EP0726909A1

EP0726909A1 - N-alkyl peptide chelate formers, their metal complexes with radionuclides, processes for producing them and radio-pharmaceutical compositions containing these compounds

Info

Publication number: EP0726909A1
Application number: EP95900059A
Authority: EP
Inventors: Hartmut Spies; Paul-Eberhard Schulze; Bernd Noll; Steffi Noll; Ludger Dinkelborg
Original assignee: Institut fuer Diagnostikforschung GmbH
Current assignee: Bayer Pharma AG
Priority date: 1993-11-01
Filing date: 1994-10-27
Publication date: 1996-08-21
Also published as: ZA948411B; DE4337600A1; KR960705842A; NO961743D0; CA2173844A1; CN1134158A; WO1995012610A1; HUT74881A; AU681919B2; JPH09508351A; AU8103894A; HU9601140D0; NO961743L

Abstract

The invention relates to N-alkyl peptide chelate formers, their metal complexes with radionuclides, processes for their production and radio-pharmaceutical compositions containing these compounds. The invention also relates to radio-pharmaceuticals containing these chelates in metal-complexed form, diagnostic kits in which the chelate may be present in non-complexed form and is complexed by the addition of either technetium or rhenium ions, and the use of such preparations for diagnostic and therapeutic purposes.

Description

N-Al yl peptide chelating agents, their metal complexes with radionuclides, processes for their preparation and radiopharmaceutical compositions containing these compounds

The invention relates to N-alkyl peptide chelating agents, their metal complexes with radionuclides, processes for their preparation and radiopharmaceutical compositions containing these compounds.

The invention further relates to radiopharmaceuticals which contain these chelates in a form complexed with metals, their diagnostic kits in which the chelate can be present in a non-complexed form and which is complexed either by adding technetium or rhenium ions and also via the use of such preparations for diagnostic and therapeutic purposes.

Radiolabelled substances are mainly used in medical diagnostics to prevent deformation and

Determine changes in the function of internal organs or changes in pathological processes in the body. For this application the patient is given a formulation, e.g. in the form of a solution for injection containing the radioactive substance. With suitable detectors (e.g. a gamma camera), pictures of organs, pathological processes and their changes in the body can be obtained by recording the emitted radiation; in the case of particularly high accumulations in organs or vessels, they serve as therapeutic agents.

In recent years, the desire grew to spezi¬ fishing, radiolabeled chemical compounds that bind to so-called carrier molecules (eg, steroids, Antikör- by, lipids, proteohormones etc.) can be coupled ^"and act" Targeting Drug "on the principle of . Of particular interest for tumor diagnosis and therapy as well as for the display of receptors (e.g. steroid conjugates,

REPLACEMENT LEAF Antibodies, etc.) are substances which are able to pass the cell wall and the blood-brain barrier and substances for checking organ functions, for example before and after transplants and for finding vascular lesions. With the aim of maintaining a higher selectivity of the radiopharmaceutical and a significant enrichment of a radionuclide in the target organ, complexing agents for a large number of radionuclides are increasingly being developed and coupled to tissue or metabolism-specific carrier molecules. For therapy, one is looking for ways to use a radioactive isotope of rhenium.

The most commonly used radionuclide is technetium-99m, which due to its favorable physical properties (no corpuscular radiation, favorable physical half-life, 140 KeV γ radiation) and the associated low radiation exposure is particularly suitable as an isotope for in-vivo diagnostics. Technetium-99m can be easily obtained from nuclide generators as [99m_ _c _ -pertechnetate. In order to obtain technetium-99m chelates, the pertechnetate is converted by suitable reducing agents (eg SnCl2, S2O4 ² ", etc.) into a lower oxidation state, in which the technetium-99m forms complexes with chelating agents or proteins. For marking potential chelating agents With technetium-99m and for the production of kits for routine clinical use, special processes have been developed and described, such that proteins can be directly donated via groups (amino, amide, thiol, etc.) of the protein (J. Nucl. Med 1986, 27, 685) or by introducing complexing agents (U.S. Patent 4,479,930 and Fritzberg, AR et al., J. Nucl. Med. 1986, 27, 957) with technetium-99m.

REPLACEMENT LEAF Complexing agents have also been developed from the group of cyclic amines (Troutner, DE et al.; J. Nucl. Med. 1980, 21, 443 and Mäcke, H.; DE-3 911 816), Cyclame (Ketring, AR; Troutner , DE et al.; J. Nucl. Med., 1980, 21, 443-448, Int. J. Nucl. Med. Biol. 1984, 11, 113, Volkert et al., Applied Radiat. Isot., 1982, 33, 891-896), N 0 ₂ systems (Pillai, MRA; Troutner, DE et al .; Inorg. Chem. 1990, 29, 1850) and also N2S2 systems (Bormans, G. et al.; Nucl Med. Biol. 1990, 17, 499) and N ₃ S systems (Fritzburg, A.; EP-A-0 173 424 and EP-A-0 250 013).

However, all of these complexing agents have considerable disadvantages. For the labeling of the cyclams as well as N2θ2 * systems known from the literature (Pillai, M.R.A. et al; Inorg. Chem. 1990, 29, 1850-1856), pH values of 10-13 are required. Furthermore, these systems do not have reactive groups which enable them to be linked to biomolecules or proteohormones. Although N2S2 and N3S systems have sufficient stability in individual cases, they are only suitable for simple excretion studies, such as urine excretion, EP-A-0 250 013. Efforts to produce the MAG3 (EP-A-0 250 013) known from the literature, which requires heating to 100 ° C. for marking (Bannister, KM et al.; J. Nucl. Med. 1990, 31, 1568-1573 ) are in progress (WO-91-16076), but have so far remained without clinical access.

For N2S2 complexes (Bormans, G. et al.; Nucl. Med. Biol. 1990, 17, 499), the shelf life between preparation and administration is less than 1 h and thus represents a serious disadvantage. Efforts to remedy deficiencies are therefore also under way here so far - without clinical relevance (Merryn, W. et al., Applied. Radiat. Isot. Vol. 42 (7), 607-612).

REPLACEMENT LEAF The complexing agents which have become known to date each have a uniform structure and can therefore also be used for diagnostic purposes only for one purpose. The molecular variations are limited to substituents on the basic structure and therefore do not allow a broad medical application as would be possible with a complex variation. They are therefore costly to manufacture and scientifically penetrate the individual complexes.

The object of the invention is to provide short-chain N-alkyl peptide chelating agents which complex with technetium and rhenium in a wide pH range at room temperature, both ionic and non-ionic complexes being formed and thus providing compounds which provide the Disadvantages of known ^99m Tc and ¹⁸⁰ ' ¹⁸⁸ Re complexes do not have.

At the same time, the requirements for the use of these compounds in humans with regard to radiation dose, stability and solubility must be fulfilled; at the same time, the simplest possible method for representing them and a kit formulation of these according to the invention must be created

Compounds / conjugates and their metal complexes are provided for their clinical use.

This object is achieved in that compounds of the general formula I

R ³ -S-CH ₂ -CO-NR ¹ - [CH ₂ -CO-NH] _n -CH ₂ -CO-R ² (I)

wherein

n represents a number 0, 1 or 2,

REPLACEMENT LEAF R ^{1 is} a straight-chain or branched alkyl radical having 1 to 20 carbon atoms, which is optionally interrupted or substituted by one to three oxygen atoms, and which optionally has a terminal -

COOH, -OH or -NH group, which is optionally esterified or etherified with glycolic acid or glycolic acid esters or ethers, the esters or ethers being formed with carboxylic acids or alcohols having up to 18 carbon atoms, or a phenyl or cyclohexyl radical which is optionally in the 4-position with a COOH, NH2 or OH group which is optionally esterified, etherified or amidated with carboxylic acids or alcohols having up to 6 carbon atoms or is substituted with a halogen atom,

R ^{2 represents} a halogen atom, a halomethyl, methyl-carboxyl, trifluoroethylcarboxyl, an NH2 * or an OH group, the carboxyl group formed in the case of R ² = OH either immediately or after esterification with an α, ω-hydroxycarboxylic acid with up to 8 carbon atoms via its terminal carboxyl group with a biomolecule, a steroid, an ergoline derivative, a benzodiazepine derivative, a cholecystokinin, a peptide, a protein, a proteohormone, an amino sugar, an endothelin, an endothelin derivative, an endothelin antagonist or an endothelin fragment is esterified or amidated,

in the rest of the general formula II

REPLACEMENT LEAF

or the general formula II a

is where

R ^{4 is} a methylene, propenylene amino, propinylene amino, methylene amino or methyleneoxy group and

R ^{8 means} a hydrogen atom or a methyl group,

a radical of the general formula III

or the general formula III a

REPLACEMENT LEAF

represents what

R ^{5 is} an -NH-, -NH-CO-N <, -NH-CO-NH or methyleneoxy group,

R ^{6 represents} a hydrogen atom, a halogen atom or a methyl group and

R ^{7 represents} a hydrogen atom or a straight-chain or branched alkyl radical having up to 6 carbon atoms,

R - * - is a hydrogen atom, an acetyl, benzoyl, p-methoxybenzyl, ace amidomethyl, benzamidornethyl, trimethylacetamidomethyl, hydroxyacetyl, ethoxyethyl, ethylthio, trityl or an easily removable sulfur protecting group

and their salts are provided with pharmaceutically acceptable acids or bases.

