DE19536780A1 - Bifunctional sulfide-containing sulfonamide chelating agents of the type 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-CR<1>R<2>-(CR<3>R<4>)n=1,2-S-CHR<5>-CHR<6>-SO2-NH-CR<7>R<8>-(CR<9>R< 10>)m=1,2-D, in which R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<9> and R<10> 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 R<8>. These new compounds are useful for complexing technetium and rhenium and are used for medical diagnosis and therapy.

Description

The invention relates to new sulfonamide groups Chelating agents containing these compounds pharmaceutical agents, their use in the Radiodiagnostics and radiotherapy, procedures for Preparation of these compounds and agents, as well Conjugates of these compounds with themselves in diseased Tissue-enriching substances, in particular Peptides.

The use of radiopharmaceuticals for diagnostic and therapeutic purposes has long been in the field of known biological and medical research. In particular, radiopharmaceuticals are used to: certain structures such as the skeleton, Organs or tissues. The diagnostic Application exposes the use of such radioactive agents ahead, which are specific to such after application Enrich structures in the patient that are being examined should. These locally accumulating radioactive Means can then by means of suitable detectors, such as for example scintillation cameras or others suitable admission procedure, tracked down, plotted or be scintigraphed. The distribution and relative Intensity of the radioactive agent detected indicates the location of a structure in which the radioactive agent is located and can be the presence of Anomalies in structure and function, pathological Represent changes etc. Similarly, you can Radiopharmaceuticals used as therapeutic agents to certain pathological tissues or areas irradiate. Such treatment requires manufacturing radioactive therapeutic agents that are in enrich certain structures, tissues or organs.

By enriching these agents, the therapeutic Radiation directly to the pathological tissue brought up.

The application of both diagnostic and therapeutic radiopharmaceuticals sets radioactive markable connections ahead. In the case of metallic Radionuclides can form the metal in free form as an ion or in the form of a metal complex with an or several ligands are present. Examples of metallic Are radionuclides that can form complexes Technetium-99m and the various rhenium isotopes. The the first is in diagnostics and the second in Therapy used. The radiopharmaceuticals contain suitable ones Carriers and additives that require injection, inhalation allow or ingestion by the patient, as well as physiological buffers, salts etc.

The most common for nuclear medicine issues Radionuclide used is Technetium-99m, which is due to its favorable physical properties (no corpuscular radiation, 6 h physical Half-life, 140 KeV gamma radiation) and the resulting resulting low radiation exposure is particularly good suitable as a radioisotope for in vivo diagnostics. Technetium-99m can be easily created from nuclide generators win as pertechnetate and is direct in this form for the production of kits for clinical Use routine needs.

The manufacture of radiopharmaceuticals initially requires Synthesis of a suitable ligand. Then will the complex with the radionuclide is shown separately (Mark). The ligand produced, always in shape a lyophilized kit is combined with a Radionuclide contained solution under complex formation  conditions implemented. For example, is the manufacture of a technetium-99m radiopharmaceutical is desired the ligand produced with the addition of a suitable one Reductant mixed with a pertechnetate solution and under suitable reaction conditions appropriate technetium complex produced. This Complexes are then appropriately presented to the patient administered by injection, inhalation or ingestion.

The solutions containing the radionuclide can, as in Case of technetium-99m, from an available mo- 99 / Tc-99m nuclide generator can be obtained, or from from a manufacturer, as in the case of rhenium-186 will. The complex formation reaction is under suitable Temperatures (e.g. 20 ° -100 ° C) within a few minutes carried out for several hours. To be a complete Ensuring complex formation is a huge surplus (more than 100 times excess to the metal radionuclide) of the ligand produced and a sufficient amount of Reducing agent for a complete reduction of the used radionuclide required.

Radiopharmaceuticals are made by combining the radionuclide complex, in an amount sufficient for diagnostic or therapeutic use, with pharmacologically acceptable radiological carriers. This radiological carrier should have favorable properties for the application of the radiopharmaceutical in the form of an injection, inhalation or ingestion. Examples of such carriers are HSA, aqueous buffer solutions, e.g. B. tris (hydroxymethyl) aminoethane (or their salts), phosphate, citrate, bicarbonate etc., sterile water, physiological saline, isotonic chloride or dicarbonate ion solutions or normal plasma ions such as Ca ²⁺ , Na⁺, K⁺ and Mg ²⁺ .

Because technetium comes in a number of oxidation states (+7 to -1), it is often necessary that radiopharmaceutical agents contain additional agents, which are known as stabilizers. These hold that Radionuclide in a stable form until it is compatible with the Ligand has reacted. These stabilizers can Agents known as transfer or auxiliary ligands that are particularly useful for Metal in a well-defined oxidation state stabilize and complex until the target ligand complexes the metal via ligand exchange. Examples of this type of auxiliary ligand are (including their salts) gluconheptonic acid, Tartaric acid, citric acid or other common Ligands, as detailed later.

Radionuclide is the standard Radiopharmaceuticals are presented first by the ligand synthesized and then with the metal radionuclide is appropriately implemented to a to form corresponding complex in the necessarily the ligand unchanged after complexation, with the exception the splitting off of any protective groups or Hydrogen ions must be present. The removal of this Groups facilitate the coordination of the ligand on Metal ion and thus leads to rapid complexation.

To form technetium-99m complexes, pertechnetate is first obtained from a nuclide generator and converted into a lower oxidation level using suitable reducing agents (e.g. SnCl₂, S₂O₄ ^2- etc.), which is then stabilized by a suitable chelator. Since technetium can exist in a number of oxidation states (+7 to -1) that can change the pharmacological properties by changing the charge of a complex, it is necessary to provide chelators or complex ligands for technetium-99m, the technetium safely, firmly and can bind stably in a defined oxidation state in order to prevent undesired biodistribution from taking place in vivo by redox processes or technetium releases from the corresponding radio diagnostics, which complicates the reliable diagnosis of corresponding diseases.

The efficiency of radionuclides in vivo Diagnostics, as well as therapy depends on the Specificity and selectivity of the labeled chelates to the target cell. An improvement on this Properties is due to coupling of the chelates Biomolecules according to the "drug targeting" principle to reach. Antibodies, whose Fragments, hormones, growth factors and substrates from Receptors and enzymes. So in the British Patent application GB 2,109,407 the use of radioactive labeled monoclonal antibody against tumor-associated antigens for which in vivo Tumor diagnostics described. Likewise, direct Protein labels 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 (U.S. Patent 4,479,930 and Fritzberg, A.R. et al. Nucl. Med. 1986, 27, 957) with technetium-99m described. However, these experimental methods are available not available for clinical use because one the selectivity too low and the other the Background activity in the organism is too high to be in to enable vivo imaging.

As a suitable complexing agent for technetium and Rhenium isotopes apply e.g. B. cyclic amines such as those from  Volkert et al. (Appl. Radiol. Isot. 1982, 33; 891) and Troutner et al. (J. Nucl. Med. 1980, 21, 443) be, but which have the disadvantage that they often only from a pH <9 are able to technetium-99m in to bind good yields. N₂O₂ systems (Pillai, M.R.A., Troutner, D.E. et al .; Inorg. Chem. 1990, 29; 1850) are in clinical use. Non-cyclical N₄ systems such. B. the HMPAO have a major disadvantage their low complex stability. Tc-99m-HMPAO must 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) within 30 Minutes after its marking, so that the percentage of decay products that another Possess pharmacokinetics and excretion, kept small can be. Such radiochemical contaminants complicate the detection of diagnosed Diseases. A coupling of these chelates or Chelating agents to others, selectively in Illness-enriching substances are not included simple means to solve, so that these in distribute generally non-specifically in the organism.

