R9)m=1,2-CO-B in which R1, R2, R3, R4, R5, R6, R7, R8, and R9 can have different meanings and B stands for a further group which is suitable for the dative bond of metal ions and for the coupling to selectively concentrating compounds. The novel compounds are used for complexing technetium and rhenium and are applied in medical diagnostics and therapy.

Description

CA 0223231~ 1998-03-17 Bifunctional 8ulfide-Containing 8ulfonamide-Chelating Agents 8uch as 8~Y for Radioactive Isotopes The invention relates to new chelating agents that contain sulfonamide groups, pharmaceutical agents that contain these compounds, their use in radiodiagnosis and radiotherapy, a process for the production of these compounds and agents, and conjugates of these compounds with substances that selectively accumulate in diseased tissue, especially peptides.
The use of radiopharmaceutical agents for diagnostic and therapeutic purposes has been known for a long time in the field of biological and medical research. In particular, radiopharmaceutical agents are used to visualize certain structures, such as, for example, the skeleton, organs, or tissue. Diagnostic application requires the use of radioactive agents which, after administration, accumulate specifically in the structures in patients that are to be examined. These radioactive agents that accumulate locally can then be traced, plotted, or scintigraphed using suitable detectors, such as, for example, scintillation cameras or other suitable recording processes. The dispersion and relative intensity of the detected radioactive agent characterize 1:he site of a structure where the radioactive agent is located and can show the presence of anomalies in structure and function, pathological changes, etc.
Similarly, radiopharmaceutical agents can be used as therapeutic agents to irradiate specific pathological tissues or regions.
Such treatment requires the production of radioactive therapeutic CA 0223231~ 1998-03-17 agents that accumulate in specific structures, tissues, or organs. By concentrating these agents, therapeutic radiation is brought to bear directly on the! pathological tissue.
The use of both diagnostic and therapeutic radiopharmaceutical agents requires compounds that can be radiolabeled. In the case of metallic radionuclides, the metal can be present in free form as an ion or in the form of a metal complex with one or more ligands. Examples of metallic radionuclides that can form complexes are technetium-99m and the various rhenium isotopes. The former is used in diagnosis, and the latter is employed in therapy. The radiopharmaceutical agents contain suitable vehicles and additives that allow injection, inhalation, or ingestion by patients, just like physiological buffers, salts, etc.
The radionuclide that is used most often for tasks in nuclear medicine is technetium-99m, which, owing to its advantageous physical properties (no corpuscular radiation, 6 hours of physical half-life, 140 KeV of gamma-radiation) and the low radiation exposure that results from it, is especially well suited as a radioisotope for in vivo diagnosis. Technetium-99m can easily be obtained from nuclide generators as pertechnetate and can be used in this form directly for the production of kits for routine clinical needs.
The production of radiopharmaceutical agents first requires the synthesis of a suitable ligand. Then, the complex with the radionuclide is visualized separately (labeling). To do this, the ligand that is produced, invariably in the form of a freeze-CA 0223231~ 1998-03-17 dried kit, is reacted under complexing conditions with a solution that contains the radionuclide. If, for example, the production of a technetium-99m radiopharmaceutical agent is desired, the ligand that is produced is mixed with a pertechnetate solution with the addition of a suitable reducing agent, and the corresponding technetium complex is produced under suitable reaction conditions. These complexes are then administered to the patient in a suitable way by injection, inhalation, or ingestion.
The solutions that contain the radionuclide can, as in the case of technetium-99m, be obtained from an available Mo-99/Tc-99m nuclide generator, or may be ordered from a manufacturer, as in the case of rhenium-186. The complexing reaction is carried out at suitable temperatures (e.g. 20~-100~C) within periods ranging from a few minutes to several hours. To ensure complete complexing, a large excess (more than a 100-fold excess in the metal-radionuclide) of the ligand that is produced and enough reducing agent to ensure complet:e reduction of the radionuclide that is used are necessary.
Radiopharmaceutical agents are produced by combining the radionuclide complex, in an amount that is sufficient for diagnostic or therapeutic application, with pharmacologically acceptable radiological vehicles. This radiological vehicle should have advantageous propert:ies for the administration of the radiopharmaceutical agent in the form of an injection, inhalation, or ingestion. Examples of such vehicles are HSA, aqueous buffer solutions, e.g., tris-(hydroxymethyl)aminoethanes CA 0223231~ 1998-03-17 (or their salts), phosphate, citrate, bicarbonate, etc., sterile water, physiological common salt solution, isotonic chloride or dicarbonate-ionic solutions or normal plasma ions, such as Ca2~, Na', K' and Mg2'.
Since technetium can be present in a number of oxidation stages (+7 to -1), it is often necessary for radiopharmaceutical agents to contain additional agents, which are known as stabilizers. The latter keep t:he radionuclide in a stable form until it has reacted with the ligand. These stabilizers can contain agents that are known as transfer or auxiliary ligands, which are especially useful for stabilizing and complexing the metal in a well-defined oxidation stage until the target ligand complexes the metal via a ligand exchange. Examples of this type of auxiliary ligands are (including their salts) gluconoheptoic acid, tartaric acid, citric acid, or other common ligands, as is explained in more detail later.
