EP0851771A2 - N2s2-type bi-functional nicotinamide chelating agents for radioactive isotopes - Google Patents

Abstract

The invention pertains to novel compounds of general formula (I) in which M stands for a radioisotope of Tc or Re, L stands for a ligand of general formula (II) in which R?1, R2, R3, R4, R5 and R6¿ can have different meanings and stand for groups which are suitable both for the coordinate bonding of metal ions and for coupling to selectively self-concentrating compounds. The novel compounds are used to form complexes of technetium and rhenium and are used in medical diagnostics and therapy.

Description

Bifunctional N ₂ S ₂ nicotinamide chelating agents for radioactive isotopes

The invention relates to new chelating agents containing nicotinamides, pharmaceutical compositions containing these compounds, their use in radiodiagnostics and radiotherapy, processes for the production of these compounds and compositions, and conjugates of these compounds with substances which accumulate selectively in diseased tissue, in particular peptides.

The use of radiopharmaceuticals for diagnostic and therapeutic purposes has long been known in the field of biological and medical research. In particular, radiopharmaceuticals are used to represent certain structures such as the skeleton, organs or tissues. The diagnostic application presupposes the use of such radioactive agents, which are specific to those after application

Enrich structures in the patient to be examined. These locally accumulating radioactive agents can then be tracked, plotted or scintigraphed using suitable detectors, such as scintillation cameras or other suitable recording methods. The distribution and relative intensity of the detected radioactive agent characterizes the location of a structure in which the radioactive agent is located and can be the presence of abnormalities in structure and function, pathological

Represent changes etc. Similarly, radiopharmaceuticals can be used as therapeutic agents to irradiate certain pathological tissues or areas. Such treatment requires the production of radioactive therapeutic agents that accumulate in certain structures, tissues or organs. 4

Ion solutions or normal plasma ions such as Ca2 +, Na ⁺ , K ⁺ and Mg ²⁺ .

Since technetium can exist in a number of oxidation states (+7 to -1), it is often necessary for radiopharmaceutical agents to contain additional agents known as stabilizers. These keep the radionuclide in a stable form until it has reacted with the ligand. These stabilizers can include agents known as transfer or auxiliary ligands that are particularly useful in stabilizing and complexing the metal in a well-defined oxidation state 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 below.

Radionuclide is the standard

Radiopharmaceuticals are shown by first synthesizing the ligand and then reacting it with the metal radionuclide in a suitable manner in order to form a corresponding complex in which the ligand must necessarily be present unchanged after complexation, with the exception of the splitting off of any protective groups or hydrogen ions that may be present. Removal of these groups facilitates coordination of the ligand to the 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 by using suitable reducing agents (eg SnCl2, ^s 2 ° 4 ^{2 ~} etc.), which is then converted by a suitable one

Chelator is stabilized. Because technetium in a row Complex formation conditions implemented. If, for example, the production of a technetium-99m radiopharmaceutical is desired, the ligand 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 suitably administered to the patient by injection, inhalation or ingestion.

The solutions containing the radionuclide can, as in the case of technetium-99m, be obtained from an available Mo-99 / Tc-99m nuclide generator, or can be obtained from a manufacturer, as in the case of rhenium-186. The complex formation reaction is carried out at suitable temperatures (e.g. 20 ° -100 ° C) within a few minutes to several hours. In order to ensure complete complex formation, a large excess of more than 100-fold excess to the metal radionuclide) of the ligand produced and a sufficient amount of reducing agent are required for a complete reduction of the radionuclide used.

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, for example tris (hydroxymethyl) aminoethane (or their salts), phosphate, citrate, bicarbonate etc., sterile water, physiological saline, isotonic chloride or dicarbonate 6

Suitable complexing agents for technetium and rhenium isotopes are e.g. cyclic amines as described by Volkert et al. (Appl. Radiol. Isot. 1982, 33; 891) and Troutner et al. (J. Nucl. Med. 1980, 21; 443), but they have the disadvantage that they are often only able to bind technetium-99m in good yields from a pH> 9. N2θ2 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 the major disadvantage of HMPAO is their low complex stability. Because of its instability (Ballinger, JR et al., Appl. Radiat. Isot. 1991, 42; 315, Billinghurst, MW et al., Appl. Radiat. Isot. 1991, 42; 607), Tc-99m-HMPAO must be used within 30 minutes after it has been marked so that the proportion of decay products that have a different pharmacokinetics and excretion can be kept low. Such radiochemical contaminants make it difficult to identify diseases to be diagnosed. A coupling of these chelates or

Chelating agents to other substances that accumulate selectively in foci of disease cannot be solved by simple means, so that these are generally distributed nonspecifically in the organism.

N2S2 chelators (Bormans, G. et al.; Nucl. Med. Biol. 1990, 17; 499) such as e.g. Ethylene dicysteine (EC; Verbruggen, AM et al .; J. Nucl. Med. 1992, 33; 551) meet the requirement for adequate stability of the corresponding technetium-99m complex, but only form when the pH of the complexing medium is> 9 Radio diagnostics with a purity greater than 69%. N3S systems (Fritzburg, A.; EP-0173424 and EP-0250013) form stable technetium-99m complexes, but must be used to form a uniform radiopharmaceutical