N₂S₂ chelators (Bormans, G. et al .; Nucl. Med. Biol. 1990, 17; 499) such as B. ethylenedicysteine (EC; Verbruggen, AT THE. et al .; J. Nucl. Med. 1992, 33; 551) meet the demand for sufficient stability of the corresponding technetium-99m complex, but only form from a pH value of the complexing medium <9 Radio diagnostics with a purity greater than 69%. N₃S- Form systems (Fritzburg, A .; EP-0173424 and EP-0250013) stable technetium-99m complexes, but have to Formation of a uniform radiopharmaceutical Temperatures of about 100 ° C are heated.  

In the past few years, the craving has been in itself enriching specifically in diseased tissues Radio diagnostics increased. This can be accomplished when complexing agents are easily selectively enriching Substances can be coupled and their not lose favorable complexing properties. There but it very often happens that after coupling a Complexing agent using one of its functional Groups at such a molecule weaken the Complex stability is observed, the appear previous approaches to coupling chelating agents selectively enriching substances little satisfactory, because a diagnostically not tolerable proportion of the isotope from the conjugate in vivo is released (Brechbiel, M.W. et al .; Inorg. Chem. 1986, 25, 2772). It is therefore necessary to be bifunctional To represent complexing agents that are both functional Groups to bind the desired metal ion as well one (other, several) functional group for binding of the selectively enriching molecule, or To design complexing agents so that only through Coupling to a selectively enriching substance desired complexing agent structure is formed and thus a weakening of the complex stability excluded becomes. Such ligands allow a specific, chemically defined binding of technetium or rhenium Isotopes on various biological materials, too when so-called prelabeling is carried out. Some chelators have been linked to monoclonal Antibodies (e.g. EP-0247866 and EP-0188256) or Fatty acids (EP-0200492). As a chelating agent however, the previously mentioned N₂S₂ systems used because of their low stability little are suitable. Because both the selectively enriching Substances in their properties, as well as Mechanisms by which they are enriched, very much  are different, it is still necessary that to vary coupling-capable chelating agents and the physiological requirements of the coupling partner with regard to its lipophilicity, membrane permeability etc. to be able to adapt.

The invention is therefore based on the object, stable To provide complex compounds that coupled or capable of coupling to different ones are selectively enriching compounds without their specificity and selectivity significantly influenced becomes. In addition, there is the task of connecting such Provide chelators or complexes that have a greater range of chemical variations of the substituents have to meet these requirements to be able to adapt. At the same time, the Requirements for using these connections on People regarding ingested radiation dose, Stability and solubility of the compounds must be fulfilled.

This object is achieved in that new, containing bifunctional sulfonamide groups Chelating agents and their coupling products specifically enriching compounds available be put.

The invention relates to compounds of general formula (I)

M-L (I)

wherein
M is a radioisotope of Tc or Re and L is a ligand of the general formula (II)

B-CR¹R²- (CR³R⁴) _{n = 1,2} -S-CHR⁵-CHR⁶-SO₂-NH-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1,2} -D (II)

means what
R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and each represents a hydrogen atom and / or a branched or unbranched C _1-6 alkyl radical,
R⁸ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a radical -CO-R¹⁵,
wherein
R¹⁵ is a hydroxyl, a branched or straight-chain, cyclic or polycyclic C _1-30 alkoxy, alkenyloxy, polyalkenyloxy, alkynyloxy, polyalkynyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, optionally with hydroxy, oxy, oxo -, Carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally interrupted by one or more heteroatoms from the series O, N, S, P, As, Se and / or is substituted or an N (RaR ^b ) group,
where Ra and R ^{b are the} same or different and / or a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C _1-30 alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl radical represent, which is optionally substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups having up to 20 carbon atoms and / or optionally by one or more heteroatoms from the O series , N, S, P, As, Se is interrupted and / or substituted,
stands,
R⁹ and R¹⁰ are the same or different and each represents a hydrogen atom and / or a branched or unbranched C _1-6 alkyl radical,
B represents a residue -SR¹¹, -NHR¹² or -OR¹³, wherein
R¹¹ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a sulfur protecting group,
R¹² represents a hydrogen atom, an amino protecting group or branched or straight-chain, cyclic or polycyclic C _1-30 alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl group, optionally with hydroxy, Oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally substituted by one or more heteroatoms from the series O, N, S, P, As , Se is interrupted and / or substituted,
R¹³ represents a hydrogen atom or an alcohol protecting group,
D for a radical -SR¹⁴, wherein
R¹⁴ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a sulfur protecting group,
or in the event that B represents a radical SR¹¹, also for a radical -NHR¹⁶ or -OR¹⁷, wherein
R¹⁶ is a hydrogen atom, an amino protecting group or a branched or straight-chain, cyclic or polycyclic C _1-30 alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl group, which are optionally with hydroxy, Oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally substituted by one or more heteroatoms from the series O, N, S, P, As , Se is interrupted and / or substituted,
R¹⁷ represents a hydrogen atom or an alcohol protecting group,
stands.

Preferred compounds of the general formula (I) are characterized in that for n and m 1 stands and that R¹, R², R⁵, R⁶, R⁸ and R⁹ are hydrogen atoms are.

Particularly preferred compounds of general formula (I) are characterized in that n and m each represent 1 and that R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹ and R¹⁰ are hydrogen atoms and R⁷ for a radical -CO -R¹⁵, wherein
R¹⁵ is a hydroxyl, a branched or straight chain C _1-30 alkoxy group or an N (RaR ^b ) group, wherein
Ra and R ^{b are the} same or different and / or a hydrogen atom, a branched or straight-chain, C _1-30 alkyl radical which is optionally substituted by carboxy, aminocarbonyl, alkoxycarbonyl or amino groups having up to 20 carbon atoms and / or optionally is interrupted and / or substituted by one or more heteroatoms from the series O, N, S,
stands.

Compounds according to the invention are particularly preferred where n and m each represent 1.

Furthermore, the invention is particularly preferred Compounds in which R¹, R², R⁵, R⁶, R⁸, R⁹ and R¹⁰ Represent hydrogen atoms.

Compounds according to the invention are particularly preferred in which R³ and R⁴ each represent a hydrogen atom and R⁷ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a radical -CO-R¹⁵,
wherein R¹⁵ is a hydroxyl, a branched or straight-chain C _1-30 alkoxy or an N (RaR ^b ) group,
wherein Ra and R ^{b are the} same or different and / or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C _1-30 alkyl radical, optionally with hydroxy, oxy, oxo, carboxy, aminocarbonyl , Alkoxycarbonyl, amino or alkoxy groups with up to 20 carbon atoms is substituted and / or optionally interrupted and / or substituted by one or more heteroatoms from the series O, N, S,
stand.

Another object of the invention relates to the new bifunctional sulfur atom-interrupted sulfonamide Ligands of the general formula (II)

B-CR¹R²- (CR³R⁴) _{n = 1,2} -S-CHR⁵-CHR⁶-SO₂-NH-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1,2} -D (II)

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, n, m, B and D each have the meaning given above to have.

Preferred compounds of the general formula (II) are characterized in that for n and m 1 stands.

Further preferred compounds of the general formula (II) are characterized in that R¹, R², R⁵, R⁶, R⁸, R⁹ and R¹⁰ are hydrogen atoms.

Particularly preferred compounds of the general formula (II) are characterized in that n and m each represent 1 and that R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹ and R¹⁰ are hydrogen atoms and R⁷ for a radical -CO -R¹⁵, wherein
R¹⁵ is a hydroxyl, a branched or straight chain C _1-30 alkoxy group or an N (RaR ^b ) group, wherein
Ra and R ^{b are the} same or different and / or represent a hydrogen atom, a branched or straight-chain, C _1-30 alkyl radical which is optionally substituted by carboxy, aminocarbonyl, alkoxycarbonyl or amino groups having up to 20 carbon atoms and / or optionally interrupted and / or substituted by one or more heteroatoms from the series O, N, S,
stands.

The invention further relates to conjugates containing a compound of general formula (I and / or II) and nucleotides of the DNA and RNA type and selectively accumulating in diseased tissue Substances with a convex bond between them exists and this in the case of carboxyl or Substances containing amino groups as natural occurring or modified oligonucleotides which are broken down by naturally occurring nucleases is prevented or difficult, peptides, proteins, Antibodies or their fragments amidic or in the case of substances containing hydroxyl groups such as Fatty alcohols ester-like or in the case of aldehyde groups containing substances are imidic.