In a standard fashion, raclionuclide-containing radiopharmaceutical agents are produced by the ligand first being synthesized and then being reac:ted with the metal-radionuclide in a suitable way to form a corresponding complex, in which the ligand necessarily must be present unchanged after complexing, with the exception of the cleavage of optionally present protective groups or hydrogen ions. The removal of these groups facilitates the coordination of the ligand on the metal ion and thus results in guick complexing.
To form technetium-99m complexes, pertechnetate is first obtained from a nuclide generat:or and shifted, with the aid of CA 0223231~ 1998-03-17 suitable reducing agents (e.g., SnCl2, S2042~, etc.), into a lower oxidation stage, which then is stabilized by a suitable chelating agent. Since technetium can be present in a number of oxidation stages (+7 to -1), which can greatly alter the pharmacological properties by altering the charge of a complex, it is necessary to provide chelating agents or complex ligands for technetium-99m that can bind technetium securely, tightly, and in a stable manner to a defined oxidation stage to keep undesirable biodistribution, which impedes reliable diagnosis of corresponding diseases, from occurring due to in vivo redox processes or technetium release-; from the corresponding radiodiagnostic agents.
The efficiency of radionuclides in in vivo diagnosis and in therapy depends on the specificity and selectivity of the labeled chelates with respect to the target cell. These properties are enhanced by coupling the chelates to biomolecules according to the "drug-targeting" principle. Offered as biomolecules are antibodies, their fragments, hormones, growth factors, and substrates of receptors and enzymes. Thus, in British Patent Application GB 2,109,407, the use of radiolabeled monoclonal antibodies against tumor-associated antigens is described for in vivo tumor diagnosis. Direct protein labelings via donor groups (amino, amide, thiol, etc.) of the protein (Rhodes, B. A. et al., J. Nukl. Med. 1986, 27, 685-693~ or by introducing complexing agents (US Patent 4,479,930 and Fritzberg, A. R. et al., Nucl.
Med. 1986, 27, 957) with technetium-99m have also been described.
These experimental methods are not available for clinical use, CA 0223231~ 1998-03-17 however, since, on the one hand, their selectivity is too low and, on the other hand, the background activity in the organism is too high to make in vivo imaging possible.
Regarded as suitable complexing agents for technetium and rhenium isotopes are, e.g., cyclic amines as they are described by Volkert et al. (Appl. Radiol. Isot. 1982, 33; 891) and Troutner et al. (J. Nucl. Med. 1980, 21; 443), which have the drawback, however, that they frequently are able to bind technetium-99m in good yields only starting from a pH > 9. Nz02 systems (Pillai, M. R. A., Troutner, D. E. et al., Inorg. Chem.
1990, 29; 1850) are in clinical use. Non-cyclic N4 systems, such as, e.g., the HMPA0, suffer from low complex stability as a major disadvantage. Because of its instability (Ballinger, J. R. et al., Appl. Radiat. Isot. 1991, 42; 315), Billinghurst, M. W. et al., Appl. Radiat. Isot. 1991, 42; 607), Tc-99m-HMPA0 must be administered within 30 minutes after it is labeled, so that the portion of decomposition products that have a different pharmacokinetics and separation can be kept small. Such radiochemical contaminants hamper the detection of diseases that are to be diagnosed. Coupling these chelates or chelating agents to other substances that accumulate selectively in foci of disease cannot be accomplished by simple means, so that the latter are dispersed in general in an unspecific manner in the organism.
N2S2 chelating agents (Bormans, G. et al.; Nucl. Med. Biol.
1990, 17; 499), such as, e.g., ethylenedicysteine (EC;
Verbruggen, A.M. et al.; J. Nucl. Med. 1992, 33; 551) CA 0223231~ 1998-03-17 specifically meet the requirement for sufficient stability of the corresponding technetium-99m complex, but form radiodiagnostic agents with a purity of greater than 69% starting only from a pH
of the complexing medium > 9. N3S systems (Fritzburg, A.; EP-0173424 and EP-0250013) form stable technetium-99m complexes but must be heated to temperatures of about 100~C to form a uniform radiopharmaceutical agent.
In recent years, the demand for radiodiagnostic agents that accumulate specifically in diseased tissue has increased. This can be accomplished if complexing agents can be readily coupled to selectively accumulating substances and, in so doing, do not lose their advantageous complexing properties. Since it very frequently happens, however, that after a complexing agent is coupled to such a molecule with the aid of its functional groups, a weakening of complex stability is observed, previous attempts to couple chelating agents to selectively accumulating substances do not appear to have been very satisfactory since a diagnostically non-tolerable portion of the isotope from the conjugate is released in vivo (}3rechbiel, M. W. et al.; Inorg.