Temperatures of about 100 ° C are heated. of oxidation levels (+7 to -1), which can change the pharmacological properties by changing the charges of a complex, it is necessary to provide chelators or complex ligands for technetium-99m, which technetium safely, firmly and stably in a defined Can bind oxidation level 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 in vivo diagnostics as well as therapy depends on the specificity and the selectivity of the labeled chelates to the target cell. These properties can be improved by coupling the chelates to biomolecules according to the "drug targeting" principle. Antibodies, their fragments, hormones, growth factors and substrates of receptors and enzymes are suitable biomolecules. The British patent application GB 2,109,407 describes the use of radioactively labeled monoclonal antibodies against tumor-associated antigens for tumor diagnosis in vivo. Likewise, direct protein labels via donor groups (amino, amide, thiol, etc.) of the protein (Rhodes, BA et al., J. Nukl. Med. 1986, 27 685-693) or by introducing complexing agents ( U.S. Patent 4,479,930 and Fritzberg, AR et al., Nucl. Med. 1986, 27, 957) with technetium-99m. However, these experimental methods are not available for clinical use because on the one hand the selectivity is too low and on the other hand the background activity in the organism is too high to enable in vivo imaging. 8th

To be able to adapt the coupling partner with regard to its lipophilicity, membrane permeability, etc.

The invention is therefore based on the object of stable complex compounds which are coupled or capable of

Coupling to different selectively enriching compounds are to be made available without their specificity and selectivity being significantly affected. In addition, there is the task of providing couplable chelators or complexes which have a greater chemical range of variation of the substituents in order to be able to adapt them to the requirements referred to above. At the same time, the requirements for the use of these compounds in humans with regard to the absorbed radiation dose,

Stability and solubility of the compounds must be fulfilled.

This object is achieved according to the invention in that new, bifunctional, thiol-substituted nicotinamides containing chelating agents and their coupling products with specifically enriching compounds are made available.

The invention relates to compounds of the 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) In recent years, the need for radio-diagnostic agents specifically enriching in diseased tissues has increased. This can be achieved if complexing agents can easily be coupled to selectively enriching substances and do not lose their favorable complexing properties. However, since it often happens that after coupling a complexing agent using one of its functional groups to such a molecule, a weakening of the complex stability is observed, the previous approaches for coupling chelating agents to substances that selectively enrich themselves are not very satisfactory, since a diagnostically not tolerable proportion of the isotope from the conjugate is released in vivo (Brechbiel, MW et al.; Inorg. chem. 1986, 25, 2772). It is therefore necessary to prepare bifunctional complexing agents which carry both functional groups for binding the desired metal ion and one (other, several) functional group for binding the selectively enriching molecule. Such bifunctional ligands enable a specific, chemically defined binding of technetium or rhenium isotopes to a wide variety of biological materials, even if so-called prelabeling is carried out. Some chelating agents coupled to monoclonal antibodies (eg EP-0247866 and EP-0188256) or fatty acids (EP-0200492) have been described. However, the previously mentioned N2S2 systems are used as chelating agents, which are not very suitable due to their low stability. Since both the selectively accumulating substances in their properties, as well as the mechanisms by which they are enriched, are very different, it is still necessary to vary the couplable chelating agent and the physiological requirements of the 10

straight-chain, cyclic or polycyclic C ₁ _30-alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl radical, optionally with hydroxy, oxy, oxo, carboxy, aminocarbonyl,

Alkoxycarbonyl, amino, aldehyde 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 0, N, S, P, As, Se ,

R ⁵ and R ^ are the same or different and each represents a hydrogen atom, a branched or unbranched C 1-6 alkyl radical or a sulfur protecting group.

Preferred compounds of the general formula (I) are distinguished in that R ¹ and R ^{3 are} hydrogen atoms.

Particularly preferred compounds of the general formula (I) are characterized in that R ¹ , R ² and R ³

Are hydrogen atoms and R ⁴ for a radical -CO-R ⁷ , wherein

R ^{7 is} a hydroxyl, a branched or straight-chain, cyclic or polycyclic C _] _.39 alkoxy, alkenyloxy, polyalkenyloxy, alkynyloxy,

Polyalkynyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, optionally substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or possibly by one or more L ⁴

(I I)

means what

R ¹ and R ^{3 are the} same or different and each represents a hydrogen atom and / or a branched or unbranched C 1-4 alkyl radical or together represent an optionally substituted, saturated or unsaturated, aliphatic or aromatic C3_g cycle,

R ² and R ^{4 are the} same or different and each for a hydrogen atom, for a branched or unbranched C _] __g alkyl radical or a radical -CO-R ⁷ , in which

R ^{7 is} a hydroxyl, a branched or straight-chain, cyclic or polycyclic C ^ _3 Q-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 is substituted and / or optionally interrupted and / or substituted by one or more heteroatoms from the series 0, N, S, P, As, Se and optionally together one Form anhydride or represents an N (R ^a R ^b ) group, where R ^a and R ^ are the same or different and / or a hydrogen atom, a branched or 12

Particularly preferred are ligands according to the invention in which R ¹ , R ² and R ^{3 are} hydrogen atoms and R ^{4 represents} a radical -CO-R ⁷ , in which

R ^{7 represents} a hydroxyl, a branched or straight-chain, cyclic or polycyclic C] _. 30-alkoxy, alkenyloxy, polyalkenyloxy, alkynyloxy, polyalkynyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which may optionally be substituted 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 or a

N is (R ^a R ^b ) group, wherein

R ^a and R ^{b are the} same or different and / or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C _] __3o-alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl radical , optionally with hydroxy, oxy, oxo, carboxy, aminocarbonyl,

Alkoxycarbonyl, amino, aldehyde 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 0, N, S, P, As, Se.

The invention further relates to conjugates containing a compound of the general formula (I and / or II) and substances which accumulate selectively in diseased tissue, with a Heteroatoms from the series O, N, S, P, As, Se is interrupted and / or substituted or is an N (R ^a R ^b ) group, where R ^a and R ^{b are} identical or different and / or a hydrogen atom, a branched or straight-chain, cyclic or polycyclic Cι_30-alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl radical, 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.

