CA2232620A1 - Bifunctional sulfide-containing sulfonamide-chelating agents such as xsny for radioactive isotopes - Google Patents

Abstract

New compounds have the general formula (I): M - L, in which M stands for a radio-isotope of Tc or Re and L stands for a ligand having the general formula (II): B-CR1R2-(CR3R4)n=1,2-S-CHR5-CHR6-SO2-NH-CR7R8-(CR9R10)m=1,2-D, in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 may have various meanings and B and D stand for another group which is suitable for binding metal ions by coordination and for coupling to selectively enriching compounds. Coupling to selectively enriching compounds may alternatively also be mediated by R8.
These new compounds are useful for complexing technetium and rhenium and are used for medical diagnosis and therapy.

Description

Bifunctional 8ulfide-Containing 8ulfon~mide-Chelating Agents 8uch as X8NY 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 the 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 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-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 complete 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 properties 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 .

(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~, ~ 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 the 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, radionuclide-containing radiopharmaceutical agents are produced by the ligand first being synthesized and then being reacted 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 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 quick complexing.
To form technetium-99m complexes, pertechnetate is first obtained from a nuclide generator and shifted, with the aid of 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, 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 pH > 9. N202 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) 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 (~Brechbiel, M. W. et al.; Inorg.
Chem. 1986, 25, 2772). It is therefore necessary to produce bifunctional complexing agents that carry both functional groups for binding the desired metal ion and a (another, several) functional group(s) for binding the selectively accumulating molecule, or to configure complexing agents in such a way that the desired complexing agent structure is formed only by coupling to a selectively accumulating substance and thus weakening of the complex stability is prevented. Such ligands make possible a 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 according 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 object of the inventio:n is compounds of general formula (I) M - :L (I) in which M means a radioisotope of Tc or Re and L is a ligand of general formula (II) B-CR1R2-(CR3R~)~12-8-CHR5-CHR6-802-NH-CR7R8-(CR9R10) Fl 2-D
(II) in which R1, R2, R3, R4, R5, R6 and R7 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, R8 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or a radical -Co-R15 in which R15 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or is optionally inter:rupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As, Se or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent 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, Se, R9 and R10 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 radical -SR11, -NHR1Z or -oR13, in which R11 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or for a sulfur protective group, R12 stands for a hydrogen atom, an amino protective group or a branc:hed or straight-chain cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl group, which optionally is substituted with CA 02232620 l998-03-l8 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 0, N, S, P, As, Se, R13 stands for a hydrogen atom or for an alcohol protective group, D stands for a radical -SR14, in which R14 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or for a sulfur protective group, or if B represents a radical SR11, also for a radical -NHR16 or -oR17, in which R16 represents a hydrogen atom, an amino protective group or a branched or straight-chain, cyclic or polycyclic C1,30 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl group, 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 or substituted by one or more heteroatoms from the series 0, N, S, P, As, Se, R17 stands for a hydrogen atom or for an alcohol protective group.