Surprisingly, a class of compounds was found which not only avoids the disadvantages mentioned, but also, as ^99m Tc ⁺⁵ complexes, a transition from N ₃ S -> N S0 -> S 0 ₂ -> N ₂ S2-N-alkyl peptide Complex system and can therefore be used in a wide range as complexing agents.

REPLACEMENT LEAF Formula IV shows an N3S-N-alkyl-peptide complex in the 99m _Tc _ _core (neutral)

R ³ S- CH2-CO-NR ¹ [CH ₂ -CO-NH] ₂ -CH ₂ -CO-R ² '

the formula V a N2θS-N-alkyl-peptide complex in the ^99m Tc core (neutral)

R ³ S-CH ₂ -CO-NR ¹ [CH ² -CO-NH] iC ^ -COOH,

formula VI a 02S2_N-alkyl-peptide complex in the ^99m Tc core (with negative charge)

R ³ S-CH ₂ -CO-NR ¹ [CH ₂ -CO-NH] ₀ -CH ₂ -COOH,

REPLACEMENT LEAF

and finally formula VII shows an N2S2 * -N-alkyl * peptide complex in ^99m Tc core (with positive charge) from R ³ S-CH ₂ -CO-NR ¹ [CH2-CO-NH] ₀ -CH ₂ -CO-R ² .

The complexes that result from the molecular variation show a surprising breadth and agreement with regard to their biological behavior. Compounds of this type, coupled to a bioligand, can be used for receptor display, which was previously the case

99m-p _c compounds has not been described and is outstandingly suitable for displaying plaques in vascular lesions and for measuring kidney function, it being possible for the compounds to be coupled in each case to bioactive ligands.

Preferred are compounds in which R ^{1 represents} a -CH ₂ - (CH ₂ ) _m -CH ₃ group with m = 1-14

REPLACEMENT LEAF or Rl is a phenyl, a p-phenylamine, a cyclohexylamine, p-hydroxyphenyl, 4-hydroxycyclohexyl, p-halophenyl or 4-halocyclohexyl group.

Also preferred are compounds of general formula I, wherein

R ^{1 is} equal to - (__H ₂ ) _q -00C-CH ₂ -00C- (CH ₂ ) r " ^CH 3,

where q and r each represent integers from 1 to 16.

Compounds of the general formula I are particularly preferred in which R ^{1 is} a straight-chain or branched alkyl radical having 1 to 6 carbon atoms or a P-bromophenyl radical.

Furthermore, compounds of the general formula I are preferred in which R ^{2 is} a radical of the general formula II

or the general formula II a

is where

REPLACEMENT LEAF R ^{4 is} a methylene, propenylamino, propinylamino, methylenamino or methyleneoxy group and

R ^{8 represents} a hydrogen atom or a methyl group.

Of these steroids, 17α-ethynyl estradiols or their 3-methyl ether are preferred.

A 17α-ethynyl group of estradiol can also be coupled to an ethene. The order of the ethyne and ethene groups is interchangeable; doubling the ethyne or ethene group is also advisable. It is important to have a minimum distance between the chelator and estradiol molecule, preferably a rigid ethyne or ethene group, so that the side chain cannot fold.

If the binding of I takes place in this preferred 17α position of the estradiol scaffold, no or only a slight decrease in the biological activity is to be expected in the chelate complex bioligand compounds obtained, as is the case for. B. in Epperly, M.W. et al [J. Steriod biochem. Molec. Biol. Vol. 39, No. 5A, 729-734, 1991].

The outstanding importance of these estrogen-chelate complexes lies in their peculiarity of penetrating the cell wall and attaching to the estrogen receptor. This applies in particular to complexing agents according to general formula I in which n = 2. At 99m ^* p _c +5 _s ± _nc \ these N3S complexes are neutral as a result of the N ¹ alkylation in the Tc core (see formula IV). While charged complexes are unable to penetrate the cell wall, e.g. B. N3S-K01T1 plex as a steroid 17α-ethynyl chelate, of the thioacetyl-glycyl-glycyl-glycyl-O-ester type (own experiments), penetrate the N - * - alkylated complexes according to the invention (N ¹ = methyl ) the cell wall and accumulate after iv

REPLACEMENT LEAF Injection in the uterus. The enrichment, expressed as the quotient between blood / uterus, is 0.2 and can be varied depending on the N ** alkyl chain length or substituents. Mamma-ca early detection using the SPECT method is thus possible. The compound according to Example 10 is particularly preferred here.

Compounds of the general formula I in which R ^{2 is} a radical of the

general formula III

or the general formula III a

is where

R ^{5 is} an -NH-, -NH-CO-N <, -NH-CO-NH or methylene oxy group,

REPLACEMENT LEAF R ^{6 represents} a hydrogen atom, a halogen atom or a methyl group and

R ^{7 represent} a straight-chain or branched alkyl radical having up to 6 carbon atoms.

These compounds of general formulas III and III a are ergoline derivatives.

Of these ergolines, the 8α-amino-6-methyl-ergoline is optionally with alkyl substituents in the 2- and / or 6-position with a chain length of C * j_ in the 2 position or Cι_3 in the 6 position and / or a methyl or halogen substituents in position 2 are preferred. In addition to αNH ₂ , the substituent in the 8-position of ergoline can also be ß-CH ₂ 0- or αNH-CO-N <or αNH-CO-NH-.

The compounds of general formula I according to the invention carry a radical R ³ at the terminal sulfur atom. This radical R ³ represents a sulfur protecting group which is necessary during the synthesis of the compounds of the general formula I according to the invention. Such a protective group must be easily removable. Suitable

R ³ are, for example, acetyl, benzoyl, p-methoxybenzyl, acetamidomethyl, benzamidomethyl, trimethylacetamidomethyl, hydroxyacetyl, ethoxyethyl or trityl groups. The benzyol group is particularly preferred.

The present invention furthermore relates to the metal chelate complexes of radioactive metal ions with the compounds of the general formula I according to the invention, in which R ¹ , R ² and R ^{3 have} the meaning indicated above.

REPLACEMENT LEAF Suitable radioactive metal ions are, for example, ions of the radioisotopes of the elements Tc, Re, Cu, Ga, Gd, Y and In. The selection of the radionuclide depends on the desired type of use of the metal chelate complexes of the general formula I according to the invention.

Different radionuclides are used for radio diagnostics or radiotherapy.

Radioactive metal ions of the isotopes of the elements Tc and Re are preferred.

The radioisotope technetium-99m is particularly preferred.

Another object of the present invention are

Conjugates containing compounds of the general formula I or metal chelate complexes of radioactive metal ions of the elements Tc, Re, Cu, Ga, Gd, Y and In with compounds of the general formula I and selectively accumulating substances in diseased tissues or in tumors, with a covalent between them Binding exists and this is present in the case of substances containing carboxy or amino groups such as peptides, proteins, antibodies or their fragments, amidically or in the case of substances containing hydroxyl groups such as fatty alcohols, ester-like or in the case of substances containing aldehyde groups imidically.

Conjugates with peptides accumulating in diseased tissue such as endotheline, partial sequences of are preferred

Endothelins, endothelin analogs, endothelin derivatives or endothelin antagonists.

Such conjugates with the compounds of the general formula I and themselves are particularly preferred

REPLACEMENT LEAF peptides accumulating in diseased tissue, the peptides having the following sequences

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

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

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

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

-Leu-Asn-

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-Trp-Leu-Asp-Lys-Glu-Ala-Val-Tyr- Phe-Ala-His-Leu-Asp-Ile-Ile-Trp,

REPLACEMENT LEAF 1 I

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

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

or the partial sequence

His-Leu-Asp-Ile-Ile-Trp

or the cyclic amino acid sequences

Cyclo- (DTrp-DAsp-Pro-DVal-Leu),

Cyclo- (DGlu-Ala-alloDIle-Leu-DTrp)

exhibit.