The invention further relates to the new bifunctional thiol-substituted nicotinamide ligands of the general formula (II)

(ι ι)

wherein

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ the above

Have meaning.

Ligands of the general formula (II) in which R ¹ and R ^{3 are} hydrogen atoms are preferred. 14

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,

Cys-Val-Tyr-Phe-Cys-His-Gln-Asp-Val-Ile-Trp,

N-acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Gln-Asp-Val-Ile-Trp,

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu,

Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu,

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe,

Arg-Val-Tyr-Ile-His-Pro-Phe, there is a convex bond and this in the case of substances containing carboxyl or amino groups, such as naturally occurring or modified oligonucleotides in which the degradation is prevented or made difficult by naturally occurring nucleases, peptides, proteins, antibodies or their fragments amidically 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.

Particularly preferred conjugates are characterized in that the substances accumulating in the diseased tissue include peptides such as endotheline, partial sequences of endothelin, endothelin analogs, endothelin derivatives, endothelin antagonists or angiotensins, partial sequences of angiotensins, angiotensin analogs, angiotensin derivatives and Angiotensin antagonists mean.

In further 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 ' ₁

Phe-Cys-His-Leu-Asp-Ile-Ile-Trp,

Cys-Ser-Cys-Ser-Ser-Trp-Leu-Asp-Lys-Glu-Cys-Val-Tyr-

Phe-Cys-His-Leu-Asp-Ile-Ile-Trp,

Cys-Thr-Cys-Phe-Thr-Tyr-Lys-Asp-Lys-Glu-Cys-Val-Tyr-

Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, 16

(ι ι)

wherein

R ¹ and R ^{3 are the} same or different and each represent a hydrogen atom and / or a branched or unbranched C ^ - ζ-alkyl radical or together an optionally substituted, saturated or unsaturated, aliphatic or aromatic C3_g cycle,

R ² and R ^{4 are the} same or different and each represents a hydrogen atom, a branched or unbranched C 1 -C 6 -alkyl radical or a radical -CO-R ⁷ , in which

R ^{7 is} a hydroxyl- a branched or straight-chain, cyclic or polycyclic C ^ _3 _Q -alkoxy-, alkenyloxy-, polyalkenyloxy-,

Alkynyloxy, polyalkynyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which is optionally substituted with hydroxyl, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups having up to 20 carbon atoms and / or optionally interrupted and / or substituted by one or more heteroatoms from the series 0, N, S, P, As, Se and optionally together form a carboxylic anhydride or an N (R ^a R ^b ) group, where R ^a and R ^{b are the} same or different and / or a hydrogen atom, a branched or straight-chain, cyclic or 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 .

The present invention furthermore further relates to compounds of the general formula (II) 18th

Carboxyl group activated in a manner known per se and in an aprotic solvent with the addition of a suitable base with compounds of the general formula (III)

H ₂ N-CR ¹ R ² -CR ³ R ⁴ -NH ₂

(III)

wherein R ¹ , R ² , R ³ and R ^{4 have} the meaning given above,

at temperatures from -20 ° C to 180 ° C to compounds of general formula (II)

( ^M )

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meaning given in claim 1,

implements

and any protective groups present are split off in a manner known per se.

The invention furthermore relates to kits which are used to produce radiopharmaceuticals, consisting of a compound of the general formula (II) or a conjugate according to the invention containing compounds of the general formula (I and / or II) and substances which accumulate selectively in tissues, a Reducing agent and optionally an auxiliary ligand, which are in the dry state or in solution, and one represent polycyclic C _] __3 _Q -alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl radicals which may be combined with hydroxyl, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, Amino,

Aldehyde 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, P, As, Se,

R ⁵ and R ^{6 are the} same or different and each represents a hydrogen atom, a branched or unbranched C 1 -C 6 -alkyl radical or a sulfur protecting group,

their conjugates with substances which selectively accumulate in diseased tissue, a covalent bond being formed between them and peptides in the case of substances containing carboxyl or amino groups such as naturally occurring or modified oligonucleotides in which the degradation is prevented or made more difficult by naturally occurring nucleases 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

and their complexes with radioisotopes of Tc and Re

The compounds of the general formula (II) according to the invention are prepared by protecting the free thiol function of 2-mercaptonicotinic acid in a manner known per se and then protecting the 20th

The chelates and chelating agents described in the present invention are thus clearly more suitable for diagnostic and therapeutic purposes than the previously known systems. The mild marking conditions are a particular advantage. Thus, after the protective groups have been split off, the ligands according to the invention and their coupling products can be labeled on substances which accumulate selectively in diseased tissues at room temperature and at a physiological pH. The choice of suitable protective groups, which can be split off with different reaction conditions depending on the coupling product, always ensures that undesired side reactions cannot occur during the purification of the coupling products. This ensures that no undesired crosslinking reactions or oxidation of free sulfhydryl groups to form disulfides

Cleaning conditions occur. Such changes often have an adverse effect on the labeling yield and radiochemical purity and thus also on the background due to non-specifically bound technetium. Sulfur protecting groups are established or split off using methods known to the person skilled in the art. Another major advantage of the compounds according to the invention is the high

Stability of the free aromatic thiols, which makes special protective measures (eg protective gas atmosphere) unnecessary when handling the coupling products. The coupling to substances which accumulate selectively in diseased tissues also takes place according to methods known per se to the person skilled in the art (for example Fritzberg et al.; J. Nucl. Med. 26, 7 (1987)), for example by reacting electrophilic groups of the complex ligand with nucleophiles Centers of substances that accumulate selectively in diseased tissues or by reaction of nucleophilic groups of the chelator with electrophilic ones Instructions for use with a reaction instruction for the implementation of the described compounds with Technetium-99m or Re in the form of a pertechnetate solution or perrhenate solution.