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, R8 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, R3, R4, R5, R6, R8, R9 and R10 are hydrogen atoms and R7 stands for a radical -Co-R15 in which R15 represents a hydroxyl group, a branched or straight-chain Cl30 alkoxy group or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, C130 alkyl radical, which optionally is substituted with carboxy, aminocarbonyl, alkoxycarbonyl or amino groups with up to 20 carbon atoms and/or optionally is interrupted and/or is substituted by one or more heteroatoms from the series O, N, S.
Especially preferred are compounds according to the invention in which n and m in each case stand for 1.
Especially preferred are also compounds according to the invention, in which R1, R2, R5, R6, R8, R9 and R10 represent hydrogen atoms.
Especially preferred are compounds according to the invention in which R3 and R4 in each case stand for a hydrogen atom and R7 stands for a hydrogen atom, a branched or unbranched C1-6 alkyl radical or a radical -Co-Rl5~
in which R15 represents a hydroxyl group, a branched or straight-chain C130 alkoxy group or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino 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.
Another subject of the invention relates to new bifunctional sulfur atom-interrupted sulfonamide ligands of general formula (II) B-CR1R2-(CR3R~ 2-S-CHR5-CHR6-go2-NH-CR7R8-(CR9R1~)~2-D
~II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, n, m, B and D
in each case have the meaning that is indicated above.
Preferred compounds of general formula (II) are distinguished in that in each case l stands for n and m.
Other preferred compounds of general formula (II) are distinguished in that R1, R2, R5, R6, R8, R9 and R10 are hydrogen atoms.
Especially preferred compounds of general formula (II) are distinguished in that in each case l stands for n and m and in CA 02232620 l998-03-l8 that R1, R2, R3, R4, R5, R6, R8, R9 and Rl~ are hydrogen atoms and R7 stands for a radical -Co-R15 in which R15 represents a hydroxyl group, a branched or straight-chain C1 30 alkoxy group or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent ahydrogen atom, a branched or straight-chain C130 alkyl radical, which optionally is substituted with carboxy, aminocarbonyl, alkoxycarbonyl or amino groups with up to 20 carbon atoms or optionally is interrupted and/or substituted by one or more heteroatoms from the series 0, N, S.
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 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 CA 02232620 l998-03-l8 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-~ I .
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-Ile-Trp, Ala-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, 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, I
Cys-Val-Tyr-Phe-Cys-His-Gln-Asp-Val-Ile-Trp, N-Acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-Hi 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, [Key:]
die Teilsequenzen = the partial sequences CA 02232620 l998-03-l8 or the cyclic amino acid sequences cyclo-(DTrp-DAsp-Pro-DVal-Leu), cyclo-(DGlu-Ala-alloDIle-Leu-DTrp).
Another subject of this invention is also compounds of general formula (II) B-CR1RZ-~CR3R~ z-S-CHR5-CHR6-Soz~NH~CR7R8~(CR9R1~)~1z~D
~II) in which R1, RZ, R3, R4, R5, R6 and R7 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, R8 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or a radical -Co-R15, in which R15 represents a hydroxyl group, a branched or straight-chain , cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or is optionally interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As, Se, or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent 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, Se, R9 and R10 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 radical -SR11, -NHR12 or -oR13 in which R11 stands for a hydrogen atom, for a branched or unbranched C16 a:lkyl radical or for a sulfur protective group, R12 stands for a hydrogen atom, an amino protective group or branched or straight-chain cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl group, 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 0, N, S, P, As, Se, R13 stands for a hydrogen atom or for an alcohol protective group, D stands for a radical -SR14, in which R14 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or for a sulfur protective group, or if B represents a radical SR11, also for a radical -NHR16 or -oR17~ in which R16 represents a hydrogen atom, an amino protective group or a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl group, 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 i5 interrupted or substituted by one or more heteroatoms from the series 0, N, S, P, As, Se, R17 stands for a hydrogen atom or for an alcohol protective group, 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 CA 02232620 l998-03-l8 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 or Re.
Another subject of this invention is a process for the production of a compound of general formula (I), characterized in that 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) B-CR1R2-~CR3R~ 2-8-CHR5-CHR6-~02-NH-CR7R8-(CR9R1~)F~ 2-D

in which R1 R2 R3 R4, R5, R6, R7, R8, R9, R10, n, m, B and D
have the meaning that is indicated above.
The production of the compounds of general formula (II) according to the invention is carried out in that 2-chloroethanesulfonic acid chloride that is optionally substituted with Rs and R6 is reacted in a way known in the art in an aprotic solvent with the addition of a suitable base with compounds of general formula (III) H2N-CR7R8-~CR9R1~)F1 2-D
(III) CA 02232620 l998-03-l8 in which R7, R8, R9, R10, m and D have the meaning that is indicated above, to compounds of general formula (IV) R5HC=CR2-So-NH-cR7R8-(cR9R1o)Flz-D

(IV) in which R5, R6, R7, R8, R9, R10, m and D 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~ to 120~C optionally 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 in a way known in the art with compounds of general formula (V) BCR1-R2-~CR3R~)~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 (II) or compounds of general formula ~I and/or II) that contain a conjugate according to the invention and substances that accumulate selectively in tissues, 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 a fatty alcohol, no decomposition product could be observed after 24 hours. It was also found by 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 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 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 N2Sz 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 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 fatty alcohols, fatty alcohol derivatives or with fatty alcohol amines or their derivatives have proven 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.

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, 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 lx10-5 to 5x104 nmol/kg 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 8-~4-Nethoxybenzyl)cy~teinethyle~ter ~1) In a solution of 27.7 g of S-4-methoxybenzylcysteine in 250 ml of absolute EtOH, HCl is introduced until saturation is achieved, and it is heated to boiling. After the reaction has been completed, it is filtered after cooling to room temperature, and the mother liquor is concentrated by evaporation again.
28.4 g of white crystals remains.
Yield: 93%
Analysis:
Cld: C 51. 06 H 6. 59 N 4.58 O 15.70 S 10.49 Fnd: C 50.88 H 6.83 N 4.45 S 10.15 N-Vinylsulfon~Yl-8-(4-methoxYbenzyl)-cysteinethYle~ter ~2) An ice-cooled solution of 3.06 g (10 mmol) of S-protected cysteine derivative 1 and 1.79 g of chloroethanesulfonyl chloride (11 mmol) in 10 ml of dichloromethane is mixed slowly with dry pyridine (44 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 20 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). 2. 37 g of a slowly crystallizing oil remains.
Yield: 66%