Particularly preferred conjugates are characterized by that the accumulating in the diseased tissue Substances peptides such as endotheline, partial sequences of Endothelin, endothelin analogues, endothelin derivatives, Endothelin antagonists or angiotensins, partial sequences of angiotensins, angiotensin analogs, angiotensin Derivatives and angiotensin antagonists as well mean chemotactic peptides.

In further preferred conjugates according to the invention the peptides have the following sequences

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,
the partial sequences
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,
or the cyclic amino acid sequences
Cyclo- (DTrp-DAsp-Pro-DVal-Leu),
Cyclo- (DGlu-Ala-alloDIle-Leu-DTrp)
on.

Another object of the present invention are furthermore compounds of the general formula (II)

B-CR¹R²- (CR³R⁴) _{n = 1,2} -S-CHR⁵-CHR⁶-SO₂-NH-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1,2} -D (II)

wherein
R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and each represents a hydrogen atom and / or a branched or unbranched C _1-6 alkyl radical,
R⁸ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a radical -CO-R¹⁵, wherein
R¹⁵ is a hydroxyl, a branched or straight-chain, cyclic or polycyclic C _1-30 alkoxy, alkenyloxy, polyalkenyloxy, alkynyloxy, polyalkynyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, optionally with hydroxy, oxy, oxo -, Carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally interrupted by one or more heteroatoms from the series O, N, S, P, As, Se and / or is substituted or an N (RaR ^b ) group,
where Ra and R ^{b are the} same or different and / or a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C _1-30 alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl radical represent, which is optionally substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups having up to 20 carbon atoms and / or optionally by one or more heteroatoms from the O series , N, S, P, As, Se is interrupted and / or substituted,
stands,
R⁹ and R¹⁰ are the same or different and each represents a hydrogen atom and / or a branched or unbranched C _1-6 alkyl radical,
B represents a residue -SR¹¹, -NHR¹² or -OR¹³, wherein
R¹¹ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a sulfur protecting group,
R¹² represents a hydrogen atom, an amino protecting group or branched or straight-chain, cyclic or polycyclic C _1-30 alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl group, optionally with hydroxy, Oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally substituted by one or more heteroatoms from the series O, N, S, P, As , Se is interrupted and / or substituted,
R¹³ represents a hydrogen atom or an alcohol protecting group,
D for a radical -SR¹⁴, wherein
R¹⁴ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a sulfur protecting group,
or in the event that B represents a radical SR¹¹, also for a radical -NHR¹⁶ or -OR¹⁷, wherein
R¹⁶ is a hydrogen atom, an amino protecting group or a branched or straight-chain, cyclic or polycyclic C _1-30 alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl group, which are optionally with hydroxy, Oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally substituted by one or more heteroatoms from the series O, N, S, P, As , Se is interrupted and / or substituted,
R¹⁷ represents a hydrogen atom or an alcohol protecting group,
stands,
their conjugates with substances which selectively accumulate in diseased tissue, a convex bond between them and these in the case of substances containing carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which the degradation by naturally occurring nucleases is prevented or made more difficult , Proteins, antibodies or their fragments are amidic or, in the case of substances containing hydroxyl groups such as fatty alcohols, ester-like or imidic in the case of substances containing aldehyde groups
as well as their complexes with radioisotopes of Tc or Re.

Another object of the present invention is a method of making a connection of the general formula (I), characterized in that Technetium-99m or Re in the form of pertechnetate or Perrhenate in the presence of a reducing agent and optionally an auxiliary ligand with a compound of the general formula (II)

B-CR¹R²- (CR³R⁴) _{n = 1,2} -S-CHR⁵-CHR⁶-SO₂-NH-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1,2} -D (II)

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, n, m, B and D have the meaning given above,
implements.

The preparation of the compounds of the invention general formula (II) takes place in that 2- or optionally substituted with R⁶ and R⁶ Chloroethanesulfonic acid chloride in a manner known per se in an aprotic solvent with the addition of a suitable base with compounds of the general formula (III)

H₂N-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1.2} -D (III)

wherein R⁷, R⁸, R⁹, R¹⁰, m and D have the meaning given above,
to compounds of the general formula (IV)

R⁵HC = CR²-SO-NH-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1,2} -D (IV)

wherein R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, m and D have the meaning given above,
implements.

These implementations are in polar and non-polar, aprotic solvents such as Dichloromethane, tetrahydrofuran, chloroform, 1,4-dioxane, Pyridine, DMF or DMSO at temperatures between -40 ° to 120 ° C if necessary with the addition of an auxiliary base for Trapping of the acids released. Such Auxiliary bases can, for example, tertiary amines, alkali and Alkaline earth hydroxides, alkali and alkaline earth carbonates be.

The resulting compounds of general Formula (IV) are optionally with the addition of a suitable auxiliary base in a manner known per se Compounds of the general formula (V)

BCR¹R²- (CR³R⁴) _{n = 1.2} -SH (V)

wherein R¹, R², R³, R⁴, n and B have the meaning given above,
implements
and any protective groups present are split off in a manner known per se.

Another object of the invention are kits for Production of radiopharmaceuticals, consisting of a Compound of general formula (II) or one conjugate according to the invention containing compounds of general formula (I and / or II) and selectively in Tissue-enriching substances, a reducing agent and optionally an auxiliary ligand, which is in dry State or in solution, as well as one Instructions for use with a reaction instruction for Implementation of the described connections with technetium 99m or Re in the form of a pertechnetate solution or Perrhenate solution.

The invention also relates to a radiopharma Zeutical composition for non-invasive in vivo Representation of organs, receptors and receptor-containing Tissues and / or atherosclerotic plaques that a Compound of general formula (I) or an invent Conjugate according to the invention containing compounds of general formula (I and / or II) and selectively in Tissue-enriching substances, if necessary with the additives customary in galenics, the Connection in a kit with Technetium-99m or Re in Prepared in the form of a pertechnetate or perrhenate solution becomes.

In a method of performing a radiodiagno The radiopharmaceutical test is being carried out Composition in an amount of 0.1 to 30 mCi, preferably from 0.5 to 10 mCi per 70 kg body weight administered to a patient and by the patient emitted radiation recorded.  

Surprisingly, many of the synthesized and Chelates labeled with technetium-99m or Re are higher Stability as comparable N₂S₂ and N₃S systems that are described in the literature. So z. B. at a substance according to the invention (Example 2), the a fatty alcohol has been coupled, none Decomposition products are observed after 24 h. Also could be determined by competition tests that the Tc-99m or Re- Chelators better than the comparable N₂S₂, N₃S and Complex propylene amine oxime systems. The in the Chelates and present invention Chelating agents are therefore clearly better for diagnostic and therapeutic purposes suitable as the previously known systems. A particular advantage lies in the mild marking conditions. So succeed Splitting off the protective groups the marking of ligands according to the invention and their coupling products selectively enriching itself in diseased tissues Substances at room temperature and at physiological pH Value. By choosing suitable protection groups, each by coupling product with different Allowing reaction conditions to be split off is always ensures that undesirable side reactions in the Purification of the coupling products does not occur can. This ensures that there are no undesirable ones Cross-linking reactions or oxidations more freely Sulfhydryl groups to disulfides under Cleaning conditions occur. Such changes often affect marker yield and radiochemical purity and therefore the background disadvantageous due to non-specifically bound technetium. The Establishment of sulfur protection groups or their Cleavage takes place according to methods that the expert are known. The coupling itself selectively in diseased Tissue-enriching substances also follow  methods known per se to the person skilled in the art (e.g. Fritzberg et al .; J.Nucl.Med. 26, 7 (1987)), for example by Implementation of electrophilic groups of the complex ligand with nucleophilic centers that selectively in diseased Tissue-enriching substances or by reaction nucleophilic groups of the chelator with electrophilic Groups of who are selective in diseased tissues enriching substances.