The invention also relates to a radiopharmaceutical composition for the non-invasive in vivo presentation of organs, receptors and receptor-containing tissue and / or of atherosclerotic plaques, which contain a compound of the general formula (I) or a conjugate according to the invention containing compounds of the general formula (I and / or II) and contains substances which accumulate selectively in tissues, optionally with the additives customary in galenics, the compound being in a kit with

Technetium-99m or Re is prepared in the form of a pertechnetate or perrhenate solution.

In a method for performing a radio-diagnostic examination, 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 emitted by the patient is recorded.

Surprisingly, many of the chelates synthesized and labeled with technetium-99m or Re show a higher stability than comparable N2S2 and N3S systems which are described in the literature. For example, in the case of a substance according to the invention (example 2) which was coupled to an alkylamine, no decomposition products were observed after 24 h. It was also possible to determine by competition tests that the Tc-99m or re-chelators described in this invention are better than the comparable N2S2, N3S and

Complex propylene amine oxime systems. The in the 22

J.Nucl.Med. 30, 351, 1989). Finally, the 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 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 for the detection of atherosclerotic have proven favorable

Vascular diseases. These derivatives were applied to WHHL rabbits, which have high LDL concentrations in the blood due to a genetic defect in the LDL receptor and thus have atherosclerotic lesions. About 1 to 6 h after application of the derivatives in WHHL rabbits, a high accumulation in atherosclerotic plaques could be demonstrated. So far, only very late stages of atherogenesis have been diagnosed with invasive procedures. The compounds according to the invention therefore offer the decisive advantage of diagnosing much earlier stages of atherosclerosis using a non-invasive method.

It is immaterial whether the described chelating agents are labeled with technetium-99m before or after coupling to the selectively enriching molecule. For coupling to the selectively enriching molecule after complexation, however, it is a prerequisite that the reaction of the radioactive complex with the enriching compound proceeds quickly, under mild conditions and almost quantitatively, so that subsequent purification is not necessary.

The preparation of the pharmaceutical according to the invention

Means are carried out in a manner known per se, in which the Groups of substances that selectively accumulate in diseased tissues.

The coupling partners include different biomolecules used. So e.g. Ligands attached to specific

Binding receptors and thus showing changes in receptor density, these include Peptides,

Steroid hormones, growth factors and neurotransmitters.

Coupling products with steroid hormone receptor-affine 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, e.g. the "epidermal growth factor" (EgF). The concentration differences can be used for the selective enrichment of cytostatics

Use tumor cells (E.Abound-Pirak et al.;

Proc.Natl.Acad.Sei. USA 86, 3778, 1989). Other biomolecules are metabolites that can be introduced into the metabolism of the cells and indicate a changed metabolism; these include e.g. Fatty acids, saccharides, peptides and amino acids. Fatty acids coupled to the less stable N2S2 systems have been described in EP-0200492. Other metabolic products such as saccharides, deoxyglucose, lactate and amino acids (leucine, methyl methionine, glycine) have been used with the help of PET technology to depict changed metabolic processes (R. Weinreich, Swiss Med. 8, 10, 1986). Not even biological substances like

Misonidazole and its derivatives, which irreversibly bind to cell components in tissues or tissue parts with reduced oxygen concentration, can be used for the specific enrichment of radioactive isotopes and thus for the visual representation of tumors or ischemic regions (ME Shelton, 24

example 1

2- (S-piperonyl) mercaptonicotinic acid 1 1.55 g of anhydrous 2-mercaptonicotinic acid (10 mmol) are suspended in 10 ml of glacial acetic acid and added to this

2.28 g of the piperonyl alcohol (15 mmol) and 2.1 ml of BF3 diethyl etherate (15 mmol). The mixture is stirred at RT for 1-2 h, during which everything dissolves clearly. The mixture is then concentrated in a rotary damper at a bath temperature of 40 ° C. The oily residue is dissolved in ethyl acetate. The protected nicotinic acid derivative crystallizes out by trituration with diethyl ether. Yield: 72% Analysis: calc. : C 58.12 H 3.83 N 4.84 O 22.12 S 11.08 Found: C 57.77 H 3.92 N 4.65 S 11.01

2- (S-Piperonyl) mercaptonicotinic acid N-hydroxysuccinimido ester 2 To a solution of 2.89 g of acid 1 (10 mmol), 2.80 ml of triethylamine and 1.15 g of N-hydroxysuccinimide (10 mmol) in 50 ml of anhydrous dichloromethane, 2.27 g of DCC (11 mmol) in 50 ml of anhydrous dichloromethane are added dropwise with stirring at -10 ° C. and the mixture is stirred for 2 hours at 0 ° C. and 4 hours at room temperature. The mixture is then cooled to -20 ° C. and the urea which has precipitated is filtered off. After the solvent has been stripped off, the residue is chromatographed (silica gel, dichloromethane). Yield: 74% Analysis:

Ber. : C 55.96 H 3.65 N 7.25 O 24.85 S 8.30 Found: C 55.65 H 3.74 N 7.41 S 8.20

NN '-Bis \ 2 - (S-piperonyl) mercaptonicotincarbamoyll - ethylenediamine 3 Complexing agents 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 customary in galenicals - in aqueous medium and then sterile filtered. Suitable additives are, for example, physiologically harmless buffers (eg tromethamine), small additions of electrolytes (eg sodium chloride), stabilizers (eg gluconate, phosphates or phosphonates). The pharmaceutical composition according to the invention is in the form of a solution or in lyophilized form and is added shortly before application with a solution of 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 lxlO ^-5 to 5xl0 ⁴ nmol / kg body weight, preferably in amounts between lxlO ^"3 to 5xl0 ² 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, for therapeutic applications between 5 and 500 mCi, preferably 10 to 350 mCi. The application is normally carried out by intravenous, intraarterial, peritoneal or intertumor injection of 0.1 to 2 ml of a solution of the agents according to the invention, intravenous application is preferred.