CA 02232620 l998-03-l8 Analysis:
Cld: C 50.12 H 5.89 N 3.80 0 22.26 8 17.84 Fnd: C 49.97 H 6.01 N 3.62 S 17.56 N-~5-[(N-tert-ButYloxycarbonyl)-~mino]-3-thi~-pentylsulfonYl}-8-~4-methoxYbenzYl~-cysteinethylester (3) 9.8 mmol of vinylsulfonamide 2 (35. 2 g) is added in drops to 100 mmol of N-Boc-2-mercaptoethylamine ( 17.6 g) and 500 ~1 of piperidine within 45 minutes while being stirred, whereby 50~C iS
not exceeded. During the reaction, 500 ~1 of piperidine is added in several portions. Then, the mixture is heated for several minutes to 50~C, contaminants are filtered out and washed with water. After drying, the solvent is drawn off, and the residue is chromatographed (silica gel, EtOAc).
Yield: 41%
Analysis:
Cld: C 49. 23 H 6.76 N 5.22 O 20.87 8 17.92 Fnd: C 49.11 H 6.87 N 5.08 8 17.82 N-~5-Amino-3-thiaPentylsulfonYl~-8-(4-methoxYbenzYl)-cysteinetbYlester (4) 8.5 g of 3 (15.8 mmol) is dissolved in 200 ml of 3 M HCl in ethyl acetate, and it is stirred for 2 hours at room temperature.
After the solvent is drawn off, 7.25 g of white crystals remains.
Yield: 97%

.

Analysis:
Cld: C 43.16 H 6 .18 N 5.92 0 16.91 S 20.34 Fnd: C 42.97 H 6.41 N 5.73 S 20.19 N-~5-Amino-3-thia-pentylsulfonyl~-cYsteinethyle~ter (S~
10 ml of HF in a 100 ml teflon round-bottom flask is condensed down to 2.87 g of 4 (5 mmol) and one drop of anisole at 0~C in a moisture-free environment. It is stirred for 30 minutes at 0~C, and then hydrogen fluoride is carefully distilled off.
The residue is taken up in dichloromethane, washed with sodium bicarbonate solution and water, dried and concentrated by evaporation. The oily residue is crystallized by trituration with diethyl ether.
Yield: 59%
Analysis:
Cld: C 34.16 H 6.37 N 8.85 O 20.22 S 30.40 Fnd: C 33.99 H 6.52 N 8.74 S 30.25 N-{5-Amino-3-thiaPentyl~ulfonyl~-cysteinethyl e~ter, technetium-99m complex 10 mg of compound 5 iS dissolved in 1.0 ml of ethanol. 50 ~1 of this ligand solution is mixed with 100 ,ul of ethanol, 150 ~1 of phosphate buffer with a pH of 8.5, 50 ~1 of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~1 of a deoxygenated tin(II) chloride solution (S mg/ml of O.lN HCl) and 100 ~1 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/min. The radiochemical purity is > 97%.

Example 1~
N-Vinylsulfonyl-8-(4-methoxYbenzyl)-cysteine ~6) 3.59 g (10 mmol) of 2 is stirred into 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 and concentrated by evaporation.
Yield: 80%
Analysis:
Cld: C 47.12 H 5.17 N 4.23 0 24.14 S 19.35 Fnd: C 46.99 H 5.28 N 4.09 S 19.18 N-~5- r (N-tert-ButoxycarbonYl)-amino]-3-thia-Pentylsulfonyl~-8-~4-methoxYbenzyl)-cysteine ~7) 9.8 mmol of vinylsulfonamide 6 (3.25 g) is added in drops to 10 mmol of N-Boc-2-mercaptoethylamine (1.76 g) and 50 ~l of piperidine within 45 minutes while being stirred, whereby 50~C is not exceeded. During the reaction, another 500 ~l of piperidine is added in several portions. Then, the mixture is heated for several minutes to 50~C, contaminants are filtered out and washed with water. After drying, the solvent is drawn off, and the crystalline residue is recrystallized from MeOH/CH2Cl2.
Yield: 37%
Analysis:
Cld: C 47.23 H 6.34 N 5.51 O 22.02 S 18.91 Fnd: C 47.11 H 6.77 N 5.38 S 18.82 N-~5-Amino-3-thiapentylsulfonYl~-8-(~-methoxYbenzyl)-CYs-His-Leu-Asp-Ile-Ile-Trp ~8) 2 mmol of acid 7 (1.02 g) and 2 mmol of NEt3 are mixed in 10 ml of dichloromethane under nitrogen atmosphere at 0~C with 2.2 mmol (560 mg) of BOP-Cl, and it is stirred for 2 hours at room temperature. Then, the solution of 2 mmol of the peptide H2N-Leu-Asp-Ile-Ile-Trp (1.32 g) (produced analogously to Barany and Nerrifield, The Peptides: Analysis, Biology, Academic Press, New York, 1980; Stewart and Young, Solid Phase Peptides Syntheses, 2nd ed., Pierce Chemical W., Rockford, II, 1984) is added in drops to anhydrous DMF, and it is stirred overnight. It is mixed with a little water, acidified and freeze-dried. The residue is taken up in 50 ml of anhydrous trifluoroacetic acid, and it is stirred for 1 hour at room temperature. Then, the trifluoroacetic acid is drawn off in a vacuum, the residue is mixed three times with dimethylformamide and in each case concentrated by evaporation. While being stirred with diethyl ether, a solid precipitates, which is filtered off and is recrystallized for purification from DMF/diethyl ether mixtures.
Yield: 39%

.