As a coupling partner u. a. different biomolecules used. So z. B. ligands that target specific Bind receptors and thus changes in receptor density show, this includes u. a. Peptides, Steroid hormones, growth factors and neurotransmitters. Coupling products with steroid hormone receptors Substances enable an improved diagnosis of Breast and prostate carcinomas (S.J. Brandes and J.A. Katzenellenbogen, Nucl.Med.Biol. 15, 53, 1988). Different tumor cells show a different Density of receptors for peptide hormones or Growth factors such as B. the "epidermal growth factor "(EgF). The concentration differences can be for the selective enrichment of cytostatics in Use tumor cells (E.Abound-Pirak et al., Proc.Natl.Acad.Sci. USA 86, 3778, 1989). Further Biomolecules are in the metabolism of the cells injectable metabolites that changed one Show metabolism; this includes e.g. B. fatty acids, Saccharides, peptides and amino acids. Fatty acids coupled to the less stable N₂S₂ systems in the EP 0200492. Other metabolic products like Saccharides, deoxyglucose, lactate and amino acids (leucine, Methyl methionine, glycine) were made using the PET technique for the visual representation of changed Metabolic processes used (R. Weinreich, Swiss Med. 8, 10, 1986). Not even biological substances like  Misonidazole and its derivatives, which are found in tissues and Tissue parts with reduced oxygen concentration bind irreversibly to cell components can specific enrichment of radioactive isotopes and thus for the visual representation of tumors or ischemic regions (M.E. Shelton, J.Nucl.Med. 30, 351, 1989). After all, that too Coupling of the new chelating agents to monoclonal Antibodies or their fragments, polysaccharides such as Dextrans or starches, bleomycins, hormones, enzymes, Polypeptides such as polylysine and nucleotides from DNA or RNA type possible. Coupling products proved to be favorable 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 for the detection of atherosclerotic Vascular diseases. These derivatives became WHHL rabbits applied by a genetic defect of the LDL Have high levels of LDL in the blood and thus have atherosclerotic lesions. About 1 to 6 h after application of the derivatives in WHHL rabbits could have a high accumulation in atherosclerotic Plaques can be detected. So far, only very much late stages of atherogenesis with invasive procedures be diagnosed. The compounds of the invention therefore offer the decisive advantage, much earlier Stages of atherosclerosis with a non-invasive Diagnose procedures.

It is irrelevant whether a marking of the described Chelating agent with technetium-99m before or after the Coupling to the selectively enriching molecule is carried out. For coupling to it yourself selectively enriching molecule after complexation, however Prerequisite that the implementation of the radioactive Complex with the enriching connection quickly,  takes place under mild conditions and almost quantitatively, so that subsequent purification is not necessary is.

The preparation of the pharmaceutical according to the invention Means are carried out in a manner known per se, in which the complexing agent according to the invention 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 common in galenics - in aqueous medium dissolves and then sterile filtered. Suitable additives are, for example, physiological harmless buffers (e.g. tromethamine), small additives of electrolytes (e.g. sodium chloride), stabilizers (e.g. gluconate, phosphates or phosphonates). The Pharmaceutical compositions according to the invention are in the form a solution or in lyophilized form shortly before application with a solution Tc-99m- Pertechnetate eluted from commercially available Mo / Tc- Generators, or a perrhenate solution.

When used in nuclear medicine in vivo, the pharmaceutical compositions according to the invention are dosed in amounts of 1 × 10 ^-5 to 5 × 10⁴ nmol / kg body weight, preferably in amounts between 1 × 10 ^-3 to 5 × 10² nmol / kg 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 application. Between 5 and 500 mCi, preferably 10 to 350 mCi, are applied for therapeutic applications. The application is usually carried out by intravenous, intraarterial, peritoneal or intertumor injection of 0.1 to 2 ml of a solution of the agent according to the invention. Intravenous administration is preferred.

The following examples serve to illustrate Explanation of the subject matter of the invention.

example 1 S- (4-methoxybenzyl) cysteine ethyl ester (1)

HCl is introduced into a solution of 27.7 g of S-4-methoxybenzylcysteine in 250 ml of absolute EtOH until it is saturated and heated to boiling. After the reaction is complete, the mixture is filtered after cooling to room temperature and the mother liquor is concentrated again. 28.4 g of white crystals remain.
Yield: 93%
Analysis:
Calcd .: C 51.06, H 6.59, N 4.58, O 15.70, S 10.49;
Opp .: C 50.88, H 6.83, N 4.45, S 10.15.

N-vinylsulfonyl-S- (4-methoxybenzyl) cysteine ethyl ester (2)

An ice-cooled solution of 3.06 g (10 mmol) of the S-protected cysteine derivative 1 and 1.79 g of chloroethanesulfonyl chloride (11 mmol) in 10 ml of dichloromethane is slowly mixed with dry pyridine (44 mmol) while cooling with ice. The mixture is allowed to warm to RT and, after the reaction has ended, 20 ml of dilute HCl are added and the dichloromethane phase is separated off. The aqueous phase is extracted several times with dichloromethane, washed with water, dried, concentrated and chromatographed (silica gel CH₂Cl₂). 2.37 g of a slowly crystallizing oil remain.
Yield: 66%
Analysis:
Calcd .: C 50.12, H 5.89, N 3.80, O 22.26, S 17.84;
Found: C 49.97, H 6.01, N 3.62, S 17.56.

N- {5 - [(N-tert-butyloxycarbonyl) amino] -3-thia pentylsulfonyl} -S- (4-methoxybenzyl) cysteine ethyl ester (3)

9.8 mmol of vinylsulfonamide 2 (35.2 g) are added dropwise to 100 mmol of N-Boc-2-mercaptoethylamine (17.6 g) and 500 μl of piperidine over the course of 45 min, with stirring, the temperature not exceeding 50 ° C. 500 ul of piperidine are added in several portions during the reaction. The mixture is then heated to 50 ° C. for a few minutes, contaminants are filtered off and washed with water. After drying, the solvent is stripped off and the residue is chromatographed (silica gel, EtOAc).
Yield: 41%
Analysis:
Calcd .: C 49.23, H 6.76, N 5.22, O 20.87, S 17.92;
Found: C 49.11, H 6.87, N 5.08, S 17.82.

N- {5-amino-3-thiapentylsulfonyl} -S- (4-methoxybenzyl) - cysteine ethyl ester (4)

8.5 g 3 (15.8 mmol) are dissolved in 200 ml 3 M HCl in ethyl acetate and stirred at RT for 2 h. After the solvent has been stripped off, 7.25 g of white crystals remain.
Yield: 97%
Analysis:
Calculated: C 43.16, H 6.18, N 5.92, O 16.91, S 20.34;
Found: C 42.97, H 6.41, N 5.73, S 20.19.

N- {5-amino-3-thia-pentylsulfonyl} cysteine ethyl ester (5)

To 2.87 g of 4 (5 mmol) and a drop of anisole, 10 ml of HF are condensed into a 100 ml Teflon round-bottom flask at 0 ° C. with exclusion of moisture. The mixture is stirred at 0 ° C. for 30 min 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. The oily residue is crystallized by trituration with diethyl ether.
Yield: 59%
Analysis:
Calc .: C 34.16, H 6.37, N 8.85, O 20.22, S 30.40;
Found: C 33.99, H 6.52, N 8.74, S 30.25.

N - {- 5-amino-3-thiapentylsulfonyl} cysteine ethyl ester, Technetium-99m complex

10 mg of compound 5 are dissolved in 1.0 ml of ethanol. 50 ul of this ligand solution with 100 ul ethanol, 150 µl phosphate buffer pH 8.5, 50 µl of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul one deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 µl of a pertechnetate solution (400-1000 µCi) transferred. The reaction mixture is after a Incubation time of 10 min using HPLC for purity of the Tc complex formed: LiChrospher RP-18 Column, 5 µ, 125 x 4.6 mm; Gradient elution of 100% A after 100% B within 15 min (eluent A: Acetonitrile / Na phosphate 5 mM, pH 2.0 (10/90); Eluent B: Acetonitrile / Na phosphate 5 mM pH 2.0 (75/25); 1 ml / min. The radiochemical purity is <97%.