The following examples serve to explain the subject of the invention in more detail. 26

N.N 'to r2-mercaptonicotincarbamoyl1 ethylenediamine.

Technetium-ggm complex

10 mg of compound 5 are dissolved in 1.0 ml of ethanol. 50 μl of this ligand solution are mixed with 250 μl of ethanol, 50 μl of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 μl of a deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 μl of a pertechnetate solution (400-1000 μCi) were added. After an incubation time of 10 min, the reaction mixture is examined by HPLC for the purity of the Tc complex formed: LiChrospher RP-18 column, 5μ, 125 x 4 mm;

Gradient elution from 100% A to 100% B within 15 min (eluent A: acetonitrile / sodium phosphate 5 mM, pH 2.0, 10/90); eluent B: acetonitrile / sodium phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is> 99%.

Example 2

2- (S-triphenylmethyl) mercaptonicotinic acid 5

1.55 g of anhydrous 2-mercaptonicotinic acid (10 mmol) are suspended in 10 ml of glacial acetic acid and about 2.6 g of triphenymethylcarbinol (10 mmol) and 2.1 ml of BF3 ~ diethyl etherate (15 mmol) are added. The mixture is stirred at RT for 1-2 h, during which everything dissolves clearly. The mixture is then concentrated in a rotary steamer at a bath temperature of 40 ° C. The oily residue is dissolved in ethyl acetate. The protected nicotinic acid derivative crystallizes out by trituration with diethyl ether. Yield: 90% Analysis:

Ber. : C 75.54 H 4.82 N 3.52 0 8.05 S 8.07 Found: C 75.06 H 4.93 N 3.64 S 8.18 At 0 ° C., 5.78 of the activated ester 2 (200 mmol) in a little anhydrous dichloromethane and 20.2 g of triethylamine (200 mmol) are added to a stirred solution of 6.01 g of ethylenediamine (100 mmol) in a little anhydrous dichloromethane. The mixture is stirred at 0 ° C. for 2 hours and at RT for a further 24 hours. It is then evaporated in vacuo and taken up in dichloromethane. It is washed twice with 0.5 N HCl and saturated sodium bicarbonate solution, dried over magnesium sulfate and the solvent is stripped off. The residue is crystallized by trituration with diethyl ether. Yield: 39% Analysis: C 59.79 H 4.35 N 9.30 O 15.93 S 10.64 C 59.61 H 4.45 N 9.24 S 10.52

N.N '-Bis \ 2-mercaptonicotincarbamoyll ethylenediamine 4 603 mg of the protected nicotinic acid derivative 3_ (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: 89% Analysis:

Ber. : C 50, 28 H 4, 22 N 16, 75 0 9, 57 S 19, 18

Ge f. : C 50, 20 H 4, 35 N 16, 56 S 19, 08 28

N.N '-Bis f2- (S-triphenylmethyl) mercaptonicotinrarbamnyl - diamingprgpjQnsäure 8

8.91 g of the ester are stirred in aqueous / ethanolic potassium hydroxide solution (4.0 g = 72 mmol KOH, 20 ml water, 40 ml ethanol) at RT for 6 h. Then it is diluted with water and with half-conc. HCl acidified. The precipitate is filtered off, washed and dried. Yield: 90% Analysis: calc. : C 73.76 H 4.91 N 6.49 0 7.42 S 7.43 Found: C 73.41 H 5.03 N 6.54 S 7.56

NN ¹ to r2-mercaptonicotincarbamoylldiaminopropionic acid R 9 863 mg of the acid £ (1 mmol) are 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 treated. After evaporation of the acid, the remaining residue is taken up in ethyl acetate and washed with sodium hydrogen carbonate solution and water and dried over sodium sulfate. After the solvent has been stripped off, a slowly crystallizing oil remains. Yield: 43% Analysis: calc. : C 47.61 H 3.73 N 14.81 O 16.91 S 16.95 Found: C 47.48 H 3.87 N 15.03 S 16.46

N.N 'to r2-mercaptonicotincarbamovl1diaminopropionic acid.

Technetium-99m complex

10 mg of compound 5_ 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 of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 μl of a deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 μl one Pertechnetate solution (400-1000 μCi) added. The reaction mixture is after a

Incubation time of 10 min using HPLC for purity 2- (S-triphenylmethyl) mercaptonicotinic acid-N-hydτ-oxy-succinimidoester 6

To a solution of 3.97 g of acid 1 (10 mmol), 2.80 ml of triethylamine and 1.15 g of N-hydroxysuccinimide (10 mmol) in 50 ml of anhydrous dichloromethane are 2.16 g with stirring at -10 ° C. DCC (11 mmol) in 50 ml of anhydrous dichloromethane were added dropwise and the mixture was stirred at 0 ° C. for 2 hours and at room temperature for 4 hours. The mixture is then cooled to -20 ° C. and the urea which has precipitated is filtered off. After the solvent has been stripped off, the residue is chromatographed (silica gel, dichloromethane). Yield: 64% Analysis: calc. : C 70.43 H 4.48 N 5.66 0 12.94 S 6.48 Found: C 70.22 H 4.68 N 5.46 S 6.44