Analysis:
Cld: C 54.67 H 6.71 N 12.99 0 17.53 S 8.11 H 6.71 Fnd: C 54.39 H 6.92 N 12.68 S 7.77 N- r 5-Amino-3-thi~p~ntyl~ulfonyll-Cy~-His-Leu-A~p-Ile-Ile-Trp (9) 10 ml of HF in a 100 ml teflon round-bottom flask is condensed down to 1. 18 g of 8 (1 mmol) and one drop of anisole at o~C in a moisture-free environment. It is stirred for 30 minutes at 0~C, and then hydrogen fluoride is carefully distilled off.
The residue is crystallized by trituration with diethyl ether.
Yield: 26%
Analysis:
Cld: C 51.82 H 6.71 N 14. 45 0 18.01 S 9.02 Fnd: C 51.35 H 6.99 N 14.28 S 8.76 L~belin~ with Tc99m 10 mg of compound 9 is dissolved in 1.0 ml of ethanol. 50 ,ul of this ligand solution is mixed with 250 ~1 of phosphate buffer with a pH of 8.5, 50 ,ul 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 ~1 of a pertechnetate solution (400-1000 ~LCi). 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/min. The radiochemical purity is > 97%.

~x~mple 2 CysteinoctYlester (10) Dry HCl gas is introduced for 1.5 hours into the mixture of 12.1 g (100 mmol) of L-cysteine and 100 ml of octanol while being stirred (heating to 140-150~C). After the reaction has been completed, it is allowed to cool, mixed with 300 ml of anhydrous ether and stirred for 30 minutes. After filtration, it is recrystallized from a mixture of ether and ethanol.
Yield: 72%
Analysis:
Cld: C 48.97 H 8.97 N 5.19 0 11.86 S 11.88 Fnd: C 48.84 H 9.08 N 5.23 S 12.12 8-Bis-(4-methoxyphenyl)-methylcy~teinoctylester (11) 2.70 g of anhydrous cysteinoctylester-hydrochloride 10 (10 mmol) is suspended in 10 ml of glacial acetic acid and about 2.76 g of S-bis-(4-methoxyphenyl)-methanol (15 mmol) and 2.1 ml of BF3-diethyletherate (15 mmol) are added to it. It is stirred for 2 hours at room temperature, whereby almost all is dissolved in clear form. Then, it is concentrated by evaporation in a rotary evaporator at a bath temperature of 40~C.
The oily residue is dissolved in ethyl acetate. By shaking with saturated sodium acetate solution, the protected cysteine CA 02232620 l998-03-l8 derivative, which is suctioned off and easily washed with water and acetone, precipitates.
Yield: 73%
Analysis:
Cld: C 62.95 H 7.72 N 2.82 0 12.90 S 6.46 Fnd: C 62.71 H 7.96 N 2.84 S 6.64 N-VinylsulfonYl-S-bis(4-methoxY~henyl)-methylcysteinoctylester ~12) An ice-cooled solution of 4.96 g (10 mmol) of S-protected cysteine derivative 11 and 1. 79 g of choroethanesulfonyl chloride (11 mmol) in 10 ml of dichloromethane is slowly mixed with dry pyridine (44 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 20 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, CH2C12)-Yield: 61%
Analysis:
Cld: C 61.18 H 7 .15 N 2. 55 0 17.46 S 11.67 Fnd: C 60.89 H 7.30 N 2.64 S 11.33 N-~5-r~N-tert-ButoxYcarbonyl)-amino~-3-thia-pentYlsulfonyl~-S-bi~(4-methoxyPhenYl~-methylcysteinoctylester ~13) 9.8 mmol of vinylsulfonamide 12 (5.39 g) in THF is added in drops to 10 mmol of N-Boc-2 mercaptoethylamine (1.76 g) and 50 ~1 of piperidine within 45 minutes while being stirred, whereby 50~C
is not exceeded. During the reaction, another 50 ~1 of piperidine is added in several portions. Then, the mixture is heated for several minutes to 50~C, contaminants are filtered out and concentrated by evaporation. The residue is taken up in ethyl acetate and washed with water. After drying, the solvent is drawn off, and the residue is chromatographed (silica gel, cH2cl2) -Yield: 59%
Analysis:
Cld: C 57.83 H 7.49 N 3.85 0 17.61 S 13.23 Fnd: C 57.67 H 7.70 N 3.68 S 13.50 N-~5-Amino-3-thiapentYlsulfonYl~-cYsteinoctylester (14) 727 mg of protected cysteine derivative 13 (1 mmol) and a trace of anisole are added to 10 ml of trifluoroacetic acid in an oxygen-free environment at room temperature, and it is refluxed for 1 hour. Then, the trifluoroacetic acid is drawn off in a vacuum, and the residue is taken up in dichloromethane. After washing with saturated sodium bicarbonate solution and water, it is dried with sodium sulfate and concentrated by evaporation.
The oily residue is crystallized by trituration with diethyl ether.