The present invention further provides a process for the preparation of the compounds of the general formula I according to the invention

R ³ -S-CH ₂ -CO-NR - * - [CH ₂ -CO-NH] _n -CH ₂ -CO-R ² (I)

wherein

n represents a number 0, 1 or 2,

R ^{1 is} a straight-chain or branched alkyl radical having 1 to 20 carbon atoms, which is optionally interrupted or substituted by one to three oxygen atoms and which optionally carries a terminal -COOH, -OH or -NH ₂ group which

REPLACEMENT LEAF optionally esterified or etherified with glycolic acid or glycolic acid esters or ethers, the esters or ethers being formed with carboxylic acids or alcohols having up to 18 carbon atoms, or representing a phenyl or cyclohexyl radical which may optionally be in the 4-position with a COOH, NH ₂ or OH group which is optionally esterified, etherified or amidated or substituted with a halogen atom with carboxylic acids or alcohols having up to 6 carbon atoms,

R ^{2 represents} a halogen atom, a halogenomethyl, methylcarboxyl, trifluoromethylcarboxyl group, an NH or an OH group, the carboxyl group formed in the case of R ² = OH either directly or after esterification with an α, ω- Hydroxycarboxylic acid with up to 8 carbon atoms via the terminal carboxyl group with a biomolecule, a steroid, an ergoline derivative, a benzodiazine derivative, a cholecystokinin, a peptide, a protein, a proteohormone, an amino sugar, an endothelin, one Endothelin derivative, an endothelin antagonist or an endothelin fragment is esterified or amidated,

in the rest of the general formula II

REPLACEMENT LEAF or the general formula II a

is where

R ^{8 represents} a hydrogen atom or a methyl group,

a radical of the general formula III

or the general formula III a

REPLACEMENT LEAF represents what

R ^{5 is} an -NH-, -NH-CO-N <, -NH-CO-NH or methylene oxy group,

R ^{6 represents} a hydrogen atom, a halogen atom or a methyl group and

R ^{7 represents} a hydrogen atom or a straight-chain or branched alkyl radical with up to 6 carbon atoms,

R ^{3 represents} a hydrogen atom, an acetyl, benzoyl, p-methoxybenzyl, acetamidomethyl, benzamidomethyl, trimethylacetamidomethyl, hydroxyacetyl, ethoxyethyl, ethylthio, trityl or an easily cleavable sulfur protecting group

and their salts with pharmaceutically acceptable acids or bases

which is characterized in that one

a) a diketopiperazine derivative of glycine or b) glycine

with a halocarboxylic acid halide and then with an alkylamine or arylamine of the general formula VI

R ¹ - NH ₂ (VI)

where R ^{1 has} the meaning given above, reacted again with a halocarboxylic acid halide and then with a compound of the general formula IV

REPLACEMENT LEAF R ³ - SH (IV)

where R ^{3 has} the meaning given above,

implements

or a compound of the general formula V

R ** - NH-CH ₂ -CO-R ² (V)

wherein R ^{2 has} the meaning given above, with a halocarboxylic acid halide and then with an alkylamine or arylamine of the general formula VI

R ¹ - NH ₂ (VI)

R ³ - SH (IV),

wherein R ^{3 has} the meaning given in above, and these compounds are optionally converted into their salt with a pharmaceutically acceptable acid or base.

The compounds of the general formula I according to the invention can also be prepared in such a way that starting from a compound of the general formula I according to the invention, where n is 0 or 1, this is reacted with a compound which has terminal groups, and thus after the coupling forms a radical R ² on the above-mentioned compound. Thereby according to the invention

REPLACEMENT LEAF Compounds of general formula I are formed in which n is 1 or 2. This means that part of the chain of the compounds of the general formula I according to the invention is provided by the coupled radical R ² .

The preparation of the metal chelate complexes of radioactive metal ions according to the invention with the compounds of the general formula I according to the invention is a further subject of the present invention.

The compounds of the general formula I are reacted, if appropriate with prior or simultaneous removal of the radical R ³ , in a manner known per se.

The production of metal chelate complexes of radioactive metal ions of the elements Tc and Re with compounds of the general formula I is carried out by adding 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 I.

R ³ -S ~ CH ₂ -CO-NR * --- [CH ₂ -CO-NH] _n -CH ₂ -CO-R ² (I)

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

The surprising variability of the compounds and their complexes is of particular inventive importance. An N3S system is obtained for compounds with n = 2 according to general formula I. If one changes from n = 2 to n = 1, an N SO-N-alkyl system with a surprisingly high complex stability can form. Finally, when n = 0, N- ^ Sx-N-alkyl

REPLACEMENT LEAF System when complexing a chelate complex, which both shows an N ₂ S -N-alkyl system or is a further dimer is an 0 S ₂ -N-alkyl complex, without a chemical covalent bridge function connecting the complex.

Because of their chemical variability and their variants in the formation of complexes, the new compounds also have an extraordinary breadth of clinical applications.

To date, there is no method that - in vivo - depicts the formation of plaques as the beginning of atherosclerosis. Atherosclerosis is a widespread disease and a preliminary stage of coronary heart disease, the consequences of which cause about 40% of the population of the industrialized countries to die. It is therefore of particular value to obtain a pictorial representation of the vascular lesions with a simple means. Thus, the N-alkyl chelates according to the invention can be used for the early detection of atherosclerotic vascular diseases.

The quotient obtained in the animal model (rabbits of the species WHHL with artificially generated atherosclerotic vascular changes: WHHL rabbits have high LDL levels in the blood due to a missing or defective LDL receptor and therefore develop atherosclerotic vascular changes) after iv administration of compounds according to the general formula I , where R ^{2 is} an endothelin, a partial sequence of endothelin, an endothelin analogue, an endothelin derivative or an endothelin antagonist, from activity in the plaque and undamaged vessel, was 1: 5 (see Figures 1 and 2) .

It was highly surprising that despite the lipophilicity of the complex, as a result of the R ¹ alkyl chain

REPLACEMENT LEAF a chain length of Cg, the excretion had taken place after only 3 hours. The lesions in the area of the aorta are surprisingly easy to represent by autoradiography. Here there is an affinity for the plaques or their receptors, given by the similarity of fat to the molecules, which is so high that, despite the decreasing concentration of the compound in the blood - as a result of excretion via the liver - the adhesion to the plaques is retained.

The affinity for plaques in atherosclerotic changes in the vessels can be influenced by varying the R ¹ alkyl group. Thus the lipophilicity can be controlled via the nature of the residue in R ¹ , and at the same time R ² as a free carboxyl group offers the necessary prerequisite for good water solubility. Instead of R ² as the free carboxylic acid, however, an amidation of this carboxyl group with an amino hydrocarbon can also contribute to water solubility.

It is known that proteins, especially short-chain proteohormones such as endotheline, lose their effectiveness when a chelator is coupled via a covalent bond. The behavior of the compounds according to the invention in the case of covalent binding to endothelines, their antagonists or fragments was therefore completely unexpected (Examples 11, 12).

The type of generation of the N-alkyl complexing agents of general formula I according to the invention with endothelines (examples 11 and 12) from chelating precursors shown here is a new method for generating such complexing sites. The stability of the new N-alkyl complexes of the general formula I corresponds to the known N3S complexes.

REPLACEMENT LEAF Non-invasive techniques for diagnosing atherosclerosis have been described, especially with radio-iodine labeling. Antibodies labeled with radioisotopes or labeled "low density lipoproteins" (LDL) which bind to atherosclerotic wall areas have been presented (Lees et al. 1983, J. Nucl. Med. 24, 154-156, Kaliman et al. 1985 , Circulation, 72, 300; Virgolini et al. 1991, Eur. J. Nucl. Med., 18, 944-947). However, these methods include decisive disadvantages, such as the antigenic effect of the antibodies on the organism and the long period (several days) required to isolate, clean and label the LDL from the patient's blood. Above all, however, these large molecules are characterized by a long half-life in the blood, which together with high background radiation in the entire body makes localization of the atherosclerotic lesions difficult, if not impossible (Shih et al. 1990 Proc. Natl. Acad. Sci., 87, 1436-1440), synthesized partial sequences of the LDL protein portion (apo-B-100), which still bind to the atherosclerotic plaques, but have a much shorter half-life in the blood and an improved signal-to-noise ratio. Due to a too low affinity for the plaque and / or the low density of the binding sites of these peptides in the plaque, no successful in vivo diagnosis of atherosclerosis could be shown with these apo-B peptides either.

In general, these compounds have the disadvantage of radioactive iodine-123. The poor availability due to the production in the cyclotron and the physical half-life of 13 hours, combined with the easy release in the organism. So it was surprising that the compounds of formula I according to the invention after covalent binding to NH groups of endothelin and

Complexation with 99m-p _ce -j_ _ne good enrichment in athero- showed ski erotic plaques. Particularly striking is the advantage that the n = 1 and n = 0 compounds generate new N-alkyl-peptide complexing agents after covalent binding to endotheline via amide formation, possibly including the NH and SH groups of the respective endothelin.