Chem. 1986, 25, 2772). It is therefore necessary to produce bifunctional complexing agents 1hat carry both functional groups for binding the desired metal ion and a (another, several) functional group(s) for binding the selectively accumulating molecule, or configuring the complexing agent in such a way that the desired complexing agent structure is formed only by coupling to a selectively accumulating substance, and thus a weakening of complex stability will not occur. Such ligands make possible a CA 0223231~ 1998-03-17 specific, chemically defined binding of technetium or rhenium isotopes to a wide variety of biological materials, even if a so-called prelabeling is carried out. Several chelating agents, coupled to monoclonal antibodies (e.g., EP-0247866 and EP-0188256) or fatty acids (EP-0200492), have been described. As chelating agents, however, the already mentioned N2S2 systems are used, which are not very suitable owing to their low stability.
Since both the selectively accumulating substances are very different in terms of their properties and also in terms of the mechanisms according to which they are concentrated, it is further necessary to vary the couplable chelating agent and to be able to adapt the physiological requirements of the coupling partner with respect to its lipophilia, membrane permeability, etc.
The object of the invention is therefore to make available stable complex compounds that are or can be coupled to various selectively accumulating compounds, without their specificity and selectivity being fundamentally affected. In addition, the object exists of preparing such couplable chelating agents or complexes that have a greater chemical variation range of the substituents, in order to be able to match the latter to the above-referenced requirements. In this case, the requirements for the application of these compounds to humans must be met in terms of the radiation dose taken up and the stability and solubility of the compounds.
This object is achieved ac:cording to the invention in that new chelating agents that contain bifunctional sulfonamide groups and their coupling products with specifically accumulating compounds are made available.
The subject of the invention is compounds of general formula (I) M - L (I) in which M means a radioisotope of Tc or Re and L means a ligand of general formula (II) Rl~-CR2R3- (CR4RS) n 1 2-8-CHR6-CHR7-So2-NH- (CR8R9) ~F1 2--CO-B
(II) in which R1 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or for a sulfur protective group, R2, R3, R4, R5, R6, R7, R8 and R9 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, B stands for a hydroxyl group, a mercapto group or a radical -NHRa, in which Ra represents a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or ary:Lalkyl radical, which optionally is substituted w:ith hydroxy, oxy, oxo, carboxy, aminocarbonyl, a:lkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se.
Preferred compounds of general formula (I) are distinguished in that n and m in each case stand for 1, and in that R1, R2, R5, R6, R7 and R4 are hydrogen atoms.
Especially preferred compounds of general formula (I) are distinguished in that n and m in each case stand for 1 and in that Rl, R2, R5, R6, R7 and R9 are hydrogen atoms, and B stands for a hydroxyl group or a radical -NHRa, in which Ra represents a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se.
Another subject of the invention relates to new bifunctional sulfur atom-interrupted sulfonamide ligands of general formula (II) R18-CR2R3- tCR~'R5) ,F1 z-B-CHR6-CHR7-Bo2-NH- (CR8R9) F1 2-CO-B
(II) in which R1, R2, R3, R4, Rs, R6, R7, R8, R9, n, m, and B in each case have the meaning that: is indicated above.

CA 0223231~ 1998-03-17 Preferred compounds of general formula (II) are distinguished in that in each case 1 stands for n and m and in that R1, RZ, R5, R6, R7 and R9 are hydrogen atoms.
Especially preferred compounds of general formula (I) are distinguished in that in each case 1 stands for n and m, and in that R1, R2, R5, R6, R7 and R9 are hydrogen atoms and B stands for a hydroxyl group or a radical -NHRa, in which Ra represents a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl, arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 2~ carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series 0, N, S, P, As and Se.
Another subject of the invention is conjugates that contain a compound of general formula (:1 and/or II) and nucleotides such as DNA and RNA, as well as substances that selectively accumulate in diseased tissue, whereby between the latter, a covalent bond exists and this is present in amide form in the case of substances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nucleases, peptides, proteins, antibodies or their fragments, or is present in imide form in the case of substances that contain CA 022323l~ l998-03-l7 hydroxyl groups, such as fatty alcohols that are in ester form or in the case of substances that contain aldehyde groups.
Especially preferred conjugates are distinguished in that the substances that accumulate in diseased tissue mean peptides such as endothelins, partial sequences of endothelins, endothelin analogs, endothelin derivatives, endothelin antagonists or angiotensins, partial sequences of angiotensins, angiotensin analogs, angiotensin derivatives and angiotensin antagonists, as well as chemotactic peptides.