CA 02232620 l998-03-l8 Yield: 67%
Analysis:
Cld: C 44.97 H 8.05 N 6.99 0 15.98 S 24.01 Fnd: C 44.75 H 8. 40 N 7.11 S 24.23 N-~5-Amino-3-thiapentYlsulfonYl~-cysteinoctylester, technetium-99m complex 10 mg of compound 14 iS dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 100 ~l of ethanol, 150 ~1 of phosphate buffer with a pH of 8.5, 50 ,ul 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 1~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 ,11, 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 (lOt90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/min. The radiochemical purity is > 95%.

Example 3 8-Tritylcysteine methyl eQter (15) The solution of 2.79 g of triphenylchloromethane in DMF is slowly added in drops to a solution of 4. 71 g of the cysteine methyl ester (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 alkalized with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase is dried and concentrated by evaporation. The remaining residue is chromatographed (silica gel, CH2Cl2).
Yield: 67 Analysis:
Cld: C 73.18 H 6.14 N 3.71 O 8.48 S 8.49 Fnd: C 73.46 H 5.96 N 3.44 S 8.59 N-VinylsulfonYl-S-tritYlcysteine methYl ester (16) An ice-cooled solution of 7.55 g (20 mmol) of S-tritylcysteine derivative 15 and 4.89 g of chloroethanesulfonyl chloride (30 mmol) in 50 ml of dichloromethane is mixed slowly with 20 ml of dry pyridine while being cooled with ice, and it is stirred for 6 hours at 0~C. It is allowed to heat to room temperature, and after the reaction has been completed, it is mixed with dilute HCl, and the dichloromethane phase is separated. The aqueous phase is extracted several times with dichloromethane, washed with water, dried and concentrated by evaporation.
Yield: 58%
Analysis:
Cld: C 64.22 H 5.40 N 3.00 O 13.69 S 13.72 Fnd: C 64.02 H 5.75 N 3.09 S 13.52 N-~5-rtN-tert-Butyloxycarbonyl)-aminol-3-thia-pentylQulfonYl~-8 tritylcYsteine methYl ester (17) 9.8 mmol of vinylsulfonamide 16 (4. 58 g) in THF is added in drops to 10 mmol of N-Boc-2 mercaptoethylamine (1. 76 g) and 50 ~1 of piperidine within 45 minutes while being stirred, whereby 50~C
is not exceeded. During the reaction, another 50 ~1 of piperidine is added in several portions. Then, the mixture is heated for several minutes to 50~C, contaminants are filtered out, and concentrated by evaporation. The residue is taken up in ethyl acetate and washed with water. After drying, the solvent is drawn off, and the residue is chromatographed (silica gel, CH2Clz/PE) ~

Yield: 45%

Analysis:
Cld: C 59.60 H 6.25 N 4.34 0 14.89 S 14.92 Fnd: C 59.37 H 6.46 N 4.43 8 14.77 N-{5-~(N-tert-ButyloxYcarbonYl)-amino~-3-thia~entylsulfonYl~-8-tritylcysteine-rN-t2-~minoethyl)amidel tl8) A solution of 6.45 g of cysteine ester 17 (10 mmol) in 50 ml of toluene is slowly added in drops to a solution of 25 g of ethylenediamine (240 mmol) at 95~C, and it is refluxed for 2 hours. After cooling to room temperature, it is concentrated by evaporation in a vacuum, and the residue is recrystallized from methanol/CH2C12.