When the compounds according to the invention are reacted with dopaminergic bioactive molecules, the receptor affinity of these compounds from the ergoline series is surprisingly not lost, but even in precursors - with or without affinity for the D2 receptor - it was possible to achieve adequate brain mobility, which is a representation of the D2 * Receptors enabled. Efforts to display receptors in the brain with ^99m Tc ⁺⁵ complexes have so far been unsuccessful. Thus, when 8α-amino-6-methyl-ergoline is reacted with mercapto-acetyl-glycyl-glycyl-glycine to form 8α-amide and complexed with 99mτ _c +5 _after iv injection on the rat (Wistar), there is no inclusion in the Brain.

If, on the other hand, the reaction is carried out with the compounds of the formula I according to the invention, where R ¹ = methyl and the amidation or esterification is carried out via R ² , an enrichment in the brain of 0.1 to 0 is obtained under analogous conditions , 5% of the dose.

REPLACEMENT LEAF With n = 1 and n = 0 complexes, new N-alkyl-peptide complex structures are formed which, in cooperation with the bioactive molecule, surprisingly mimic structures of dopaminergic compounds and show a high concentration in the brain, which makes the D- Receptors can be used (Formula IX).

The compounds according to the invention are prepared by the processes known to those skilled in the art [A Specialist Periodical Report; Amino acids, peptides and proteins;

The Chemical Society, Burlington House, London, W1VOBN]. To prepare the compounds with R ¹ = CH3 and R ² = OH, the starting point is sarcosine and this is reacted with chloroacetyl chloride. The resulting chloroacetyl sarcosine is reacted with thiobenzoic acid in the usual way and structures with n = 0 are obtained

R ³ S-CH ₂ -CO-N- (CH ₂ -CO-NH) ₀ -CH ₂ -COR ²

/ CH ₃

Compound A

The compounds with n = 2 are prepared by reacting the diketopiperazine of glycine with chloroacetyl chloride. The resulting chloroacetylglycyl

REPLACEMENT LEAF Glycine is then reacted with N-methylamine or, for the introduction of longer residues, with N-alkylamines, phenylamines, alkyloxaalkylamines, cycloalkylamines or glycatedlycolic acid esters. By reacting again with chloroacetyl chloride and subsequent thiobenzoylation, compounds of the formula n = 2 are obtained.

R ³ S-CH ₂ -CO-N- (CH ₂ -CO-NH) ₂ -CH ₂ -COR ² / R ¹

Compound B

R ¹ stands for the variations on the sarcosyl nitrogen atom

The corresponding compounds with n = 1 are obtained by reacting salts of glycine with N-protected sarcosyl compounds or by reacting glycine with chloroacetyl chloride with subsequent aminolysis of the chloromethyl group. Another reaction with chloroacetyl chloride and subsequent thiobenzylation gives the title compounds with n = 1.

R3S-CH ₂ -C0-N- (CH ₂ -CO-NH) -L-CH ₂ -COR ² /

Rl

Compound C

The compounds A, B, C react in a conventional manner with reaction partners carrying amino groups or hydroxyl groups. For this purpose, A to C are dissolved in N-methylpyrrolidone, with BOP (B. Castro et al. Tetrahedron Letters 14 (1975) 1219) or TBTU (Knorr et al. Tetrahe- dron Letters 30 (1989), 1927 ) pre-activated and then reacted with the amino component. Esterifications

REPLACEMENT LEAF are preferably carried out with dicyclohexylcarbodiimide in the presence of dimethylaminopyridine. For the synthesis of compounds with an estrogen as a bioligand, one starts from an estrogen which already has an unsaturated substituent in 17α such as propargylamine or propargyl alcohol residue and reacts this with one of the compounds A to C in the manner described.

The compounds A to C are reacted with peptides, in particular with endothelin components, according to methods customary in peptide chemistry, either conventionally in solution, preferably in dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or mixtures of these components. When using the

The solid-phase method can also be used to acylate the amino component under customary conditions on the synthetic resin. Cleavage from the synthetic resin provides the desired compounds. Preparative cleaning, if necessary, is carried out chromatographically on an RP 18

Column in a water / acetonitrile gradient containing 0.1% trifluoroacetic acid.

The reaction with peptides in solution was carried out analogously to the reactions with peptides in the reaction with amino groups or hydroxyl group-bearing ergolines. The reactions were carried out in N-methylpyrrolidone. The preparative cleaning is also carried out as indicated for peptides.

The other R ⁴ residues are obtained after construction of the protected dipeptides A - C in which R ¹ , where R ² = OH, after activation with

NH ₂ -CH ₂ C1,

NH ₂ -CH ₂ -CH = CHJ or

REPLACEMENT LEAF NH ₂ -CH ₂ - C = CJ

is implemented and after the palladium-O reaction the 17α-ethynyl steroid is covalently bound with the desired complexing agent via a C-C bond.

The complex formation is preferred in an aqueous medium, at a pH between 6 and 9 and at room temperature, by reducing Na pertechnetate with e.g.

Tin (II) chloride or dithionide, optionally carried out via an auxiliary ligand such as sodium citrate or sodium tartrate, the protective group R ^{3 being} split off beforehand or in situ.

Activation of the R ² carboxyl group formed in the case of R ² = OH or replacement of the carboxyl group by an NCS or similarly reactive group lead to peptide chelates covalently attached to a larger protein or proteohormones, endotheline, endothelin analogues, endothelin antagonists, endothelin derivatives To bind partial sequences of endothelins and subsequently carry out complexation.

As indicated in the preparation procedure, can be ^99m Tc and according to the invention ¹⁸⁶ ^'188 Re complexes at room temperature, neutral to weakly alkaline pH and with or without Umchelatisierung (eg via a Heptagluconat- ^99m Tc-complex) in yields of 95% as Create complexes. Their slight salt formation via a free cation leads to good water solubility.

Production of the metal complexes: The protective group is cleaved off according to methods known to the person skilled in the art (see "Protective groups in organic synthesis" T.N. Greene, John; Wiley and Sons 1981).

REPLACEMENT LEAF Between 370 MBq and 1850 MBq, preferably 740 to 1480 MBq, are usually used for use in human diagnostics. The compounds according to the invention are provided in the form of a kit for use in humans. The kit contains at least one chelator according to the general formula I in free form or bound to ligands.

Another object of the invention is a cold kit, which a chelating agent according to the general formula I in free form or to a bioactive molecule, such as. contains an ergoline, estradiol or endothelin derivative, which is capable of binding metal atoms.

The splitting off of the protective groups introduced intermediately to carry out the synthesis often presents considerable difficulties. Chelating agents with peptide linkages in particular are severely affected when the -S protective group (R ³ ) is split off by simultaneous cleavage of the peptide chain or lead to fragments which can no longer be used, and it was all the more surprising that the simultaneous presence of Hydrogen / Pd / CaC03, that is to say deprotection under hydrogenating conditions, in the presence of the alkali customarily used, there is a high cleavage which can reach up to 80%.

This decisive improvement in the synthesis of the free chelate complexes is of great importance insofar as it enables deprotection before the kit formulation and the extraction of the chelator without protective groups is technically considerably improved.

REPLACEMENT LEAF The cleavage method according to the invention is described using example 3. While a mixture that was difficult to separate was obtained with the usual cleavage with alkali, a ~ 100 was obtained with deprotection with alkali in the presence of hydrogen / Pd / CaCO3

% material yield with over 80% of the desired material.

It may be mentioned by way of example that the reaction with amines or alcohols proceeds via activation of the carboxylic acid R2 = OH, methods known to the person skilled in the art being used.

Examples of activated groups are: acid chlorides, mixed anhydrides [Org. Prep. Proc. Int. 1975, 7, 215], activated esters [Adv. Org. Chem. Part B, 472]. The linkage with biomolecules can take place directly or via linkers, here the carbodiimide method (Fieser, Reagents for Organic Synthesis 10, 142) is mentioned. The linkage is such that a covalent bond is formed between the chelate and the biomolecule.

When using steroids as biomolecules, estradiol derivatives with substituents in the 17α position are preferably used. The synthesis of such compounds is e.g. described by Blickenstaff for 17α-ethynyl derivatives of estradiol. (Blickenstaff A.; Steroids 46, 889 (1985); USP 462.426). The synthesis of Blickenstaff, Brandes and Poirier is described for estradiol derivatives with 17α-propargyl substituents with terminal NH2 or OH function. (Blickenstaff et al.; Steroids 48, 223 (86); Brandes, A. et al. Dissertation 87-01441, 1986, University of Illinois, D. Poirier et al. J. Steroids. Biochem. Molec. Biol. 38, No. 6, 759-774, 1991).