In other preferred conjugates according to the invention, the peptides have the following sequences Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Ser-Ser-Trp-Leu-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Thr-Cys-Phe-Thr-Tyr-Lys-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Ala-Ser-Ser-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr--Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Lys-Asp-Met-Thr-Asp-Lys-Glu-Cys-Leu-Asn-Phe-Cys-His-Gln-Asp-Val-Il.e-Trp, Ala-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, CA 022323l~ l998-03-l7 Ala-Ser-Ala-Ser-Ser-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Thr-Cys-Phe-Thr-Tyr-Lys-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, Cys-Val-Tyr-Phe-Cys-His-Gln-Asp-Val-Ile-Trp, N-Acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Gln-Asp-Val-Ile-Trp, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Sar-Arg-Val-Tyr-Val-His-Pro-Ala, For-Met-Leu-Phe, For-Met-Leu-Phe-Lys, die Teilsequenzen His-Leu-Asp-Ile-Ile-Trp, [Key:] D-Trp-Leu-Asp-Ile-Ile-Trp, die Teilsequenzen = the partial sequences CA 022323l5 l998-03-l7 Phe-D-Trp-Leu-Asp-Ile-Ile-Trp, Val-Tyr-Ile-His-Pro-Phe, Val-Tyr-Ile-His-Pro, or the cyclic amino acid sequences cyclo-(DTrp-DAsp-Pro-DVal-Leu), cyclo-(DGlu-Ala-alloDIle-I.eu-DTrp).
Another subject of this invention is also compounds of general formula (II) R18-CR2R3- tCR~R5) n 1 2-8-CHR6-CHR7-802-NH- tCR8R9) ~F1 z~CO--B
tII) in which R1 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or for a sulfur protective group, R2, R3, R4, R5, R6, R7, R8 and R9 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, B stands for a hydroxyl group, a mercapto group or a radical -NHRa, in which R~ stands for a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, CA 0223231~ 1998-03-17 aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series 0, N, S, P, As, and Se, their conjugates with substances that selectively accumulate in diseased tissue, whereby between the latter, a covalent bond exists and this is present in amide form in the case of substances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nucleases, peptides, proteins, antibodies or their fragments, or is present in imide form in the case of substances that contain hydroxyl groups, such as fatty alcohols that are in ester form or in the case of substances that contain aldehyde groups, as well as their complexes with radioisotopes of Tc and Re.
The production of the compounds of general formula (II) according to the invention is carried out in that 2-chloroethanesulfonic acid chloride that optionally is substituted with R3 and R4 is reacted in a way that is known in the art in an aprotic solvent with the addition of a suitable base with compounds of general formula (III) HzN-tCR8R9)~1z-Co-B
(III) in which R8, R9, m and B have the meaning that is indicated above, CA 0223231~ 1998-03-17 to compounds of general formula (IV) R4HC=CR5-802-NH-CR6R7-(CR8R9),F~ 2-CO-B
(IV) in which R4, R5, R6, R7, R8, R9, m and B have the meaning that is indicated above.
These reactions are implemented in polar and nonpolar aprotic solvents, such as, for example, dichloromethane, tetrahydrofuran, chloroform, 1,4-dioxane, pyridine, DMF or DMSO
at temperatures of between -40~ and 120~C with the addition of an auxiliary base to recover acids that are liberated. Such auxiliary bases can be, for example, tertiary amines, alkali and alkaline-earth hydroxides, alkali and alkaline-earth carbonates.
The compounds of general formula (IV) that result from this are reacted optionally with the addition of a suitable auxiliary base, such as, for example, a t;ertiary amine, with compounds of general formula (V) R18-CR2R3-(CR4R5) 12-8H
(V) in which R1, R2, R3, R4, n and B have the meaning that is indicated above, and optionally present protective groups are cleaved off in a way that is known in the art.
Another subject of the invention is kits, which are used for the production of radiopharmaceutical agents and which consist of a compound of general formula lII) or compounds of general formula (I and/or II) that contain a conjugate according to the invention and substances that accumulate selectively in tissues, CA 0223231~ 1998-03-17 a reducing agent and optionally an auxiliary ligand, which are present in the dry state or in solution, as well as directions for use with a set of reaction instructions for the reaction of the described compounds with technetium-99m or Re in the form of a pertechnetate solution or perrhenate solution.
The subject of the invention is also a radiopharmaceutical composition for noninvasive in-vivo visualization of organs, receptors and receptor-containing tissue and/or arteriosclerotic plaque, which contains a compound of general formula (I) or compounds of general formula (I and/or II) that contain a conjugate according to the invention and substances that accumulate selectively in tissues, optionally with the additives that are commonly used in galenicals, whereby the compound is prepared in a kit with technetium-99m or Re in the form of a pertechnetate or perrhenate solution.
In a method for implementing a radiodiagnostic investigation, the radiopharmaceutical composition is administered to a patient in an amount of 0.1 to 30 mCi, preferably 0.5 to 10 mCi per 70 kg of body weight, and the radiation that is given off by the patient is recorded.