Yield: 85%

Analysis:
Cld: C 58.90 H 6.59 N 8.33 0 11.89 S 14.30 Fnd: C 58.69 H 6.74 N 8.37 S 14.15 For-Met-Leu-Phe-~N-{N'-{5- r (N''-tert-butoxycarbonYl)-~mino]-3-thia-Pentylsulfonyl~-8-tritylcysteinyl~-2-aminoethyl}~mide~ (19 2.11 g of EDC (11 mmol) in 10 ml of anhydrous dimethylformamide is added in drops to a solution of 6.72 g of cysteine derivative 18 (10 mmol), 1.01 g of triethylamine and 1.15 g of N-hydroxysuccinimide (10 mmol) in 50 ml of anhydrous dimethylformamide while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of For-Met-Leu-Phe (11 mmol) in DMF is added in drops within 60 minutes. It is first stirred for another 2 hours at 0~C, and stirred for 12 hours at room temperature. The product is filtered off from N,N'-dicyclohexylurea, and the filtrate is concentrated by evaporation in a vacuum and taken up in dichloromethane. After filtration has again been 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: 35%
Analysis:
Cld: C 59.37 H 6.74 N 8.98 0 13.18 S 11.74 Fnd: C 59.09 H 6.91 N 8.77 S 12.01 CA 02232620 l998-03-l8 For-Net-Leu-Phe-~N-[N'-(5-amino-3-thia-PentylsulfonYl)-cysteinyll-2-aminoethgl~amide~ ~20) 1.09 g of peptide 19 (1 mmol) is treated for 45 minutes at 0~C with 10 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 180 mg of an oil.
Yield: 24%
Analysis:
Cld: C 48. 04 H 6. 85 N 13. 07 O 14.93 S 17.10 Fnd: C 47.82 H 6. 89 N 12.85 S 16. 84 For-Met-Leu-Phe-~N-rN'-(S-amino-3-thia-PentYlsulfonyl)-cystQinyl]-2-aminoethyl}~mide}, technetium-99m complex 10 mg of compound 20 iS dissolved in 1.0 ml of ethanol. 50 ~1 of this ligand solution is mixed with 100 ,ul of ethanol, 150 ,ul of phosphate buffer with a pH of 8.5, 50 ~Ll of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~ of a deoxygenated tin(II) chloride solution (5 mg/ml of O.lN HCl) and 100 ~1 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~, 125 X 4. 6 mm; gradient elution of 100% A after 100% B
within 15 minutes (eluant A: acetonitrile/Na-phosphate 5 mmol, CA 02232620 l998-03-l8 .

pH 2.0 (10/90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/min. The radiochemical purity is > 98%.

Ex~mple ~
N-~S-Hydroxy-3-thiaDentylsulfonyl~-S-tritylcysteine methyl ester (21~
4.65 g of vinylsulfonic acid 15 (10 mmol) is added to a stirred solution of 7. 81 g of mercaptoethanol (100 mmol) from 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: 46%
Analysis:
Cld: C 59.43 H 5.73 N 2.57 0 14.66 S 17.63 Fnd: C 59.09 H 5.95 N 2.41 S 17.43 N-~5-HydroxY-3-thiapentylsulfonyl~-cYsteine methyl e~ter ~22) 2.73 g of cysteine derivative 21 (5 mmol) is treated for 45 minutes at 0~C with 35 ml of anhydrous HF in the presence of 13 ml of anisole and 7 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.
Yield: 75%

. 44 .

Analysis:
Cld: C 31.67 H 5.65 N 4.62 0 26.37 S 31.71 Fnd: C 31.32 H 5.89 N 4.40 S 31.81 N-~5-Hydroxy-3-thi~DentylsulfonYl~-cysteino methyl ester.
technotium-9sm complex lo mg of compound 22 is dissolved in 1.0 ml of ethanol. 50 ~1 of this ligand solution is mixed with 100 ~1 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 ~1 of a deoxygenated tin(II) chloride solution (5 mg/ml of O.lN HCl) and 100 ~1 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/min. The radiochemical purity is > 97%.

Example 5 N-~5-Chloro-3-thiaPentylsulfonyl~-8-trityl-cysteine methyl oster (23) A solution of 5.46 g of cysteine derivative 21 (10 mmol) in 50 ml of anhydrous carbon tetrachloride is mixed under nitrogen atmosphere with 3.14 g of pulverized triphenylphosphine (12 mmol) and refluxed. After cooling, it is diluted with 50 ml of hexane and stored for some time at -20~C. The precipitate is suctioned CA 02232620 l998-03-l8 .