REPLACEMENT LEAF An overview of the linking of triple and double bonds, for example after the palladium-0 reaction, can be found in Aldrichchimica Acta, Vol. 15, No. 1, 1982; Shunichi Murahashi et al. , Stephen A. Godleski, Tetrahedron Letters, Vol. 22, No. 24, pp 2247-2250, 1981; Tetrahedron Letters, Vol. 29, No. 24, 2973-2976, 1988; described. Here, for example, I is reacted with R ² = - NH-CH ₂ -C≡CH in the coupling with, for example, 17α [2-halogeno-ethenyl] -estradiol in accordance with the references mentioned.

It is known from the literature that ergot alkaloids of the 6-methyl-8-substituted ergoline type have a broad spectrum of chemical variation without a connection between action and substituents in position 8 being clearly recognizable to date [Ergot Alkaloids and Related Compounds , Editors: B. Berde and HO Schild, Springer-Verlag, Berlin, Heidelberg, New York, 1978].

A preferred dopaminergic ligand is ergoline. An overview of synthetic routes to 8-substituted ergolines can be found at Ergot Alkaloids and Related Compounds, Editors B. Berde and H.O. Schild, Springer-Verlag Berlin, Heidelberg, New York, 1978, Chapter II Chemical Background, J. Ruisemmann and P.A. Stadler.

The reaction with the 8α-amino or 8β-hydroxy-methyl-ergoline is preferred. It takes place via an activated group in R ² , for example that with benzotriazol-1-yl-tetra-methyl-uronium tetrafluoroborate or according to the known carbodiimide method.

When the n = 1 and n = 0 complex or partial complexing agents are used according to the invention, new complexes are generated with the inclusion of nitrogen in the 8α-amino and 6-N-methyl group of the ergoline.

REPLACEMENT LEAF Another object of the invention is the use of the metal chelates for diagnostic and / or therapeutic purposes and pharmaceutical compositions which contain at least one chelate of the general formula I according to the invention, optionally with the additives customary in galenics.

For use in humans, the compounds according to the invention are provided in the form of a cold or hot kit. The kit contains at least one chelator according to formula I in free or bound form, the ligands preferably being obtained from the class of ergolines, estriols, endothelins, short-chain synthetic peptides and cholecystokinins.

Examples

General complex formation with sodium gluconate

^99m Tc gluconate:

2 ml of ^99m Tc generator eluate are added to 2 ml of 0.1 M sodium gluconate solution and mixed with 10 μl of 0.01 M SnCl ₂ (in

0.01 M HC1) added. The quantitative pertechnetate reduction is then checked by thin-layer chromatography.

TLC (silica gel / acetone): ^99m Tc gluconate Rf: 0-0.1;

99m _Tc0 4- _{Rf: 0 9}

example 1

[ ^99m Tc] mercaptoacetyl sarcosine

1st stage: chloroacetyl sarcosine:

0.07 mol sarcosine are dissolved in 50 ml IN sodium hydroxide solution and at 0 ° C in portions with 0.08 mol chloroacetyl chloride

REPLACEMENT LEAF and 110 ml IN sodium hydroxide solution. After 45 minutes the addition is complete and the reaction solution is acidified with 20 ml of 5N hydrochloric acid.

The product is evaporated to dryness under reduced pressure and the residue is extracted three times with 50 ml of cold acetone each time. The acetone is removed under reduced pressure and the residue is extracted with 100 ml of ether. The ether is evaporated off and the oil which remains is taken up in a little ether and brought to crystallization with vigorous stirring. Yield: 77% of theory TLC: silica gel // butanol / glacial acetic acid / water 2: 1: 1 Rf: 0.65 (iodine vaporization)

2nd stage: benzoylmercaptoacetyl sarcosine:

0.02 mol of chloroacetyl sarcosine are dissolved in 750 ml of methanol with stirring in a protective gas atmosphere at room temperature. A solution of 0.041 mol of thiobenzoic acid, dissolved in 20 ml of methanol and neutralized with sodium methylate, is slowly added dropwise and the mixture is stirred for a further 12 h.

The solvent is removed under reduced pressure and the residue is taken up in 2N hydrochloric acid. The reaction product precipitates as a brown oil, which is separated from the supernatant solution and extracted with chloroform. The chloroform is removed under reduced pressure and ether is added to the residue. The reaction product is precipitated by cooling and intensive stirring, filtered off and dried on the clay plate.

REPLACEMENT LEAF pH titration and IR spectrum showed that the reaction product consisted of a mixture of 60% methyl ester and 40% free amino acid.

3rd stage: splitting off of the protective group:

0.08 mmol of the mixture obtained are suspended in 2 ml of absolute methanol, 2 mg of Pd / CaC03 (5%) are added, and at a hydrogen pressure of 66 kPa with stirring, a solution of 0.13 mmol of sodium methylate in 1 ml of absolute methanol implemented. The mixture is stirred for a further 15 min and then the solution is neutralized with methanolic Dowex 50WX8. The catalyst and the resin are filtered off, the substance is lyophilized and the impurities are extracted with 2 ml of benzene. The benzene is then separated off and the substance is lyophilized from ethanol.

The resulting product mixture of ester and free acid is separated on Sephadex G10. (Column 14 x 1000, 20 ml / h, RI detector) Mercapto-acetyl-sarcosine methyl ester is separated as the second fraction, cf. Example 1 a).

Mercaptoacetyl Sarcosine: TLC:

Silica gel // butanol / glacial acetic acid / water 2: 1: 1

Rf: 0.7 (ninhydrin)

RP 18 / methanol Rf: 0.85 (ninhydrin)

^• - H NMR (DMSO) TMS δ2, 9 (SH, 1H), δ3, 1 (N-CH3, 3H), δ3, 9 (-CH2, 2H)

Labeling of N-methyl-MAGl

About 1 mg of N-methyl-MAG1, dissolved in 200 μl of water, is added to 2 ml of ^99m Tc-gluconate solution. After a reac

REPLACEMENT LEAF 15-20 min, the purity is checked by TLC on silica gel 60/95% ethanol.

The main amount of activity runs with Rf = 0.1 (approx. 80%); further peaks at Rf = 0.2 (approx. 10%) and Rf = 0.4 (approx. 10%). An anionic Tc-MAGl complex is detected in the electropherogram with a relative mobility ^u Pertechn. / ^u TcMAGl ^from ° ' ² -

Example 1 a:

When the reaction mixture from Example 1, stage 3 is separated, 20% mercapto-acetyl-sarcosine methyl ester is obtained as a colorless oil.

Example 2

Mercapto-acetyl-hexylaminoacetic acid

1st stage: hexylaminoacetic acid

0.021 mol of chloroacetic acid are mixed with 0.1 mol of hexylamine and left to stand for 5 days at room temperature. The thick syrup is then stirred into 500 ml of acetone and crystallized in the form of white leaves. Yield 2.1 g (63% of theory)

DC:

Silica gel // butanol / glacial acetic acid / water 2: 1: 1 Rf: 0.6 (ninhydrin)

2nd stage: chloroacetyl-hexylaminoacetic acid:

0.01 mol hexylaminoacetic acid is dissolved in 10 ml IN sodium hydroxide solution, cooled and alternately at 0 ° C with 1.5 ml (1 ml = 0.012 mol) chloroacetyl chloride and 20 ml IN sodium hydroxide solution.

REPLACEMENT LEAF tron lye added. The reaction is complete after 30 minutes and stirring is continued for a further 30 minutes with gentle heating. The mixture is acidified with 3 ml of 5N hydrochloric acid and the resulting brown oil is separated off.

The oil is extracted several times with hot water and used as a colorless oil for the next synthesis step without further purification.