Surprisingly enough, many of the chelates that are synthesized and labeled with technetium-99m or Re show higher stability than comparable N2S2 and N3S systems, which are described in the literature. Thus, e.g., in the case of a substance according to the invention (Example 2), which was coupled to an endothelin partial sequence, no decomposition product could be observed after 24 hours. It was also found by CA 0223231~ 1998-03-17 competitive tests that the Tc-99m or Re chelating agents described in this invention complex better than the comparable N2S2, N3S and propylenaminoxime systems. The chelates and chelating agents that are described in this invention are thus clearly better suited for diagnostic and therapeutic purposes than the previously known systems. Special advantage lies in the restrained labeling conditions. Thus, after the protective groups are cleaved off, the labeling of the ligands according to the invention as well as their coupling products on substances that accumulate selectively in diseased tissue is possible at room temperature and at physiological pH. By selecting suitable protective groups, which can be cleaved off under different reaction conditions depending on the coupling product, it is always ensured that undesirable secondary reactions cannot occur in the purification of the coupling products. This carries the danger that no undesirable cross-linking reactions or oxidations of free sulfhydryl groups to disulfides occur under purification conditions. Such alterations often affect the labeling yield and radiochemical purity and thus also the background by unspecifically bound technetium in a disadvantageous manner. The establishment of sulfur protective groups or their cleavage is carried out according to methods that are known to one skilled in the art. The coupling to substances that selectively accumulate in diseased tissue is also carried out according to methods that are known to one skilled in the art (e.g., Fritzberg et al.; J.
Nucl. Med. 26, 7 (1987)), for example by reaction of electrophilic groups of the complex ligand with nucleophilic CA 0223231~ 1998-03-17 centers of the substances that accumulate selectively in diseased tissue or by reaction of nucleophilic groups of the chelating agent with electrophilic groups of the substances that selectively accumulate in diseased tissue.
As coupling participants, i.a., various biomolecules are used. Thus, e.g., ligands that bind to specific receptors and can thus detect alterations of the receptor thickness include, i.a., peptides, steroid hormones, growth factors and neurotransmitters. Coupling products with steroid hormone-receptor-affine substances make possible an improved diagnosis of breast and prostate cancer (S. J. Brandes and J. A.
Katzenellenbogen, Nucl. Med. Biol. 15, 53, 1988). On various occasions, tumor cells exhibit an altered density of receptors for peptide hormones or growth factors, such as, e.g., the "epidermal growth factor" (EgF). The concentration differences can be used for selective concentration of cytostatic agents in tumor cells (E. Abound-Pirak et al.; Proc. Natl. Acad. Sci. USA
86, 3778, 1989). Other biomolecules are metabolites that can be incorporated into the metabolism of cells, which show an altered metabolism; these include, e.g., fatty acids, saccharides, peptides and amino acids. Fatty acids that are coupled to the less stable N2S2 systems were described in EP-0200492. Other metabolic products, such as saccharides, deoxyglucose, lactate and amino acids (leucine, methyl methionine, glycine), were used with the aid of PET technology for graphic visualization of altered metabolic processes (R. Weinreich, Swiss Med. 8, 10, 1986). Also, nonbiological substances such as misonidazole and CA 0223231~ 1998-03-17 its derivatives, which bind irreversibly to cell components in tissues or tissue parts at reduced oxygen concentration, can be used for specific concentration of radioactive isotopes and thus for graphic visualization of tumors or ischemic regions (M. E.
Shelton, J. Nucl. Med. 30, 351, 1989). Finally, the coupling of new chelating agents to monoclonal antibodies or their fragments, polysaccharides such as dextrans or starches, bleomycins, hormones, enzymes, polypeptides such as polylysine and nucleotides such as DNA or RNA is also possible. Coupling products of the chelates according to the invention or their complexes with technetium-99m or Re with endothelins, endothelin derivatives or with partial sequences of endothelins or their derivatives have proven especially advantageous for the detection of arteriosclerotic vascular diseases. These derivatives were administered to WHHL rabbits, which show high LDL concentrations in the blood by a genetic defect of the LDL receptor and thus have arteriosclerotic lesions. About 1 to 6 hours after the derivatives are administered to WHHL rabbits, a large degree of concentration in arteriosclerotic plaque was detected. Up until now, only very late stages of artherogenesis could be diagnosed with an invasive process. The compounds according to the invention therefore offer the decisive advantage of diagnosing many earlier stages of arteriosclerosis with a noninvasive process. Coupling products of the chelates according to the invention or their complexes with technetium-99m or Re with fatty alcohols, fatty alcohol derivatives or with fatty alcohol amines or their derivatives have proven advantageous for the detection CA 0223231~ 1998-03-17 of arteriosclerotic vascular diseases. These derivatives were administered to WHHL rabbits, which show high LDL concentrations in the blood by a genetic defect of the LDL receptor and thus have arteriosclerotic lesions. About 1 to 6 hours after the derivatives are administered to WHHL rabbits, a large degree of concentration in arteriosclerotic plaque was detected. Up until now, only very late stages of artherogenesis could be diagnosed with an invasive process. The compounds according to the invention therefore offer the decisive advantage of diagnosing many earlier stages of arteriosclerosis with a noninvasive process.
It is unimportant whether a labeling of the described chelating agent with technetium-99m is carried out before or after coupling to the selectively accumulating molecule. For coupling to the selectively accumulating molecule after complexing, however, there is a precondition that the reaction of the radioactive complex with the accumulating compound proceeds quickly under conservative conditions and almost quantitatively, so that subsequent purification is not necessary.