N.N '-Bis \ 2 - (S-triphenylmethyl) mercaptonicotincarbamoyll - diaminopropionic acid ethyl ester 7

9.89 g of the activated ester £ (20 mmol) in a little water-free dimethylforamide and then 5.05 g of triethylamine are added to a suspension of 2.05 diaminopropionic acid ethyl ester dihydrochloride (10 mmol) in a little anhydrous dimethylformamide at 0 ° C. (50 mmol) added. The mixture is stirred at 0 ° C. for 2 hours and at RT for a further 24 hours. It is then evaporated in vacuo and taken up in dichloromethane. It is washed twice with 0.5 N HCl and saturated sodium bicarbonate solution, dried over magnesium sulfate and the solvent is stripped off. The residue is chromatographed (silica gel, dichloromethane). Yield: 29% Analysis: C 74.13 H 5.20 N 6.29 0 7.18 S 7.20 C 73.83 H 5.45 N 6.34 S 7.28 30th

946 mg of the amide 2JL (1 mmol) are 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 evaporation of the acid, the remaining residue is taken up in dichloromethane and washed several times with water and dried. Chromatographic purification on silica gel with dichloromethane gives 272 mg of an oil. Yield: 59% Analysis: calc. : C 54.64 H 5.90 N 15.17 0 10.40 S 13.89 Found: C 55.04 H 6.03 N 15.43 S 13.66

N.N '- to T2-mercaptonicotincarbamoyπ diamino-propionic acid hexylamiri 11. Technetium-99m-Komp] ex 10 mg of the compound 11. are dissolved in 1.0 ml of ethanol. 50 μl of this ligand solution are mixed with 250 μl of ethanol, 50 μl of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 μl of a deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 μl of a pertechnetate solution (400-1000 μCi) were added. After an incubation time of 10 min, the reaction mixture is examined for the purity of the Tc complex formed by means of HPLC: LiChrospher RP-18 column, 5μ, 125 x 4.6 mm; Gradient elution from 100% A to 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 4

NN '-Bis \ 7 - (S-TriphenylmethyDmercaptonicotincarbamoyl 1 - ethylenediaminocarbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp 12 To a solution of 863 mg of acid £ (1 mmol), 280 μl triethylamine and 115 mg N -Hydroxysuccinimide (1.0 mmol) in 10 ml of anhydrous dichloromethane are added with stirring of the Tc complex formed examined: LiChrospher RP-18 column, 5μ, 125 x 4.6 mm; Gradient elution from 100% A to 100% B within 15 min (eluent A: acetonitrile / sodium phosphate 5 mM, pH 2.0 (10/90); eluent B: acetonitrile / sodium phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is> 97%.

Example 3

N.N '-Bis \ 2 - (S-Triphenylmetyhl) mercaptoniπotinnarbamoyl 1 - diaminopropionic acid hexylamide 10

To a solution of 4.32 g of the acid £ (5 mmol), 1.5 ml of triethylamine and 575 mg of N-hydroxysuccinimide (5 mmol) in 100 ml of anhydrous dichloromethane, 1.13 g of DCC ( 5.5 mmol) in 25 ml of anhydrous dichloromethane was added dropwise and the mixture was stirred at 0 ° C. for 2 hours. A solution of 506 mg of hexylamine (5 mmol) in dichloromethane is then added dropwise within 30 minutes. The mixture is first stirred at 0 ° C. for a further 2 hours and stirred at room temperature for 12 hours. The product is filtered off from the urea and the filtrate is evaporated in vacuo and taken up in dichloromethane. After renewed filtration, it is washed twice with 0.5 N HCl and saturated sodium bicarbonate solution

Magnesium sulfate dried and the solvent removed. The residue is crystallized by trituration with diethyl ether. Yield: 81% Analysis:

Ber. : C 74.89 H 5.86 N 7.40 O 5.07 S 6.78 Found: C 74.71 H 5.98 N 7.31 S 6.91

NN 'to T2-mercaptonicotincarbamoyll diamino-propionsänrehexvlamid 11 32

N.N '-Bis r2-mercaptonicotincarbamovl1 ethylene-diaminocarbonyl -D-Trp-Leu-Asp-I] e-Ile-Trp. Technetium-99m complex

10 mg of compound 12 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 of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 μl of a deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 μl one Pertechnetate solution (400-1000 μCi) added. The reaction mixture is after a

Incubation time of 10 min examined by HPLC for the purity of the Tc complex formed: LiChrospher RP-18 column, 5μ, 125 x 4.6 mm; Gradient elution from 100% A to 100% B within 15 min (eluent A: acetonitrile / sodium phosphate 5 mM, pH 2.0 (10/90); eluent B: acetonitrile / sodium phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is> 96%.

Example 5

Diaminosuccinic acid ethyl ester 14

In the mixture of 5 g of diaminosuccinic acid (34 mmol) and 100 ml of ethanol, 1.5 h of dry HCl gas are introduced with stirring and the mixture is heated to boiling for 6 h. To

Cooling to room temperature, the solvent is removed. There remain 6.97 g of white crystals.