Example 1a N-vinylsulfonyl-S- (4-methoxybenzyl) cysteine (6)

3.59 g (10 mmol) 2 are stirred in aqueous methanolic potassium hydroxide solution at 50 ° C. for 3 hours. After cooling, it is diluted with 400 ml of water and the undissolved solution is filtered off. The filtrate is acidified with HCl, extracted with dichloromethane, dried and concentrated.
Yield: 80%
Analysis:
Calculated: C 47.12, H 5.17, N 4.23, O 24.14, S 19.35;
Found: C 46.99, H 5.28, N 4.09, S 19.18.

N- {5 - [(N-tert-butoxycarbonyl) amino] -3-thia pentylsulfonyl} -S- (4-methoxybenzyl) cysteine (7)

9.8 mmol of vinylsulfonamide 6 (3.25 g) are added dropwise to 10 mmol of N-Boc-2-mercaptoethylamine (1.76 g) and 50 .mu.l of piperidine over the course of 45 min, with stirring, the temperature not exceeding 50 ° C. 500 ul of piperidine are added in several portions during the reaction. The mixture is then heated to 50 ° C. for a few minutes, contaminants are filtered off and washed with water. After drying, the solvent is stripped off and the crystalline residue is recrystallized from MeOH / CH₂Cl₂.
Yield: 37%
Analysis:
Calculated: C 47.23, H 6.34, N 5.51, O 22.02, S 18.91;
Found: C 47.11, H 6.77, N 5.38, S 18.82.

N- {5-amino-3-thiapentylsulfonyl} -S- (4-methoxybenzyl) -Cys- His-Leu-Asp-Ile-Ile-Trp (8)

2 mmol of the acid 2 (1.02 g) and 2 mmol of NEt₃ are mixed in 10 ml of dichloromethane under a nitrogen atmosphere at 0 ° C with 2.2 mmol (560 mg) of BOP-Cl and 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) (prepared in analogy to Barany and Merrifield, The Peptides: Analysis, Biology, Academic Press, New York, 1980; Stewart and Young, Solid Phase Peptides Syntheses, 2nd ed., Pierce Chemical W., Rockford, II, 1984) were added dropwise in anhydrous DMF and stirred overnight. A little water is added, acidified and freeze-dried. The residue is taken up in 50 ml of anhydrous trifluoroacetic acid and stirred at room temperature for 1 h. Then the trifluoroacetic acid is drawn in a vacuum, the residue is mixed three times with dimethylformamide and evaporated in each case. When stirred with diethyl ether, a solid precipitates, which is filtered off and recrystallized from DMF / diethyl ether mixtures for purification.
Yield: 39%
Analysis:
Calcd .: C 54.67, H 6.71, N 12.99, O 17.53, S 8.11;
Found: C 54.39, H 6.92, N 12.68, S 7.77.

N- [5-amino-3-thiapentylsulfonyl] -Cys-His-Leu-Asp-Ile-Ile- Trp (9)

10 ml of HF are condensed into a 100 ml Teflon round-bottom flask at 1.18 g of 8 (1 mmol) and a drop of anisole at 0 ° C. with exclusion of moisture. The mixture is stirred at 0 ° C. for 30 min and then hydrogen fluoride is carefully distilled off. The residue is crystallized by trituration with diethyl ether.
Yield: 26%
Analysis:
Calcd .: C 51.82, H 6.71, N 14.45, O 18.01, S 9.02;
Found: C 51.35, H 6.99, N 14.28, S 8.76.

Marking with Tc99m

10 mg of compound 9 are dissolved in 1.0 ml of ethanol. 50 ul of this ligand solution with 250 ul Phosphate buffer pH 8.5, 50 µl of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul one deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 µl of a pertechnetate solution (400-1000 µCi) transferred. The reaction mixture is after a Incubation time of 10 min using HPLC for purity of the Tc complex formed: LiChrospher RP-18 Column, 5 µ, 125 x 4.6 mm; Gradient elution of 100% A after 100% B within 15 min (eluent A: Acetonitrile / Na phosphate 5 mM, pH 2.0 (10/90); Eluent B: Acetonitrile / Na phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is <97%.  

Example 2 Cysteine octyl ester (10)

In the mixture of L-cysteine 12.1 g (100 mmol) and 100 ml octanol, 1.5 hours of dry HCl gas are introduced with stirring (heating to 140-150 ° C). After the reaction is allowed to cool, 300 ml of anhydrous ether are added and the mixture is stirred for 30 min. After filtration, the mixture is recrystallized from a mixture of ether and ethanol.
Yield: 72%
Analysis:
Calcd .: C 48.97, H 8.97, N 5.19, O 11.86, S 11.88;
Found: C 48.84, H 9.08, N 5.23, S 12.12.

S-bis (4-methoxyphenyl) methylcysteine octyl ester (11)

2.70 g of anhydrous cysteine octyl ester hydrochloride 10 (10 mmol) are suspended in 10 ml glacial acetic acid and about 2.76 g of the S-bis (4-methoxyphenyl) methanol (15 mmol) and 2.1 ml of BF₃ diethyl etherate (15 mmol) added. It is stirred at RT for 2 h, with almost everything becoming clear solves. Then the rotary evaporator at 40 ° C. Bath temperature reduced.

The oily residue is dissolved in ethyl acetate. The protected cysteine derivative precipitates by shaking with saturated sodium acetate solution, which is filtered off with suction and washed well with water and acetone.
Yield: 73%
Analysis:
Calculated: C 62.95, H 7.72, N 2.82, O 12.90, S 6.46;
Found: C 62.71, H 7.96, N 2.84, S 6.64.

N-vinylsulfonyl-S-bis (4-methoxyphenyl) - methylcysteine octyl ester (12)

An ice-cooled solution of 4.96 g (10 mmol) of the S-protected cysteine derivative 11 and 1.79 g of chloroethanesulfonyl chloride (11 mmol) in 10 ml of dichloromethane is slowly mixed with dry pyridine (44 mmol) while cooling with ice. The mixture is allowed to warm to RT and, after the reaction has ended, 20 ml of dilute HCl are added and the dichloromethane phase is separated off. The aqueous phase is extracted several times with dichloromethane, washed with water, dried, concentrated and chromatographed (silica gel, CH₂Cl₂).
Yield: 61%
Analysis:
Calcd .: C 61.18, H 7.15, N 2.55, O 17.46, S 11.67;
Found: C 60.89, H 7.30, N 2.64, S 11.33.

N- {5 - [(N-tert-butoxycarbonyl) amino] -3-thia pentylsulfonyl} -S-bis (4-methoxyphenyl) - methylcysteine octyl ester (13)

9.8 mmol of vinylsulfonamide 12 (5.39 g) in THF are added dropwise to 10 mmol of N-Boc-2 mercaptoethylamine (1.76 g) and 50 .mu.l of piperidine in 45 minutes with stirring, the temperature not exceeding 50.degree. During the reaction 50 ul piperidine are added in several portions. The mixture is then heated to 50 ° C. for a few minutes, impurities are filtered off and concentrated. The residue is taken up in ethyl acetate and washed with water. After drying, the solvent is stripped off and the residue is chromatographed (silica gel, CH₂Cl₂).
Yield: 59%
Analysis:
Calculated: C 57.83, H 7.49, N 3.85, O 17.61, S 13.23;
Found: C 57.67, H 7.70, N 3.68, S 13.50.

N- {5-Amino-3-thiapentylsulfonyl} cysteine octyl ester (14)

727 mg of the protected cysteine derivative 13 (1 mmol) and a trace of anisole are added to 10 ml of trifluoroacetic acid with exclusion of oxygen at room temperature and the mixture is heated under reflux for 1 h. The trifluoroacetic acid is then stripped off in vacuo 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. The oily residue is crystallized by trituration with diethyl ether.
Yield: 67%
Analysis:
Calcd .: C 44.97, H 8.05, N 6.99, O 15.98, S 24.01;
Found: C 44.75, H 8.40, N 7.11, S 24.23.