The production of the pharmaceutical agents according to the invention is carried out in a way that is known in the art, whereby the complexing agents according to the invention are dissolved in aqueous medium with the addition of a reducing agent, preferably tin(II) salts, such as -chloride, -pyrophosphate or -tartrate -- and optionally with the addition of the additives that are commonly used in galenicals -- and then sterilized by filtration. Suitable additives are, for example, CA 0223231~ 1998-03-17 physiologically harmless buffers (e.g., tromethamine), small additions of electrolytes (e.g., sodium chloride), stabilizers (e.g., gluconate, phosphates or phosphonates). The pharmaceutical agent according to the invention is present in the form of a solution or in freeze-dried form and is mixed shortly before administration with a Tc-99m-pertechnetate solution, eluted from commercially available MoTc generators or a perrhenate solution.
In the case of nuclear-medicine in vivo use, the pharmaceutical agents according to the invention are dosed in amounts of lxlO-5 to 5x104 nmoltkg of body weight, preferably in amounts of between lx10-3 to 5X102 nmol/kg of body weight.
Starting from an average body weight of 70 kg, the amount of radioactivity for diagnostic applications is between 0.05 to 50 mCi, preferably 5 to 30 mCi per 70 kg of application. For therapeutic uses, between 5 and 500 mCi, preferably 10 to 350 mCi, is administered. The administration is carried out normally by intravenous, intraarterial, peritoneal or intertumoral injection of 0.1 to 2 ml of a solution of the agent according to the invention. Intravenous administration is preferred.
The following examples are used for a more detailed explanation of the subject of the invention.

Example 1 N-Vinylsulfonyl-glycine methyl ester (1) An ice-cooled solution of 8.91 g (100 mmol) of glycine methyl ester and 17.9 g of chloroethanesulfonyl chloride (110 mmol) in 100 ml of dichloromethane is slowly mixed with dried pyridine (400 mmol) while being cooled with ice. It is allowed to heat to room temperature, and after the reaction has been completed, it is mixed with 200 ml of dilute HCl, and the dichloromethane phase is separated. The aqueous phase is extracted several times with dichloromethane, washed with water, dried, concentrated by evaporation and chromatographed (silica gel CH2Cl2). 12.9 g of a slowly crystallizing oil remains.
Yield: 72%
Analysis:
Cld: C 33.52 H 5.06 N 7.82 O 35.72 S 17.90 Fnd: C 33.24 H 5.23 N 7.66 S 17.61 N-t5-Hydroxy-3-thiapentyl~ulfonYll-qlycine methyl ester (2) 1.79 g of vinylsulfonic acid 1 (10 mmol) is added to a stirred solution of 7.81 g of mercaptoethanol (100 mmol) and 150 mg of triton-B solution while being cooled, and it is stirred for 20 hours in an oxygen-free environment at room temperature.
Then, it is mixed with water and extracted several times with ethyl acetate. The combined organic extracts are washed with bicarbonate solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed (silica gel, EtOAc).

Yield: 63%

CA 022323l~ l998-03-l7 Analysis:
Cld: C 32.67 H 5.88 N 5. 44 O 31.09 S 24.92 Fnd: C 32. 59 H 5. 75 N 5. 41 S 24.86 N-(5-Chloro-3-thi~pentylsulfonYl)-glycine methYl ester (3) A solution of 2.57 g of glycine derivative 2 (10 mmol) in 50 ml of anhydrous carbon tetrachloride is mixed under a nitrogen atmosphere with 3.14 g of pulverized triphenylphosphine ( 12 mmol), and it is refluxed. After cooling, it is diluted with 50 ml of hexane and stored for some time at -20~C. The precipitate is suctioned off, and the procedure as above is repeated until precipitate no longer settles out. Then, it is dried and concentrated by evaporation.
Yield: 62%
Analysis:
Cld: C 30.49 H 5.12 N 5. 08 O 23.21 S 23.26 Fnd: C 30.16 H 5.56 N 5. 33 S 23.24 N-(5-Thiouronyl-3-thi~pentylsulfonyl)-glycine methyl ester ~4) The solution of 5.51 g of 3 (20 mmol) in ethanol is added in drops to a solution of 1. 52 g of thiourea in ethanol and then refluxed for 2 hours. After the solvent is drawn off, a crystalline residue remains, which is crystallized from ethanol.
Yield: 57%
Analysis:
Cld: C 27.31 H 5.16 N 11. 94 O 18.19 S 27.34 Fnd: C 27.11 H 5.52 N 11. 54 S 27.80 CA 022323l~ l998-03-l7 N-(5-NercApto-3-thi~pentylsulfonYl~-glycine (5) 3.52 g (10 mmol) of 4 iS stirred under protective gas in aqueous-methanolic potassium hydroxide solution for 3 hours at 50~C. After cooling, it is diluted with 400 ml of water, and the undissolved material is filtered out. The filtrate is acidified with HCl, extracted with dichloromethane, dried, concentrated by evaporation and recrystallized.