DC:

Silica gel // butanol / glacial acetic acid / water 2: 1: 1 Rf: 0.75 (vapor deposition)

3rd stage: Benzoylmercaptoacetyl-hexylaminoacetic acid:

0.018 mol of chloroacetyl-hexylamino acid are stirred in 500 ml of methanol under nitrogen. 0.036 mol of thiobenzoic acid are neutralized with sodium methylate and added to the solution within 30 minutes. The mixture is stirred under protective gas for a further 12 h. The methanol is removed under reduced pressure, the residue is acidified with 2N hydrochloric acid and the yellow oil which separates out. Yield: 370 mg DC:

Silica gel // butanol / glacial acetic acid / water 2: 1: 1 Rf: 0.5

Example 3

[99m-p _c ] Mercaptoacetyl sarcosyl diglycine

1st stage: chloroacetyl diglycine:

10 g of glycine anhydride are dissolved in a 250 ml three-necked flask in 50 ml of 2N sodium hydroxide solution at room temperature. To

REPLACEMENT LEAF The solution is cooled to 0 ° C. for 45 minutes and 11.1 g of chloroacetyl chloride and 24 ml of 5N sodium hydroxide solution are added dropwise, while stirring and cooling are continued. The addition is complete after 45 min. Then 40 ml of 5N hydrochloric acid are added, the solution decolorizing and the substance starting to crystallize. It is left to stand at 0 ° C. for about 1 h and suction filtered. It is washed several times with cold water and recrystallized from hot water. Yield: 5 g

The mother liquor is concentrated under reduced pressure. The precipitate is recrystallized from water. Yield: 2.5 g mp: 173 ° C

TLC: silica gel // n-butanol / glacial acetic acid / water / 4: 1: 1

Rf: 0.75 (iodine vaporization)

IR (fixed in KBr): v _{c = 0} 1636, 1676; 6 ^** ^ 1550; v ₀ 0H 1708 cm ^"1

2nd stage: sarkosyl diglycine

5 g of chloroacetyl diglycine are mixed with 15 ml of 33% aqueous methylamine solution and left to stand for 2 days at room temperature. The solution is then concentrated to a syrup thickness under reduced pressure, the syrup is heated on a water bath and mixed with 50 ml of hot ethanol. The precipitate is allowed to settle in the cold and is suctioned off through a G4 frit. It is dissolved in 43 ml of hot water and 43 ml of hot ethanol are added. The product crystallizes out, the product is filtered off with suction and lyophilized.

Yield: 3 g = 60% of theory. Th. Mp: 237 ° C DC: Silufol // n-butanol / glacial acetic acid / water / 4: 1: 1 Rf: 0.3 (ninhydrin)

REPLACEMENT LEAF IR (fixed in KBr): v _{c = 0} 1620, 1650, 6- ^ 1540; v _C QOH ^{1672 cm_1} ^• JH NMR (DMSO) TMS δ2, 8 (N-CH ₃ , 3H), δ3, 8-4.1 (-CH ₂ -, 6H)

3rd stage: chloroacetyl-sarkosyl-diglycine:

2 g of sarkosyl diglycine are dissolved in 10 ml of IN NaOH at room temperature and then 1 ml of chloroacetyl chloride and 16 ml of IN NaOH are alternately added at 0 ° C. with stirring within 30 minutes. The mixture is stirred for a further 30 min, acidified with 3 g of 5N HCl and the product is evaporated to dryness under reduced pressure. The resulting crystals are dissolved in hot water and ethanol is added to the solution. The sodium chloride which has precipitated is filtered off and the filtrate is concentrated under reduced pressure. The desired product is extracted by repeated treatment with 30 ml of hot acetone each time, the acetone is removed under reduced pressure and the residue is taken up in a little water and lyophilized.

Yield: 1.1 g = 53% of theory. Th.

Mp: 74 ° C

TLC: Silufol // n-butanol / glacial acetic acid / water 4: 1: 1

Rf: 0.7 (iodine evaporation) IR (fixed in KBr): v _{c = 0} 1655; 0 ^* ^ 1550; V _C00 H ¹⁷ 0 cm ^"1

4th stage: benzoylmercaptoacetyl-sarkosyl-diglycine:

1 g of chloroacetyl-sarkosyl diglycine is dissolved in 140 ml of methanol, p.a., with stirring and under a protective gas at room temperature.

0.8 g of thiobenzoic acid are dissolved in 3 ml of methanol in an Erlenmeyer flask and neutralized with sodium methylate.

REPLACEMENT LEAF siert. This solution is slowly added dropwise to the starting solution with stirring and under a protective gas atmosphere and stirring is continued for a further 12 hours. The solvent is removed under reduced pressure and the residue is taken up in 2N HCl. It is suctioned off and washed neutral with warm water. The mixture is then washed with 20 ml of chloroform, 20 ml of acetonitrile and 20 ml of ether and the residue is dried under reduced pressure. Yield: 0.83 g = 61% of theory Mp: 134 ° C

TLC: Silufol // n-butanol / glacial acetic acid / water 4: 1: 1

Rf: 0.8 (iodine vaporization)

IR (fixed in KBr): v _{c = o} 1620, -6- ^ 1550 cm " ¹ , V _COO H1720 cm ^-1

5th stage: mercaptoacetyl-sarkosyl-diglycin

Alkaline deprotection:

The cleavage of the protective group after the usual procedure with sodium methylate led to a highly contaminated end product. Only about 25% of the mercaptoacetyl-sarkosyl-diglycin is contained. In addition to an unidentified by-product, this saponification mainly produces mercaptoacetyl sarcosine and diglycine. The desired product is only obtained in low yield.

Alkaline elimination under hydrogenation conditions:

0.08 mmol of substance are suspended in 2 ml of anhydrous methanol, 2 mg of Pd / CaCO 3 (5%) are added and, at a hydrogen pressure of 60 kPa, the mixture is reacted with a solution of 0.13 mmol of sodium methylate in 1 ml of anhydrous methanol. The mixture is stirred for a further 15 minutes and then the solution is neutralized with methanolic Dowex 50WX8. The catalyst and resin are filtered off

Substance lyophilized and extracted with 2 ml of benzene.

REPLACEMENT LEAF The benzene is then separated off and the substance is lyophilized from ethanol.

Yield: 10.2 mg = 61% of theory. Th., Colorless oil DC: Silufol // n-butanol / glacial acetic acid / water 4: 1: 1 Rf: 0.4 (ninhydrin) RP 18 // methanol Rf = 0.8 (ninhydrin) IR (solid in KBr): v _{c = 0} 1650, 1680; δjjjjl550, v _C0 0H ^{1745 c _1} -LH-NMR (DMSO) TMS δ 2.8 (SH, 1H), δ3.0 (N-CH ₃ , 3H), δ 3.5- 4.1 (-CH ₂ , 8H), 58.1-8.2 (CO-NH-, 2H)

[99m ^> p _c ] mercaptoacetyl sarcosyl diglycine

1 ml of ^99m Tc-gluconate solution is mixed with a solution of 0.4 mg of pure substance from precursor 4 in 0.5 ml of water. The reaction is complete after 30 minutes. TLC: (silica gel 60, 95% ethanol): two components Rf 0-0.1 (40%), Rf 0.8 (60%) electrophoresis (pH 7.0): both components migrate as anions.

Example 4

Synthesis of [ ^99m Tc] -Mercaptoacetyl-Hexylglycyl-Diglycin

1st stage: hexylglycyl diglycine

0.0048 mol of chloroacetyl diglycine are mixed with 0.05 mol of hexylamine and 5 ml of ethanol and left to stand. After 6 days the solvent is removed under reduced pressure. The oily residue is poured into 50 ml of acetone and heated. After cooling, the yellow one

REPLACEMENT LEAF Solution separated and the white residue washed again with about 5 ml of acetone. The product is dried on the clay plate. Yield: 610.5 mg (47% of theory) TLC:

Silufol // n-butanol / glacial acetic acid / water 2: 1: 1

Rf: 0.3 (ninhydrin)

RP 18 // methanol, Rf: 0.7 (ninhydrin)

2nd stage: chloroacetyl-hexylglycyl-diglycine

0.0022 mol of hexylglycyl diglycine are dissolved in 5 ml of 1N sodium hydroxide solution and stirred for 30 minutes at room temperature. The solution is then cooled. At 0 ° C., 0.3 ml of chloroacetyl chloride and 4 ml of 1N sodium hydroxide solution are added alternately within 30 minutes. Then stirring is continued for 30 minutes without cooling.

After acidification with 5N hydrochloric acid, the solvent is removed under reduced pressure and the product is obtained as a yellow oil. After repeated extraction with 100 ml of hot acetone each time, the acetone is removed under reduced pressure and the residue is slurried with 30 ml of acetone. The white sediment is dried on the clay plate.

Yield: 311 mg (40% of theory)

TLC: Silufol // n-butanol / glacial acetic acid / water 2: 1: 1

Rf: 0.75 (iodine vaporization)

3rd stage: Benzoylmercaptoacetyl-hexylglycyl-diglycin

0.00089 mol of chloroacetyl-hexylglycyl diglycine are dissolved in 70 ml of methanol (especially pure for microelectronics) and stirred under protective gas (N). 0.002 mol of thiobenzoic acid are dissolved in 5 ml of methanol and neutralized with 0.4 ml of sodium methanoate. This solution is under protective gas

REPLACEMENT LEAF slowly added and stirring continued for 12 hours. The methanol is removed under reduced pressure and the residue is taken up in 2N HCl. The hydrochloric acid is also removed under reduced pressure, the residue is washed with water and the wash water is thoroughly washed through

Decanted away. A little methanol is added to the viscous residue and the product precipitates. It is washed with acetronitrile and dried on the clay plate. Yield: 253.3 mg (67% of theory)

TLC: Silufol // Butanol / glacial acetic acid / water 2: 1: 1 Rf: 0.8 (UV)

4th stage: mercaptoacetyl-hexylglycyl-diglycine

0.064 (28.8 mg) mmol of benzoylmercaptoacetyl-hexylglycyl-diglycine are suspended in 2 ml of methanol, 2.7 mg of 5% Pd / CaC03 are added and attached to the hydrogenation apparatus. 0.04 ml of Na methanol and 1 ml of methanol are placed in an angled flask. The apparatus is evacuated and then flushed with hydrogen.