N- {5-amino-3-thiapentylsulfonyl} cysteine octyl ester, Technetium-99m complex

10 mg of compound 14 are dissolved in 1.0 ml of ethanol. 50 ul of this ligand solution with 100 ul ethanol, 150 µl phosphate buffer pH 8.5, 50 µl of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul one deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 µl of a pertechnetate solution (400-1000 µCi) transferred. The reaction mixture is after a Incubation time of 10 min using HPLC for purity of the Tc complex formed: LiChrospher RP-18 Column, 5 µ, 125 x 4.6 mm; Gradient elution of 100% A after 100% B within 15 min (eluent A: Acetonitrile / Na phosphate 5 mM, pH 2.0 (10/90); Eluent B: Acetonitrile / Na phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is <95%.

Example 3 S-tritylcysteine methyl ester (15)

The solution of 2.79 g of triphenylchloromethane in DMF is slowly added dropwise to a solution of 4.71 g of the cysteine methyl ester (10 mmol) and triethylamine (10 mmol) in DMF and the mixture is stirred at RT for 12 hours. Then water is added, the mixture is made weakly alkaline with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase is dried and concentrated. The remaining residue is chromatographed (silica gel, CH₂Cl₂).
Yield: 67%
Analysis:
Calcd .: C 73.18, H 6.14, N 3.71, O 8.48, S 8.49;
Found: 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 the S-tritylcysteine derivative 15 and 4.89 g of chloroethanesulfonyl chloride (30 mmol) in 50 ml of dichloromethane is slowly mixed with ice cooling with 20 ml of dry pyridine and stirred at 0 ° C for 6 h. The mixture is allowed to warm to RT and, after the reaction has ended, dilute HCl is added and the dichloromethane phase is separated off. The aqueous phase is extracted several times with dichloromethane, washed with water, dried and concentrated.
Yield: 58%
Analysis:
Calc .: C 64.22, H 5.40, N 3.00, O 13.69, S 13.72;
Found: C 64.02, H 5.75, N 3.09, S 13.52.

N- {5 - [(N-tert-butyloxycarbonyl) amino] -3-thia pentylsulfonyl} -S-tritylcysteine methyl ester (17)

9.8 mmol of vinylsulfonamide 16 (4.58 g) in THF are added dropwise to 10 mmol of N-Boc-2 mercaptoethylamine (1.76 g) and 50 .mu.l of piperidine in 45 minutes with stirring, the temperature not exceeding 50.degree. During the reaction 50 ul piperidine are added in several portions. The mixture is then heated to 50 ° C. for a few minutes, impurities are filtered off and concentrated. The residue is taken up in ethyl acetate and washed with water. After drying, the solvent is stripped off and the residue is chromatographed (silica gel, CH₂Cl₂ / PE).
Yield: 45%
Analysis:
Calcd .: C 59.60, H 6.25, N 4.34, O 14.89, S 14.92;
Found: C 59.37, H 6.46, N 4.43, S 14.77.

N- {5 - [(N-tert-butyloxycarbonyl) amino] -3- thiapentylsulfonyl} -S-tritylcysteine- [N- (2- aminoethyl) amide] (18)

A solution of 6.45 g of cysteine ester 17 (10 mmol) in 50 ml of toluene is slowly added dropwise at 95 ° C. to a solution of 25 g of ethylenediamine (240 mmol) and the mixture is boiled under reflux for 2 hours. After cooling to room temperature, the mixture is concentrated in vacuo and the residue is recrystallized from methanol / CH₂Cl₂.
Yield: 85%
Analysis:
Calcd .: C 58.90, H 6.59, N 8.33, O 11.89, S 14.30;
Found: C 58.69, H 6.74, N 8.37, S 14.15.

For-Met-Leu-Phe - {{N- {N ′ - {5 - [(N ′ ′ - tert-butyloxycarbonyl) - amino] -3-thia-pentylsulfonyl} -S-tritylcysteinyl} -2- aminoethyl} amide} (19)

To a solution of 6.72 g of the 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 are added 2.11 g with stirring at -10 ° C EDC (11 mmol) in 10 ml of anhydrous dimethylformamide were added dropwise and the mixture was stirred at 0 ° C. for 2 hours. A solution of For-Met-Leu-Phe (11 mmol) in DMF is then added dropwise within 60 minutes. It is initially stirred for a further 2 hours at 0 ° C. and stirred for 12 hours at room temperature. The product is filtered off from the N, N'-dicyclohexylurea and the filtrate is evaporated in vacuo and taken up in dichloromethane. After renewed filtration, the mixture is washed twice with 0.5 N HCl and saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and the solvent is stripped off. The residue is crystallized by trituration with diethyl ether.
Yield: 35%
Analysis:
Calcd .: C 59.37, H 6.74, N 8.98, O 13.18, S 11.74;
Found: C 59.09, H 6.91, N 8.77, S 12.01.

For-Met-Leu-Phe - {{N- [N ′ - (5-amino-3-thia-pentylsulfonyl) - cysteinyl] -2-aminoethyl} 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 has been evaporated off, the remaining residue is taken up in 5% acetic acid, washed several times with diethyl ether and lyophilized. Chromatographic purification on Sephadex G-10 with 0.2 M acetic acid gives 180 mg of an oil.
Yield: 24%
Analysis:
Calcd .: C 48.04, H 6.85, N 13.07, O 14.93, S 17.10;
Found: C 47.82, H 6.89, N 12.85, S 16.84.

For-Met-Leu-Phe - {{N- [N ′ - (5-amino-3-thia-pentylsulfonyl) - cysteinyl] -2-aminoethyl} amide}, technetium-99m complex

10 mg of compound 20 are dissolved in 1.0 ml of ethanol. 50 µl of this ligand solution are mixed with 100 µl ethanol, 150 µl phosphate buffer pH 8.5, 50 µl deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul one deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 µl of a pertechnetate solution (400-1000 µCi) transferred. The reaction mixture is after a Incubation time of 10 min using HPLC for purity of the Tc complex formed: LiChrospher RP-18  Column, 5 µ, 125 x 4.6 mm; Gradient elution of 100% A after 100% B within 15 min (eluent A: Acetonitrile / Na phosphate 5 mM, pH 2.0 (10/90); Eluent B: Acetonitrile / Na phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is <98%.

Example 4 N- {5-hydroxy-3-thiapentylsulfonyl} -S- tritylcysteine methyl ester (21)

To a stirred solution of 7.81 g mercaptoethanol (100 mmol) of 150 mg Triton-B solution are cooled 4.65 g of vinyl sulfonic acid 15 (10 mmol) were added and Stirred at RT for 20 h with exclusion of oxygen.

Then water is added and the mixture is extracted several times with ethyl acetate. The combined organic extracts are washed with bicarbonate solution, dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel EtOAc).
Yield: 46%
Analysis:
Calcd .: C 59.43, H 5.73, N 2.57, O 14.66, S 17.63;
Found: C 59.09, H 5.95, N 2.41, S 17.43.

N- {5-hydroxy-3-thiapentylsulfonyl} - cysteine methyl ester (22)

2.73 g of the 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 has been evaporated off, the remaining residue is taken up in 5% acetic acid, washed several times with diethyl ether and lyophilized.
Yield: 75%
Analysis:
Calcd .: C 31.67, H 5.65, N 4.62, O 26.37, S 31.71;
Found: C 31.32, H 5.89, N 4.40, S 31.81.