Yield: 64%
Analysis:
Cld: C 27.79 H 5.05 N 5.40 O 24.68 S 37.09 Fnd: C 28.17 H 5.35 N 5. 48 S 36.61 N-(5-Merc~pto-3-thiapentYlsulfonyl)-glycine, technetium-99m complex 10 mg of compound 5 iS dissolved in 1.0 ml of ethanol. 50 ,ul of this ligand solution is mixed with 100 ,ul of ethanol, 150 ,ul of phosphate buffer with a pH of 8.5, 50 ,lll of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ,ul of a deoxygenated tin(II)-chloride solution (5 mg/ml of O.lN HCl) and 100 ~l of a pertechnetate solution (400-1000 ,UCi). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed: LiChrospher RP-18 column, 5 ,U, 125 X 4.6 mm; gradient elution of 100% A after 100%
B within 15 minutes (eluant A: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/minute. The radiochemical purity is > 92%.

CA 022323l~ l998-03-l7 Example 2 N- r ( 5-Triphenylmethylmercapto)-3-thiapentylsulfonYl]-qlycine ~6) The solution of 2.79 g of triphenylchloromethane in DMF is slowly added in drops to a solution of 2.59 g of glycerine derivative 5 (10 mmol) and triethylamine (10 mmol) in DMF, and it is stirred for 12 hours at room temperature. Then, it is mixed with water, weakly acidified with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is dried and concentrated by evaporation. The remaining residue is chromatographed (silica gel, CH2Cl2/MeOH).
Yield: 57%
Analysis:
Cld: C 59.86 H 5.43 N 2.79 O 12.76 S 19.14 Fnd: C 59.46 H 5.66 N 2. 44 S 19.

Hooc-Trp-Ile-Ile-Asp-Leu-D-Trp-phe-{N-~5 triPhenylmethylmercapto~-3-thiapentylsulfonyl]Gly~ t7 211 mg of EDC (1.1 mmol) in 5 ml of anhydrous dimethylformamide is added in drops to a solution of 502 mg of acid 6 (1 mmol), 280 ,ul of triethylamine and 115 mg of N-hydroxysuccinimide (1.0 mmol) in 10 ml of anhydrous dimethylformamide while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of 992 mg of H2N-Phe D-Trp-Leu-Asp-Ile-Ile-Trp-COOH (1.0 mmol) in DMF is added in drops within 30 minutes. It is first stirred for another 2 hours at 0~C, and then stirred for 12 hours at room temperature. The product is filtered off from urea, and the filtrate is concentrated by evaporation in a vacuum and taken up in dichloromethane. After filtration was again performed, it is washed twice with 0.5N HCl and saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is crystallized by trituration with diethyl ether.
Yield: 33%
Analysis:
Cld: C 63.48 H 6.42 N 9.49 O 14.09 S 6.52 Fnd: C 63.09 H 6.66 N 9.37 S 6.46 HOOC-Trp-Ile-Ile-Asp-Leu-D-Trp-Phe-rN-(5-mercapto-3-thiabutyl~ulfonyl~Glyl ~8) 1.48 g of peptide 7 (1 mmol) is treated for 45 minutes at 0~C with 20 ml of anhydrous HF in the presence of 5 ml of anisole and 3.5 ml of diethyl sulfide. After the acid is evaporated, the remaining residue is taken up in 5% acetic acid, washed several times with diethyl ether and freeze-dried. Chromatographic purification on Sephadex G-10 with 0.2 M acetic acid yields 470 mg of an oil.
Yield: 38%
Analysis:
Cld: C 57.45 H 6.54 N 11.36 O 16.86 S 7.10 Fnd: C 57.34 H 6.43 N 11.40 S 7.92 CA 0223231~ 1998-03-17 HOOC-Trp-Ile-Ile-Asp-Leu-D-Trp-Phe-[N-t5-mercapto-3-thiaPentylsulfonyl~GlY~ technetium-99m comPlex 10 mg of compound 8 is dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 100 ~l of ethanol, 150 ~l of phosphate buffer with a pH of 8. 5, 50 ~l of a deoxygenated aqueous citrate solution (50 mg/ml), 2. 5 ~l of a deoxygenated tin(II) chloride solution (5 mg/ml of O.lN HCl) and 100 ~l of a pertechnetate solution (400-1000 ~Ci). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed: LiChrospher RP-18 column, 5 ~, 125 x 4.6 mm; gradient elution of 100% A after 100 B within 15 minutes (eluant A: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/minute. The radiochemical purity is > 96%.

Claims (14)

1. Compounds of general formula (I) M - I. (I) in which M means a radioisotope of Tc or Re and L means a ligand of general formula (II) R1S-CR2R3-(CR4R5)n=1,2-S-CHR6-CHR7-SO2-NH-(CR8R9)=1,2-CO-B
(II) in which R1 stands for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or for a sulfur protective group, R2, R3, R4, R5, R6, R7, R8 and R9 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C1-6 alkyl radical, B stands for a hydroxyl group, a mercapto group or a radical -NHRa, in which Ra represents a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C1-30 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se.