Yield: 74%

Analysis: Ber. : C 34.67 H 6.55 N 10.11 O 23.09

Found: C 34.82 H 6.71 N 9.96

NN '-Bis \ 2 - Lq-Tri.phenylmethyl) mercaptonicotincarbamoyll diamino-succinic acid ethyl ester 15 To a stirred solution of 2.77 g 2JL (10 mmol) in a little anhydrous THF at 0 ° C 744 mg of the activated -10 ° C. 211 mg of DCC (1.1 mmol) in 5 ml of anhydrous dichloromethane were added dropwise and the mixture was stirred at 0 ° C. for 2 hours. A solution of 845 mg of H2N-D-Trp-Leu-Asp-Ile-Ile-Trp-COOH (1 mmol) and DMF is then added dropwise within 30 minutes. The mixture is first stirred at 0 ° C. for a further 2 hours and stirred at room temperature for 12 hours. The product is filtered off from the urea 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 bicarbonate solution, dried over magnesium sulfate and the solvent is stripped off. The residue is crystallized by trituration with diethyl ether. Yield: 36% Analysis:

Ber. : C 68, 94 H 5, 96 N 9, 95 0 11, 36 S 3, 80

Gef. : C 70, 02 H 6, 08 N 9, 78 S 3, 52

N.N '-Bis r∑-mercaptonicotincarbamoyll ethylene-diaminocarbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp 13

1.69 g of the peptide 12 (1 mmol) is treated for 45 minutes at 0 ° C. with 20 ml of anhydrous HF in the presence of 5 ml of anisole and 3.5 ml of diethyl sulfide. After the acid 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 579 mg of an oil. Yield: 48% Analysis: calc. : C 58.79 H 6.02 N 13.94 O 15.93 S 5.32 Found: C 58.39 H 6.31 N 13.88 S 5.22 34

Analysis:

Ber. : C 72.95 H 4.54 N 6.30 0 9.00 S 7.21

Found: C 72.65 H 4.67 N 6.11 S 7.44

NN ¹ -Bis \ 2 - (S-triphenylmethyl) mercaptonicotincarbamoyl 1 - 2.3-diamino-2-tcarbonyl (Val-Tyr-Ile-His-Pro-Phe) - propionic acid 18

The solution of 775 mg of the peptide H2N-Val-Tyr-Ile-His-Pro is added to a solution of 889 mg of the acid anhydride and 505 mg of triethylamine in anhydrous dimethylformamide.

Phe-COOH slowly added in a little dimethylformamide and stirred for 24 hours at room temperature. The solvent is then stripped off in vacuo and the residue is crystallized by trituration with diethyl ether. Yield: 31% Analysis:

Ber. : C 67.85 H 5.69 N 10.10 0 12.50 S 3.85 Found: C 67.54 H 5.78 N 10.01 S 3.47

NN '-Bis \ 2-mercaptonicotincarbamoyll -2.3-diamino-2-tcarbonyl (Val-Tyr-Ile-His-Pro-Phe) 1-propionic acid 19 1.66 g of the peptide 12 (1 mmol) is at 45 ° C for 45 minutes treated with 20 ml of anhydrous HF in the presence of 5 ml of anisole and 3.5 ml of diethyl sulfide. After evaporation of the acid, the remaining residue is taken up in 5% acetic acid and washed several times with diethyl ether and lyophilized. Chromatographic purification on Sephadex G-10 with 0.2 M acetic acid gives 636 mg of an oil. Yield: 54% Analysis:

Ber. : C 57.03 H 5.64 N 14.25 O 17.64 S 5.44 Found: C 57.23 H 5.71 N 14.18 S 5.23

NN '-Bis \ 2-mercaptonicotincarbamoyll ethylene-diaminocarbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp. Technetium-99m complex Ester (20 mmol) in a little anhydrous THF and 2.02 g triethylamine (20 mmol) were added. The mixture is stirred at 0 ° C. for 2 hours and at RT for a further 24 hours. It is then evaporated in vacuo and taken up in dichloromethane. It is washed twice with 0.5 N HCl 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: 41% Analysis:

Ber. : C 72.33 H 5.23 N 5.82 0 9.97 S 6.66 Found: C 72.09 H 5.43 N 5.76 S 6.46

N.N '-Bis \ 2 - (S-triphenylmethyl) mercaptonicotincarbamoyll - diamino-succinic acid 16

5.87 of the ester are in aqueous / ethanolic potassium hydroxide solution

(4.0 g = 72 mmol KOH, 20 ml water, 40 ml ethanol) stirred at RT for 6 h. Then it is diluted with water and with half-conc. HCl acidified. The precipitate is filtered off, washed and dried.

Yield: 87%

Analysis:

Ber. : C 71.50 H 4.67 N 6.18 0 10.58 S 7.07 Found: C 70.94 H 4.85 N 6.16 S 7.11

NN ¹ -Bis \ 2 - (S-triphenylmethyl) mercaptonicotincarbamoyl 1 - diamino-succinic anhydride 17

3.32 g (5 mmol) of the succinic acid derivative and 1.17 g (15 mmol) of acetyl chloride are heated under reflux until the succinic acid derivative has completely dissolved. The excess acetyl chloride is removed in vacuo and the residue is dried over phosphorus pentoxide in vacuo and recrystallized from dichloromethane / petroleum ether. Yield: 81% 36

claims

Compounds of the general formula (I)

M (I)

wherein

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

(ι ι)

means what

R ¹ and R ^{3 are the} same or different and each represents a hydrogen atom and / or a branched or unbranched C ^ - ζ-alkyl radical or together an optionally substituted, saturated or unsaturated, aliphatic or aromatic C ^ - β cycle,

R ² and R ^{4 are} identical or different and each for a hydrogen atom, for a branched or unbranched C -g-alkyl radical or a radical -CO-R ⁷ , wherein

R ^{7 is} a hydroxyl, a branched or straight-chain, cyclic or polycyclic Cι_3n- alkoxy, alkenyloxy, polyalkenyloxy, mg of compound 12 are dissolved in 1.0 ml of ethanol. 50 ul of this ligand solution are mixed with 100 ul ethanol, 150 ul phosphate buffer pH 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 0.1 N HCl) and 100 μl of a pertechnetate solution (400-1000 μCi) are added. After an incubation time of 10 min, the reaction mixture is examined for the purity of the Tc complex formed by means of HPLC: LiChrospher RP-18 column, 5μ, 125 x 4.6 mm; Gradient elution from 100% A to 100% B within 15 min (eluent A: acetonitrile / sodium phosphate 5 mM, pH 2.0 (10/90); eluent B: acetonitrile / sodium phosphate 5 mM, pH 2.0 (75/25); 1 ml / min. The radiochemical purity is> 94%.