off, and the procedure as above is repeated until precipitate no longer settles out. Then, it is freeze-dried and concentrated by evaporation.
Yield: 89%
Analysis:
Cld: C 57.48 H 5.36 N 2.48 0 11.34 S 17.05 Fnd: C 57.16 H 5.56 N 2.33 S 16.84 N-~5-Thiouronyl-3-tbiapentYlsulfonYl}-S-trityl-cysteine methYl ester hydrochloride (24) The solution of 11. 3 g of 23 (20 mmol) in ethanol is added in drops to a solution of 1. 52 g of thiourea in ethanol, and then it is refluxed for 2 hours. After the solvent is drawn off, a crystalline residue remains, which is recrystallized from ethanol.
Yield: 60%
Analysis:
Cld: C 55.29 H 5.63 N 6.91 0 10.52 S 15.82 Fnd: C 54.97 H 5.82 N 6.77 S 15. 80 N-~5-Mercapto-3-thiaPentyl~ulfonyl~-~-trityl-cY~teine ~25) 6.08 g (10 mmol) of 24 iS stirred into 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: 52%
Analysis:
Cld: C 57.01 H 5.34 N 2.56 O 11.68 S 23.42 Fnd: C 56.87 H 5.55 N 2.48 S 23.81 N-~5-MercaPto-3-thiapentylsulfonYl~-cY~teine (26~
2.74 g of cysteine derivative 25 (5 mmol) is treated for 45 minutes at 0~C with 35 ml of anhydrous HF in the presence of 13 ml of anisole and 7 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. The residue is crystallized by renewed trituration with diethyl ether.
Yield: 23%
Analysis:
Cld: C 27.53 H 4.95 N 4.59 O 20.95 S 41.99 Fnd: C 27.11 H 4.78 N 4.40 S 42.21 N-~5-Mercapto-3-thiaPentYl~ulfonyl}-cysteine, technetium-99m complex 10 mg of compound 26 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 ,ul 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 CA 02232620 l998-03-l8 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 S mmol, pH 2.0 (lO/9O); eluant B: acetonitrile/Na-phosphate S mmol, pH
2.0 (75/25); 1 ml/min. The radiochemical purity is > 96%.

Example 6 N,N'-tert-ButyloxYc~rbonyl-vinylsulfonyl-ethylenedi~mine (27 An ice-cooled solution of 1. 60 g (10 mmol) of N-tert-butyloxycarbonylvinylsulfonylethylene diamine and 1.79 g of chloroethanesulfonyl chloride (11 mmol) in 10 ml of dichloromethane is mixed slowly with 20 ml of dry pyridine (44 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 20 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). 1. 75 g of white crystals remain.
Yield: 70%
Analysis:
Cld: C 43.19 H 7.25 N 11.19 0 25.57 S 12.81 Fnd: C 42.97 H 7.41 N 11. 32 S 12.56 CA 02232620 l998-03-l8 N,N'-tert-ButyloXYcarbonyl-~5-hydroxY-3-thi~PFntylsulfonyl) ethYlenediamine (28) 2.50 g of vinylsulfonic acid 27 (lO mmol) is added to a stirred solution of 7. 81 g of mercaptoethanol (100 mmol) of 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: ~7%
Analysis:
Cld: C 40.23 H 7.37 N 8.53 O 24.36 S 19.53 Fnd: C 40.59 H 7.75 N 8.41 S 19.43 N,N'-tert-ButYloxyc~rbonYl-(5-chloro-3-thiapentylsulfon~Yl)-ethylenedi~mine (29) A solution of 3. 28 g of ethylenediamine derivative 28 (lO
mmol) in 50 ml of anhydrous carbon tetrachloride is mixed under nitrogen atmosphere with 3.14 g of pulverized triphenylphosphine (12 mmol) and 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: 69%

Analysis:
Cld: C 38.09 H 6.68 N 8.09 O 18.45 S 18.49 Fnd: C 38.16 H 6.56 N 8. 33 S 18.24 N,N'-tert-Butyloxycarbonyl-~5-thiouronYl-3-thiaPentYlsulfonYl)-ethYlenediamine hydrochloride ~30) The solution of 6. 94 g of 29 (20 mmol) in ethanol is added in drops to a solution of 1. 52 g of thiourea in ethanol, and it is then refluxed for 2 hours. After the solvent is drawn off, a crystalline residue remains, which is recrystallized from ethanol.
Yield: 71%
Analysis:
Cld: C 34.07 H 6.43 N 13.25 0 15.13 S 22.74 Fnd: C 33.97 H 6.82 N 13.34 S 22.80 N,N'-tert-ButyloxYcarbonyl-~5-mercapto-3-thiapentYlsulfonyl)-ethYlene~iamine ~31) 4.23 (10 mmol) of 30 iS stirred into 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: 59%

CA 02232620 l998-03-l8 Analysis:
Cld: C 38.35 H 7.02 N 8.13 0 18.58 S 27.92 Fnd: C 38.17 H 7.35 N 8.48 S 27.61 N-(5-Mercapto-3-thi~pentyl~ulfonyl)-ethylenediamine t32) 5.44 g of 31 (15.8 mmol) is dissolved under protective gas in 200 ml of 3 M HCl in ethyl acetate, and it is stirred for 2 hours at room temperature. After the solvent is drawn off, 3.55 g of white crystals remains.
Yield: 92%
Analysis:
Cld: C 29.49 H 6.60 N 11. 46 O 13.09 S 39.36 Fnd: C 28.17 H 6.41 N 11.73 S 39.19 N-tS-Merc~Pto-3-thiapentYlsulfonYl)-ethylenediamine, technetium-99m complex 10 mg of compound 32 iS dissolved in l.0 ml of ethanol. 50 ,ul of this ligand solution is mixed with 100 ,ul of ethanol, 150 1 of phosphate buffer with a pH of 8.5, 50 ~1 of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~1 of a deoxygenated tin(II) chloride solution (5 mg/ml of 0.lN HCl) and lO0 ~Ll 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/min. The radiochemical purity is > 94%.