2. Compounds according to claim 1, characterized in that n and m in each case stand for 1.
3. Compounds according to claim 1 or 2, wherein R1, R2, R5, R6, R7 and R9 represent hydrogen atoms.
4. Ligands of general formula (II) R1S-CR2R3-(CR4R5)n=1,2-S-CHR6-CHR7-SO2-NH-(CR8R9)m=1,2-CO-B
(II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, n, m and B in each case have the meaning that is indicated in claim 1.
5. Ligands according to claim 4, wherein n and m in each case stand for 1.
6. Ligands according to claim 5 or 6, wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 represent hydrogen atoms.
7. Conjugates that contain a compound of general formula (I
and/or II) and substances that selectively accumulate in diseased tissue, whereby between the latter, a covalent bond exists and this is present in amide form in the case of substances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nucleases, peptides, proteins, antibodies or their fragments, or is present in imide form in the case of substances that contain hydroxyl groups, such as fatty alcohols that are in ester form or in the case of substances that contain aldehyde groups.
8. Conjugates according to claim 7, wherein the substances that accumulate in diseased tissue mean peptides such as endothelins, partial sequences of endothelins, endothelin analogs, endothelin derivatives, endothelin antagonists or angiotensins, partial sequences of angiotensins, angiotensin analogs, angiotensin derivatives and angiotensin antagonists, as well as chemotactic peptides.
9. Conjugates according to claim 7, wherein the peptides have the following sequences or portions of them , , , , , , Ala-Ser-Ala-Ser-Ser-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Thr-Cys-Phe-Thr-Tyr-Lys-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, , N-Acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Gln-Asp-Val-Ile-Trp, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Sar-Arg-Val-Tyr-Val-His-Pro-Ala, For-Met-Leu-Phe, For-Met-Leu-Phe-Lys, die Teilsequenzen His-Leu-Asp-Ile-Ile-Trp, D-Trp-Leu-Asp-Ile-Ile-Trp, Phe-D-Trp-Leu-Asp-Ile-Ile-Trp, Val-Tyr-Ile-His-Pro-Phe, Val-Tyr-Ile-His-Pro, oder die zyclischen Aminosäuresequenzen Cyclo-(DTrp-DAsp-Pro-DVal-Leu), Cyclo-(DGlu-Ala-alloDIle-Leu-DTrp) [Key:]
die Teilsequenzen = the partial sequences oder die zyclischen Aminosäuresequenzen = or the cyclic amino acid sequences
10. Process for the production of a compound of general formula (I), wherein technetium-99m or Re in the form of pertechnetate or perrhenate is reacted in the presence of a reducing agent and optionally an auxiliary ligand with a compound of general formula (II) R1S-CR2R3-(CR4R5)n=1,2-S-CHR6-CHR7-SO2-NH-(CR8R9)m=1,2-CO-B
(II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, n, m and B have the meaning that is indicated in claim 1.
11. Process for the production of ligands of general formula (II), wherein 2-chloroethanesulfonic acid chloride that optionally is substituted with R5 and R6 is reacted in a way that is known in the art in an aprotic solvent with the addition of a suitable base with compounds of general formula (III) H2N-(CR8R9)m=1,2-CO-B
(III) in which R8, R9, m and B have the meaning that is indicated in claim 1, at temperatures of -20° to 180°C to compounds of general formula (IV) R4HC=CR5-SO2-NH-CR6R7-(CR8R9)m=1,2-CO-B
(IV) in which R4, R5, R6, R7, R8, R9, m and B have the meaning that is indicated in claim 1, and these compounds of general formula (IV) are reacted optionally with the addition of a suitable auxiliary base at temperatures of -20°C to 180°C in a way that is known in the art with compounds of general formula (V) R1S-CR2R3-(CR4R5)n=1,2-SH

(V) in which R1, R2, R3, R4, n and B have the meaning that is indicated in claim 1, and optionally present protective groups are cleaved off in a way that is known in the art.
12. Kit for the production of radiopharmaceutical agents that consists of a compound of general formula (II) according to one of claims 4 to 6 or a conjugate according to one of claims 7 to 9 as well as a reducing agent and optionally an auxiliary ligand, which are present in the dry state or in solution, as well as directions for use with a set of reaction instructions for the reaction of the described compounds with technetium-99m or Re in the form of a pertechnetate solution or perrhenate solution.
13. Radiopharmaceutical composition for noninvasive in vivo visualization of organs, receptors and receptor-containing tissue and/or arteriosclerotic plaque, wherein it contains a compound according to one of claims 1 to 3 or a conjugate according to claims 7 to 9 and optionally additives that are commonly used in galenicals, whereby the compound is prepared in a kit according to claim 12 with technetium-99m or Re in the form of a pertechnetate or perrhenate solution.
14. Process for radiodiagnostic investigation, wherein a radiopharmaceutical composition according to claim 13 is administered to a patient in an amount of 0.1 to 30 mCi, preferably 0.5 to 10 mCi per 70 kg of body weight, and the radiation that is given off by the patient is recorded.
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WO1997012636A2 (en) 1997-04-10
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EP0851770A2 (en) 1998-07-08
DE19536785A1 (en) 1997-03-27

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