N- {5-hydroxy-3-thiapentylsulfonyl} cysteine methyl ester, Technetium-99m complex

10 mg of compound 22 are dissolved in 1.0 ml of ethanol. 50 ul of this ligand solution with 100 ul ethanol, 150 µl of phosphate buffer pH 8.5, 50 µl of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul one deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 µl of a pertechnetate solution (400-1000 µCi) transferred. The reaction mixture is after a Incubation time of 10 min using HPLC for purity of the Tc complex formed: LiChrospher RP-18 Column, 5 µ, 125 x 4.6 mm; Gradient elution of 100% A after 100% B within 15 min (eluent A: Acetonitrile / Na phosphate 5 mM, pH 2.0 (10/90); Eluent B: Acetonitrile / Na phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is <97%.

Example 5 N- {5-chloro-3-thiapentylsulfonyl} -S-trityl cysteine methyl ester (23)

A solution of 5.46 g of the cysteine derivative 21 (10 mmol) in 50 ml of anhydrous carbon tetrachloride is mixed with 3.14 g of powdered triphenylphosphine (12 mmol) under a nitrogen atmosphere and heated under reflux. After cooling, it is diluted with 50 ml of hexane and kept at -20 ° C for some time. The precipitate is suctioned off and the procedure is repeated as above until no further precipitation occurs. It is then dried and concentrated.
Yield: 89%
Analysis:
Calcd .: C 57.48, H 5.36, N 2.48, O 11.34, S 17.05;
Found: C 57.16, H 5.56, N 2.33, S 16.84.

N- {5-thiouronyl-3-thiapentylsulfonyl} -S-trityl cysteine methyl ester hydrochloride (24)

The solution of 11.3 g of 23 (20 mmol) in ethanol is added dropwise to a solution of 1.52 g of thiourea in ethanol and the mixture is then boiled under reflux for 2 h. After the solvent has been stripped off, a crystalline residue remains which is recrystallized from ethanol.
Yield: 60%
Analysis:
Calcd .: C 55.29, H 5.63, N 6.91, O 10.52, S 15.82;
Found: C 54.97, H 5.82, N 6.77, S 15.80.

N- {5-mercapto-3-thiapentylsulfonyl} -S-trityl-cysteine (25)

6.08 g (10 mmol) 24 are stirred in aqueous methanolic potassium hydroxide solution at 50 ° C. for 3 hours. After cooling, it is diluted with 400 ml of water and the undissolved solution is filtered off. The filtrate is acidified with HCl, extracted with dichloromethane, dried, concentrated and recrystallized.
Yield: 52%
Analysis:
Calcd .: C 57.01, H 5.34, N 2.56, O 11.68, S 23.42;
Found: C 56.87, H 5.55, N 2.48, S 23.81.

N- {5-mercapto-3-thiapentylsulfonyl} cysteine (26)

2.74 g of the 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 has been evaporated off, the remaining residue is taken up in 5% acetic acid, washed several times with diethyl ether and lyophilized. The residue is crystallized by trituration with diethyl ether.
Yield: 23%
Analysis:
Calc .: C 27.53, H 4.95, N 4.59, O 20.95, S 41.99;
Found: C 27.11, H 4.78, N 4.40, S 42.21.

N- {5-mercapto-3-thiapentylsulfonyl} cysteine, technetium- 99m complex

10 mg of compound 26 are dissolved in 1.0 ml of ethanol. 50 ul of this ligand solution with 100 ul ethanol, 150 µl of phosphate buffer pH 8.5, 50 µl of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul one deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 µl of a pertechnetate solution (400-1000 µCi) transferred. The reaction mixture is after a Incubation time of 10 min using HPLC for purity of the Tc complex formed: LiChrospher RP-18 Column, 5 µ, 125 x 4.6 mm; Gradient elution of 100% A after 100% B within 15 min (eluent A: Acetonitrile / Na phosphate 5 mM, pH 2.0 (10/90); Eluent B: Acetonitrile / Na phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is <96%.

Example 6 N, N'-tert-butyloxycarbonyl-vinylsulfonyl-ethylenediamine (27)

An ice-cooled solution of 1.60 g (10 mmol) of the N-tert-butyloxycarbonylvinylsulfonylethylenediamine and 1.79 g of chloroethanesulfonyl chloride (11 mmol) in 10 ml of dichloromethane is slowly mixed with 20 ml of dry pyridine (44 mmol) with ice cooling. The mixture is allowed to warm to RT and, after the reaction has ended, 20 ml of dilute HCl are added and the dichloromethane phase is separated off. The aqueous phase is extracted several times with dichloromethane, washed with water, dried, concentrated and chromatographed (silica gel CH₂Cl₂). 1.75 g of white crystals remain.
Yield: 70%
Analysis:
Calcd .: C 43.19, H 7.25, N 11.19, O 25.57, S 12.81;
Found: C 42.97, H 7.41, N 11.32, S 12.56.

N, N'-tert-butyloxycarbonyl- (5-hydroxy-3- thiapentylsulfonyl) ethylenediamine (28)

2.50 g of vinylsulfonic acid 27 (10 mmol) are added to a stirred solution of 7.81 g of mercaptoethanol (100 mmol) of 150 mg of Triton-B solution while cooling, and the mixture is stirred at RT for 20 h with the exclusion of oxygen. Then water is added and the mixture is extracted several times with ethyl acetate. The combined organic extracts are washed with bicarbonate solution, dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel EtOAc).
Yield: 57%
Analysis:
Calc .: C 40.23, H 7.37, N 8.53, O 24.36, S 19.53;
Found: C 40.59, H 7.75, N 8.41, S 19.43.

N, N'-tert-butyloxycarbonyl- (5-chloro-3- thiapentylsulfonyl) ethylenediamine (29)

A solution of 3.28 g of the ethylenediamine derivative 28 (10 mmol) in 50 ml of anhydrous carbon tetrachloride is mixed with 3.14 g of powdered triphenylphosphine (12 mmol) under a nitrogen atmosphere and heated under reflux. After cooling, it is diluted with 50 ml of hexane and kept at -20 ° C for some time. The precipitate is suctioned off and the procedure is repeated as above until no further precipitation occurs. It is then dried and concentrated.
Yield: 69%
Analysis:
Calcd .: C 38.09, H 6.68, N 8.09, O 18.45, S 18.49;
Found: 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 dropwise to a solution of 1.52 g of thiourea in ethanol and the mixture is then boiled under reflux for 2 h. After the solvent has been stripped off, a crystalline residue remains which is recrystallized from ethanol.
Yield: 71%
Analysis:
Calc .: C 34.07, H 6.43, N 13.25, O 15.13, S 22.74;
Found: C 33.97, H 6.82, N 13.34, S 22.80.

N, N'-tert-butyloxycarbonyl- (5-mercapto-3- thiapentylsulfonyl) ethylenediamine (31)

4.23 (10 mmol) 30 are stirred in aqueous methanolic potassium hydroxide solution at 50 ° C. for 3 hours. After cooling, it is diluted with 400 ml of water and filtered off from the undissolved. The filtrate is acidified with HCl, extracted with dichloromethane, dried, concentrated and recrystallized.
Yield: 59%
Analysis:
Calc .: C 38.35, H 7.02, N 8.13, O 18.58, S 27.92;
Found: C 38.17, H 7.35, N 8.48, S 27.61.

N- (5-mercapto-3-thiapentylsulfonyl) ethylenediamine (32)

5.44 g of 31 (15.8 mmol) are dissolved in 200 ml of 3 M HCl in ethyl acetate under a protective gas and the mixture is stirred at RT for 2 h. After the solvent has been stripped off, 3.55 g of white crystals remain.
Yield: 92%
Analysis:
Calcd .: C 29.49, H 6.60, N 11.46, O 13.09, S 39.36;
Found: C 28.17, H 6.41, N 11.73, S 39.19.