Claims (16)

Claims

1. Compounds of general formula (I) M - L (I) in which M means a radioisotope of Tc or Re and L is a ligand of general formula (II) B-CR1R2-(CR3R4)n=1,2-S-CHR5-CHR6-SO2-NH-CR7R8-CR9R10)n=1,2-D
(II) in which R1, R2, R3, R4, R5, R6 and R7 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, R8 stands for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or a radical -CO-R15, in which R15 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C1-30 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or is optionally interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As, Se, or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent 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, Se, R9 and R10 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 radical -SR11, -NHR12 or -OR13, in which R11 stands for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or for a sulfur protective group, R12 stands for a hydrogen atom, an amino protective group or branched or straight-chain cyclic or polycyclic C1-30 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl group, 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, Se, R13 stands for a hydrogen atom or for an alcohol protective group, D stands for a radical -SR14, in which R14 stands for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or for a sulfur protective group, or if B represents a radical SR11, also for a radical -NHR16 or -OR17, in which R16 represents a hydrogen atom, an amino protective group or a branched or straight-chain, cyclic or polycyclic C1-30 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl group, 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, Se, R17 stands for a hydrogen atom or for an alcohol protective group.

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, R8, R9 and R10 represent hydrogen atoms.

4. Compounds according to claim 3, wherein R3 and R4 in each case stand for a hydrogen atom, and R7 stands for a hydrogen atom, a branched or unbranched C1-6 alkyl radical or a radical -Co-R15, in which R15 represents a hydroxyl group, a branched or straight-chain C1-30 alkoxy group or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C1-30 alkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or is substituted by one or more heteroatoms from the series 0, N, S.

5. Ligands of general formula (II) B-CR1R2-(CR3R4)n=1-2-S-CHR5-CHR6-SO2-NH-CR7R8-(CR9R10)n=1,2-D
(II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, n, m, B and D
in each case have the meaning that is indicated in claim 1.

6. Ligands according to claim 5, wherein n and m in each case stand for 1.

7. Ligands according to claim 5 or 6, wherein R1, R2, R5, R6, R8, R9 and R10 represent hydrogen atoms.

8. Ligands according to claim 7, wherein R7 stands for a hydrogen atom, a branched or unbranched C1-6 alkyl radical or a radical -Co-R15, in which R15 represents a hydroxyl group, a branched or straight-chain C1-30 alkoxy group or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C1-30 alkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or is substituted by one or more heteroatoms from the series O, N, S.

9. 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.

10. Conjugates according to claim 9, 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.

11. 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 cyclischen Aminosäuresequenzen [Key:]
die Teilsequenzen = the partial sequences oder die cyclischen Aminosäuresequenzen = or the cyclic amino acid sequences cyclo-(DTrp-DAsp-Pro-DVal-Leu), cyclo-(DGlu-Ala-alloDIle-Leu-DTrp).

12. 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) B-CR1R2-(CR3R4)n=1,2-S-CHR5-CHR6-SO2-NH-CR7R8-(CR9R10)n=1,22-D
(II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, n, m, B and D
have the meaning that is indicated in claim 1.

13. Process for the production of ligands of general formula (II), wherein 2-chloroethane-sulfonic acid chloride that is optionally substituted with R5 and R6 is reacted in a way known in the art in an aprotic solvent with the addition of a suitable base with compounds of general formula (III) H2N-CR7R8- (CR9R10) n=1,2-D
(III) in which R7, R8, R9, R10, m and D have the meaning that is indicated in claim 1, at temperatures of -20°C to 180°C to compounds of general formula (IV) R5HC=CR6-SO2-NH-CR7R8-(CR9R10)n=1,2-D
(IV) in which R5, R6, R7, R8, R9, R10, m and D 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° to 180°C in a way known in the art with compounds of general formula (V) BCR1R2-(CR3R4)n=1,2SH
(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.

14. Kit for the production of radiopharmaceutical agents that consists of a compound of general formula (II) according to one of claims 5 to 8 or a conjugate according to one of claims 9 to 11 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.

15. 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 4 or a conjugate according to claims 9 to 11 and optionally additives that are commonly used in galenicals, whereby the compound is prepared in a kit according to claim 14 with technetium-99m or Re in the form of a pertechnetate or perrhenate solution.

16. Process for radiodiagnostic investigation, wherein a radiopharmaceutical composition according to claim 15 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.