The methanolate is added and the mixture is stirred at a hydrogen pressure of 60 kPa for 15 minutes. The solution is acidified with methanolic Dowex 50WX8, the resin is filtered through a pleated filter (argon bell), washed with methanol and then lyophilized. The residue is extracted three times with 4 ml of benzene, the benzene is removed by decanting, the residue is again taken up in methanol and lyophilized. The product was purified on a Sephadex column. Yield: 9.8 mg (42% of theory) TLC: silufol // butanol / glacial acetic acid / water 2: 1: 1 Rf.0.5 (ninhydrin)

REPLACEMENT LEAF ! H-NMR (DMSO) TMS δl, 2 (- CH3, 3H), δ3, 1 (SH, 1H), δ3, 2 (N-CH2, 10H), δ3, 7 (-CH2, 6H), δ3, 8 (CH2 - SH, 2H) δ8, 2-8, 5 (-NH, 2H)

[99m-p _c ] -Mercaptoacetyl-hexyl-glycyl-diglycine:

1 ml of ^99m Tc-gluconate solution is mixed with 400 μl 0.1 N NaOH and 30 μl precursor 4 solution - 1.63 mg / 100 μl water. After standing for 40 minutes, the reaction mixture is neutralized with 2 ml of a 0.1 M sodium phosphate buffer solution (pH 7.0). The reaction mixture is stable for at least 2 hours. TLC (silica gel 60; 95% ethanol): Rf 0.7 (95%) electrophoresis (pH 7.0): migration as an anion

Example 4 a

Enrichment of [99mTc] -Mercaptoacetyl-Hexyl-glycine-

Diglycine in atherosclerotic plaques from aortas in WHHL rabbits.

99.9 GBq (2.7 mCi) of the substance labeled according to Example 4 was diluted to 1 ml with phosphate-buffered saline and applied to an anesthetized WHHL rabbit Rompun / Ketavet (1: 2) via an ear vein. The rabbit was sacrificed 5 hours after application and both autoradiography of the aorta and Sudan III staining were carried out to show the atherosclerotic plaques (Figure 1). The enrichment factor between normal and atherosclerotic wall areas was between 3 and 5, depending on the formation of the plaques (Sudan III staining). The in vivo representation of a WHHL rabbit is shown in Figure 2.

REPLACEMENT LEAF Example 5

S-Bzl-acetyl-Sar-Gly-Gly- [8α-ergolinylamide]

200 mg of S-Bzl-acetyl-Sar-Gly-Gly-OH and 161 mg of benzotriazol-1-yl tetramethyl uronium tetrafluoroborate were dissolved in 1 ml of N-methylpyrrolidone and 172 μl of diisopropylethylamine were added. After 3 minutes, the colorless solution is added dropwise to a stirred solution of 120 mg of 8c_-amino-ergoline. The red-brown solution is stirred at room temperature for a further 4 hours, the progress of the reaction being monitored by HPLC chromatography on a VYDAC C18 column (4.6 x 250 mm) by applying a gradient from 10% to 60% B in 25 min (eluent A 1000 ml water / 2 ml trifluoroacetic anhydride, mobile phase B 500 ml

Acetonitrile / 100 ml water / l ml trifluoroacetic acid anhydride).

The reaction mixture is prepared on a VYDAc column (40 x 300 mm) without further pretreatment

Creation of a gradient from 20% to 30% B separated in 20 min (eluent composition as indicated above).

It is then lyophilized.

Yield: 75 mg. A mass spectrum showed the expected molecular weight.

Example 6

S-Bzl-acetyl - [Nl -hexyl] -Gly-Gy-Gly- [8α-ergolinylamide]

60 mg of S-Bzl-acetyl- [N * --- hexyl] -Gly-Gy-Gly-OH and 40 mg of benzotriazol-1-yl-tetramethyl-uronium tetrafluoroborate were suspended in 0.6 ml of N-methylpyrrolidone and passed through Add 17.2 μl diisopropylethylamine in solution. This solution was added dropwise to a solution of 30 mg of 8α-amino-ergoline in 0.4 ml of N-methylpyrrolidone. To

REPLACEMENT LEAF The reaction solution was worked up for 4 hours. The crude reaction mixture was chromatographed preparatively (as described for Example 5). Subsequent lyophilization gave the desired product. Yield: 30 mg of a pseudocrystalline product.

The mass spectrum showed the expected molecular weight.

Example 7

S-Bzl-acetyl-Sar-Gly- [8α-ergolinylamide]

180 mg of S-Bzl-acetyl-Sar-Gly-OH and 161 mg of benzotriazol-1-yl-tetramethyl uronium tetrafluoroborate were dissolved in 1 ml of N-methyl-pyrrolidone and 172 μl of diisopropylethylamine were added. After 3 minutes, the colorless solution is added dropwise to a solution of 120 mg of 8α-amino-ergoline with stirring. The red-brown solution is stirred at room temperature for 4 hours and - as described in Example 5 - worked up and chromatographed. Yield: 70 mg (pseudocrystalline) An MS showed the expected peak.

Example 8

S-Bzl-acetyl-Sar- [8α-ergolinyl-amide]

120 mg of S-Bzl-acetyl-Sar-OH and 161 mg of benzotriazol-1-yl-tetramethyl uronium tetrafluoroborate were dissolved in 1 ml of N-methyl-pyrrolidone and 172 μl of diisopropylethylamine were added.

The reaction is then carried out analogously to Example 5 and, after working up and separating, 52 mg of a pseudocrystalline compound are obtained. An MS shows the expected mass peak.

Example 9

REPLACEMENT LEAF 3,17ß-dihydroxy-17α- [5 (S-benzoylthio-acetyl-sarkosyl-glycyl-) amino-pent-l-en-3-yne] -1,3,5-estratriene

It is added to a suspension of 130.0 mg of 17β-hydroxy-17α-iodovinyl-1, 3, 5-estratriene-3-tetrahydropyranyl ether, 0.35 g [S-benzoyl-thioacetyl-sarcosyl-glycyl-propargylamide], 11.0 mg of benzyl-triethylammonium chloride, 11.5 mg of tetrakis (triphenylphosphine) palladium (0), 9 mg of copper (I) iodide, suspended in 5 ml of toluene and stirred for 90 hours at room temperature. Water is added, the mixture is extracted with toluene and the mixture is dried. The solvent is removed under reduced pressure, the residue is taken up in 10 ml of tetrahydrofuran, 190 mg of pyridinium paratoluenesulfonic acid in 5 ml of ethanol are added and the mixture is heated under reflux for 3 hours. The solvent is then removed under reduced pressure and the mixture is purified on a silica gel column using methylene chloride / methanol (8: 1). Yield: 30% of theory Th.

The substance shows an Rf of 0.4 in TLC (CH Cl ₂ / MeOH] 5: 5.

Example 10

3, 17β-dihydroxy-17α- [N- (benzoyl-thio-acetyl-sarkosyl-glycyl) -amino-propyne-1] -1,3,5 estratriene

It is added to a suspension of 110 mg of 17β-hydroxy-17α-propargylamino-1, 3, 5-estratriene-3-tetrahydropyranyl ether, in 3 ml of DMF and 350 mg of S-benzoyl-thioacetyl-sarcosyl-glycine in 3 ml DMF. The mixture is stirred under protective gas at 100 ° C. for 24 hours.

REPLACEMENT LEAF After adding 10 ml of tetrahydrofuran, the crystals are filtered off with suction and concentrated under reduced pressure. The residue is taken up in 20 ml of tetrahydrofuran, 100 mg of pyridinium-para-toluenesulfonic acid are dissolved in 3 ml of ethanol, and the mixture is heated under reflux for 1 hour. After removal of the solvent, the methanol / methylene chloride (1: 8) system is used to clean the silica gel low-pressure column.

The substance showed an Rf of 0.6 in TLC (CH ₂ Cl ₂ / MeOH) 5: 5.