N- (5-mercapto-3-thiapentylsulfonyl) ethylenediamine, Technetium-99m complex

10 mg of compound 32 are dissolved in 1.0 ml of ethanol. 50 µl of this ligand solution are mixed with 100 µl ethanol, 150 µl phosphate buffer pH 8.5, 50 µl deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul one deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 µl of a pertechnetate solution (400-1000 µCi) transferred. The reaction mixture is after a Incubation time of 10 min using HPLC for purity of the Tc complex formed: LiChrospher RP-18 Column, 5 µ, 125 x 4.6 mm; Gradient elution of 100% A after 100% B within 15 min (eluent A: Acetonitrile / Na phosphate 5 mM, pH 2.0 (10/90); Eluent B: Acetonitrile / Na phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is <94%.

Claims (16)

1. Compounds of the general formula (I) ML (I) wherein
M is a radioisotope of Tc or Re and L is a ligand of the general formula (II) B-CR¹R²- (CR³R⁴) _{n = 1.2} -S-CHR⁵-CHR⁶-SO₂-NH-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1.2} -D (II) means where
R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and each represents a hydrogen atom and / or a branched or unbranched C _1-6 alkyl radical,
R⁸ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a radical -CO-R¹⁵, wherein
R¹⁵ is a hydroxyl, a branched or straight-chain, cyclic or polycyclic C _1-30 - alkoxy, alkenyloxy, polyalkenyloxy, alkynyloxy, polyalkynyloxy, aryloxy, alkylaryloxy or arylalkyloxyy group, optionally with hydroxyl, oxy, Oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms are substituted and / or optionally interrupted by one or more heteroatoms from the series O, N, S, P, As, Se and / or is substituted or an N (RaR ^b ) group,
where Ra and R ^{b are the} same or different and / or a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C _1-30 alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl radical represent, which is optionally substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups having up to 20 carbon atoms and / or optionally by one or more heteroatoms from the O series , N, S, P, As, Se is interrupted and / or substituted,
stands,
R⁹ and R¹⁰ are the same or different and each represents a hydrogen atom and / or a branched or unbranched C _1-6 alkyl radical,
B represents a residue -SR¹¹, -NHR¹² or -OR¹³, wherein
R¹¹ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a sulfur protecting group,
R¹² represents a hydrogen atom, an amino protecting group or branched or straight-chain, cyclic or polycyclic C _1-30 alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl group, optionally with hydroxy , Oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally substituted by one or more heteroatoms from the series O, N, S, P, As, Se is interrupted and / or substituted,
R¹³ represents a hydrogen atom or an alcohol protecting group,
D for a radical -SR¹⁴, wherein
R¹⁴ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a sulfur protecting group,
or in the event that B represents a radical SR¹¹, also for a radical -NHR¹⁶ or -OR¹⁷, wherein
R¹⁶ is a hydrogen atom, an amino protecting group or a branched or straight-chain, cyclic or polycyclic C _1-30 - alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl group, which are optionally with Hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally substituted by one or more heteroatoms from the series O, N, S, P, As, Se is interrupted and / or substituted,
R¹⁷ represents a hydrogen atom or an alcohol protecting group. 2. Compounds according to claim 1, characterized in that n and m each represent 1. 3. Compounds according to claim 1 or 2, characterized characterized in that R¹, R², R⁵, R⁶, R⁸, R⁹ and R¹⁰ Represent hydrogen atoms. 4. Compounds according to claim 3, characterized in that R³ and R⁴ each represent a hydrogen atom and R⁷ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a radical -CO-R¹⁵,
wherein R¹⁵ is a hydroxyl, a branched or straight-chain C _1-30 alkoxy or an N (RaR ^b ) group,
where Ra and R ^{b are the} same or different and / or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C _1-30 -alkyl radical, which may be substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, Alkoxycarbonyl, amino or alkoxy groups with up to 20 carbon atoms is substituted and / or optionally interrupted and / or substituted by one or more heteroatoms from the series O, N, S. 5. Ligands of the general formula (II) B-CR¹R²- (CR³R⁴) _{n = 1.2} -S-CHR⁵-CHR⁶-SO₂-NH-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1.2} -D (II) where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, n, m, B and D each have the meaning given in claim 1. 6. Ligand according to claim 5, characterized in that n and m each represent 1. 7. Ligand according to claim 5 or 6, characterized net that R¹, R², R⁵, R⁶, R⁸, R⁹ and R¹⁰ are hydrogen represent atoms. 8. ligand according to claim 7, characterized in that R⁷ represents a hydrogen atom, a branched or unbranched C _1-6 alkyl radical or a radical -CO-R¹⁵,
wherein R¹⁵ is a hydroxyl, a branched or straight-chain C _1-30 alkoxy or an N (RaR ^b ) group,
where Ra and R ^{b are the} same or different and / or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C _1-30 alkyl radical, optionally with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl -, Amino or alkoxy groups with up to 20 carbon atoms is substituted and / or optionally interrupted and / or substituted by one or more heteroatoms from the series O, N, S. 9. Conjugates containing a compound of the general Formula (I and / or II) and selectively in diseased tissue-enriching substances, whereby there is a covalent bond between them and this in the case of carboxyl or amino groups containing substances such as naturally occurring or modified oligonucleotides in which the Degradation through naturally occurring nucleases is prevented or difficult, peptides, proteins, Antibodies or their fragments amidic or in In the case of substances containing hydroxyl groups, such as Fatty alcohols ester-like or in the case of Substances containing aldehyde groups imidically is present. 10. Conjugates according to claim 9, characterized in that that those accumulating in diseased tissue Substances peptides such as endotheline, partial sequences of Endothelin, endothelin analogue, 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, characterized in that the peptides have the following sequences or parts thereof 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-Le u-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,
the partial sequences
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,
or the cyclic amino acid sequences
Cyclo- (DTrp-DAsp-Pro-DVal-Leu),
Cyclo- (DGlu-Ala-alloDIle-Leu-DTrp)
exhibit. 12. A process for the preparation of a compound of general formula (I), characterized in that technetium-99m or Re in the form of pertechnetate or perrhenate 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) _{m = 1,2} -D (II) where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, n, m, B and D have the meaning given in claim 1,
implements. 13. A process for the preparation of ligands of the general formula (II), characterized in that 2-chloroethane-sulfonyl chloride optionally substituted with R sulf and R⁶ in a manner known per se in an aprotic solvent with addition of a suitable base with compounds of the general formula ( III) H₂N-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1,2} -D (III) in which R⁷, R⁸, R⁹, R¹⁰, m and D have the meaning given in claim 1,
at temperatures from -20 ° to 180 ° C to compounds of the general formula (IV) R⁵HC = CR⁶-SO₂-NH-CR⁷R⁸- (CR⁹R¹⁰) _{m = 1,2} -D (IV) wherein R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, m and D have the meaning given in claim 1,
implements
and these compounds of the general formula (IV) optionally with the addition of a suitable auxiliary base at temperatures from 200 to 180 ° C in a manner known per se with compounds of the general formula (V) BCR¹R²- (CR³R⁴) _{n = 1.2} -SH (V ) wherein R¹, R², R³, R⁴, n, and B have the meaning given in claim 1,
implements
and any protective groups present are split off in a manner known per se. 14. Kit for the production of radiopharmaceuticals, consisting of a compound of the general formula (II) according to one of claims 5 to 8 or a conjugate according to one of claims 9 to 11 and one Reducing agent and optionally one Auxiliary ligands that are in the dry state or in  Solution available, as well as an instruction manual with a reaction regulation for the implementation of the described compounds with Technetium-99m or Re in the form of a pertechnetate solution or Perrhenate solution. 15. Radiopharmaceutical composition for not invasive in vivo representation of organs, receptors and tissue containing receptor and / or athero sclerotic plaques, characterized in that a connection according to one of claims 1 to 4 or a conjugate according to claims 9 to 11 as well as, if necessary, with the galenics usual Contains additives, the compound in a kit according to claim 14 with Technetium-99m or Re in the form a pertechnetate or perrhenate solution becomes. 16. procedure for radiodiagnostic examination, characterized in that a radiopharmaceutical The composition of claim 15 in an amount of 0.1 to 30 mCi, preferably from 0.5 to 10 mCi per 70 kg body weight administered to a patient and the radiation emitted by the patient is recorded becomes.