Claims

38

Compounds according to claim 2, characterized in that R ³ and R ^{4 are} different and R ³ for a hydrogen atom and R ⁴ for a radical -CO-R ⁷ , wherein

R ^{7 represents} a hydroxyl, a branched or straight-chain Cχ_30 alkoxy or an N (R ^a Rb) group, wherein

R ^a and R * - ^{1 are the} same or different and / or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C ^ .30-alkyl radical, which 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.

4. Compounds according to claim 2, characterized in that R ³ and R ^{4 are the} same and together form a carboxylic anhydride.

5. Ligands of the general formula (II)

(M) Alkynyloxy, polyalkynyloxy, aryloxy, alkylaryloxy or arylalkyloxy groups, optionally with hydroxyl, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20

Is substituted and / or optionally interrupted and / or substituted by one or more heteroatoms from the series O, N, S, P, As, Se and optionally together form a carboxylic acid anhydride or an N (R ^a R ^b ) group, where R ^a and R are the same or different and / or a hydrogen atom, a branched or straight-chain, cyclic or polycyclic Cι_3Q-alkyl, alkenyl,

Represent polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl, optionally with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde 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 0, N, S, P, As, Se,

R ⁵ and R ^{6 are the} same or different and each represents a hydrogen atom, a branched or unbranched Cx.g-alkyl radical or a sulfur protecting group.

2. Compounds according to claim 1, characterized in that R ¹ and R ^{2 represent} a hydrogen atom. 40

these in the case of substances containing carboxyl or amino groups, such as naturally occurring or modified oligonucleotides in which the degradation is prevented or made more difficult by naturally occurring nucleases, peptides, proteins, antibodies or their fragments amidic or, in the case of substances containing hydroxyl groups such as fatty alcohols, ester-like or is present in the case of substances containing aldehyde groups imidically.

10. Conjugates according to claim 9, characterized in that the substances accumulating in diseased tissue are 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 and chemotactic peptides mean.

11. Conjugates according to claim 7, characterized in that the peptides have the following sequences or parts thereof

i I

Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr

¹ 1

Phe-Cys-His-Leu-Asp-Ile-Ile-Trp,

I 1

Cys-Ser-Cys-Ser-Ser-Trp-Leu-Asp-Lys-Glu-Cys-Val-Tyr-

¹ 1

Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each have the meaning given in claim 1.

6. Ligands according to claim 5, characterized in that R ¹ and R ² are hydrogen.

7. Ligands according to claim 5 or 6, characterized ^ ³ and R ^{4 are} different and R ³ for a hydrogen atom and R ⁴ for a radical -CO-R ⁷ , wherein

R ^{7 is} a hydroxyl, a branched or straight-chain Cι_3Q alkoxy or an N (R ^a R ^) -

Group, where R ^a and ΉP are the same or different and / or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic Cι_30-alkyl radical, which 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 0, N, S.

8. Compounds according to claim 6, characterized in that R ³ and R ^{4 are the} same and together

Form carboxylic anhydride.

9. conjugates containing a compound of the general formula (I and / or II) and substances which accumulate selectively in diseased tissue, a covalent bond being present between them and 42

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 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,

I 1

Cys-Ser-Cys-Lys-Asp-Met-Thr-Asp-Lys-Glu-Cys-Leu-Asn-

¹ 1

Phe-Cys-His-Gln-Asp-Val-Ile-Trp,

I I

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,

Cys-Val-Tyr-Phe-Cys-His-Gln-Asp-Val-Ile-Trp,

N-acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Gln-Asp-Val-Ile-Trp,

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu,

Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, 44

(ι ι)

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 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 general formula (II) according to one of claims 5 to 8 or a conjugate according to one of claims 9 to 11 and a reducing agent and optionally one

Auxiliary ligands that are in the dry state or in solution, as well as instructions for use with a reaction instruction 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 the non-invasive in vivo presentation of organs, receptors and receptor-containing tissue and / or of atherosclerotic plaques, characterized in that it contains a compound according to one of claims 1 to 4 or a conjugate according to one of claims 9 to 11 and optionally with the additives customary in galenics, the compound being in a kit according to claim 14 with technetium-99m or Re or perrhenate in the presence of a reducing agent and optionally an auxiliary ligand with a compound of the general formula (II)

R ^{J 4}

(ι ι)

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meaning given in claim 1,

implements

13. A process for the preparation of ligands of the general formula (II), characterized in that S-protected nicotinic acid is converted in a manner known per se in an aprotic solvent with the addition of a suitable base into an optionally activated ester and then with compounds of the general formula (III)

H ₂ N-CR ¹ R ² -CR ³ R ⁴ -NH ₂

(III)

wherein R ¹ , R ² , R ³ and R ^{4 have} the meaning given in claim 1,

at temperatures from -20 ° to 180 ° C to compounds of the general formula (II) is prepared in the form of a pertechnetate or perrhenate solution.

16. A method for radiodiagnostic examination, characterized in that a radiopharmaceutical composition according to claim 15 in an amount of 0.1 to 30 mCi, preferably 0.5 to 10 mCi per 70 kg body weight is administered to a patient and the radiation emitted by the patient is recorded becomes.