Yield: 71 mg

Example 11

0.001 mol of S-Bzl-acetyl-Sar-Gly-OH and 322 mg of benzotriazol-1-yl-tetramethyl-uronium tetrafluoroborate are dissolved in 3 ml of DMF with the addition of 344 μl of diisopropylethylamine. It is used to form the benzotriazolyl ester 5

Preactivated minutes and then added the clear solution to 33 mmol protected His (Trt) -Leu-Asp (OBut) -Ile-Ile-Trp resin. The suspension is stirred for one hour, then washed several times with DMF, suction filtered and dried. The dried resin is then treated as usual with TFA / Scavanger in order to remove the protective groups from the product. The cleaning is carried out as described for example 5.

The compound obtained according to Example 10 is complexed with ^99m Tc according to the method given as the general method (Example 1).

Example 12

REPLACEMENT LEAF 0.010 mol of His (Trt) -Leu-Asp (OBut) -Ile-Ile-Trp-OH, produced on sasrin resin, are dissolved in a mixture of DMF / NMP with the addition of 0.010 mol of diisopropylethylamine and with stirring with 0.010 mol of S-Bzl-acetyl-Sar-OH, prepared as in Example 11, dissolved in 3 ml of DMF. The mixture is stirred for 2 hours and then the solvent is removed. The remaining residue is stirred with water and suction filtered, washed and dried. The protective groups are removed as usual and the product is obtained by pouring it into ether. The cleaning is carried out as described for example 5.

S-Bzl-acetyl- [N14-bromophenyl] -Gly-Gly-Gly-OH

1st stage: chloroacetyl diglycine

10 g of glycine anhydride are dissolved in a 250 ml three-necked flask in 50 ml of 2N sodium hydroxide solution at room temperature. After 45 minutes, the still somewhat cloudy solution is cooled to about 0 ° C. and 11.1 g (7.8 ml) of chloroacetyl chloride and 24 ml of 5N sodium hydroxide solution are added dropwise with stirring. The addition is complete after 45 min. The solution turns pink. 40 ml of 5N hydrochloric acid are then added, the solution decolourising and the substance starting to crystallize. One leaves approx.

Stand for 1 hour at 0 ° C and sucks off the precipitate. It is washed several times with cold water and recrystallized from hot water. Yield: 5 g mp: 173-174 ° C

The mother liquor is concentrated under reduced pressure and the residue is also recrystallized from water. Yield: 2.5 g mp: 173 ° C

REPLACEMENT LEAF Overall yield: 7.5 g = 41% of theory

DC:

Silufol // n-butanol / glacial acetic acid / water 4: 1: 1

2nd stage: 4-bromophenyl-triglycine

0.0144 mol of chloroacetyl diglycine are refluxed with 0.029 mol of 4-bromoaniline in 20 ml of ethanol and 20 ml of IN NaOH for 7 hours. After removing the solvent under reduced pressure, the remaining residue is extracted three times with 50 ml of warm acetone each. The product which remains is recrystallized from hot water. The crude product is used in stage 3. Yield: approx. 60%.

3rd stage: chloroacetylation of 4-bromophenyl-triglycine

0.01 mol of 4-bromophenyl-triglycine are dissolved in 10 ml of IN NaOH at room temperature and then 0.012 mol of chloroacetyl chloride and 20 ml of IN NaOH are alternately added at 0 ° C. with stirring within 30 minutes. The mixture is stirred for a further 30 min, acidified with 5N HCl and the product is evaporated to dryness under reduced pressure. The resulting crystals are dissolved in hot water and ethanol is added to the solution. The sodium chloride which precipitates is filtered off and the filtrate is concentrated on a rotary evaporator. The desired product is extracted by repeated treatment with 30 ml of hot acetone each time, the acetone is removed under reduced pressure and the residue is taken up in a little water and lyophilized. Yield: 50% of theory TLC: Silufol // n-butanol / glacial acetic acid / water 2: 1: 1 Rf: 0.6

REPLACEMENT LEAF 4th stage: S-Bzl-acetyl- [N ¹ -Bromphenyl] -Gly-Gly-Gly-OH

0.01 mol of the chloroacetyl product are dissolved in 140 ml of methanol with stirring and protective gas at room temperature. For this purpose, 0.02 mol of thiobenzoic acid are dissolved in 20 ml of methanol and neutralized with sodium methylate, slowly added dropwise with stirring and under a protective gas and stirred for a further 12 hours. The solvent is removed under reduced pressure and the residue is taken up in 2N HCl. The resulting crystals are suctioned off and washed neutral with warm water. The mixture is then washed with 20 ml of chloroform, 20 ml of acetonitrile and 20 ml of ether and the residue is dried under reduced pressure. Yield: 60% of theory

Stage 5: Thio-acetyl- [N ¹ -Bromphenyl] -Gly-Gly-Gly-OH

0.08 mmol of substance from stage 4 are suspended with 2 ml of anhydrous methanol, mixed with 2 mg of Pd / CaC03 (5%), and stirred at a hydrogen pressure of 66 kPa with a solution of 0.13 mmol of sodium methylate 1 ml of absolute methanol implemented. The mixture is stirred for a further 15 minutes and then the solution is neutralized with methanolic Dowex 50WX8. The catalyst and the resin are filtered off, the substance is lyophilized and extracted with 2 ml of benzene. The benzene is then separated off and the substance is lyophilized from ethanol. The cleaning is done by preparative HPLC.

TLC: Silufol // Butanol / glacial acetic acid / water 2: 1: 1

Rf: 0.8

Yield: 40% of theory

99m _Tc [thioacetyl- [N ¹ ^ bromophenyl] -Gly-Gly-Gly-OH

REPLACEMENT LEAF As described for the general complexation before Example 1, thioacetyl- [N ¹ -bromophenyl] -Gly-Gly-Gly-OH is reacted with a [ ^99m Tc] gluconate preparation.

REPLACEMENT LEAF

Claims

1. Compounds of the general formula I

R ³ -S-CH ₂ -CO-NR ---- [CH ₂ -CO-NH] _n -CH ₂ -CO-R ² (I)

wherein

n represents a number 0, 1 or 2,

R ^{1 is} a straight-chain or branched alkyl radical having 1 to 20 carbon atoms, which is optionally interrupted or substituted by one to three oxygen atoms, and which optionally carries a terminal -COOH, -OH or -NH ₂ group, which may also be present Glycolic acid or glycolic acid esters or ethers is esterified or etherified, the esters or ethers being formed with carboxylic acids or alcohols having up to 18 carbon atoms, or a phenyl or cyclohexyl radical, which may be in the 4-position with a COOH -, NH ₂ - or OH group, which is optionally esterified, etherified or amidated or substituted with a halogen atom, with carboxylic acids or alcohols having up to 6 carbon atoms,

R ^{2 represents} a halogen atom, a halomethyl, methyl carboxyl, trifluoromethyl carboxyl, an NH ₂ - or an OH group, the carboxyl group formed in the case of R ² = OH either directly or after esterification with an α, ω -Hydroxycarboxylic acid with up to 8 carbon atoms via their terminal carboxyl group with a biomolecule, a

REPLACEMENT LEAF Steroid, an ergoline derivative, a benzodiazepine derivative, a cholecystokinin, a peptide, a protein, a proteohormone, an aminosugar, an endothelin, an endothelin derivative, an endothelin antagonist or an endothelin fragment is esterified or amidated,

a radical of the general formula II

or the general formula II a

is where

R ^{8 represents} a hydrogen atom or a methyl group,

REPLACEMENT OIL a radical of the general formula III

or the general formula III a

represents what

R ^{5 is} an -NH-, -NH-CO-N <, -NH-CO-NH or methylene oxy group,

R represents a hydrogen atom, a halogen atom or a methyl group and

REPLACEMENT LEAF and their salts with pharmaceutically acceptable acids or bases.

2. Compounds according to claim 1, characterized in that R ^{1 is} a straight-chain or branched alkyl radical having 1 to 6 carbon atoms or a p-bromophenyl radical.

3. Compounds according to at least one of claims 1 and 2, characterized in that R ^{2 represents} an OH or CH3-O group.

4. Compounds according to at least one of claims 1 and 2, characterized in that R ^{2 is} a radical of the general formula II

or the general formula II a

is where

REPLACEMENT LEAF R ^{4 is} a methylene or propynylene amino group and

R ^{8 represents} a hydrogen atom,

5. Compounds according to at least one of claims 1 and 2, characterized in that R ^{2 is} a radical of the general formula III

or the general formula III a

R ⁵

is where

R ^{5 is} an NH group,

R6 is a hydrogen atom or a methyl group and

R ^{7 represents} a methyl, ethyl or n-propyl radical.

REPLACEMENT LEAF 6. Compounds according to at least one of claims 1 to 5, characterized in that R ^{3 is} a hydrogen atom or a benzoyl radical.

7. Compounds according to claim 1, namely

17α- [5- (mercapto-acetyl-sarkosyl-glycyl-amino-1-penten-3-ynyl] estra-1, 3, 5 (10) -triene-3, 17ß-diol,

6-N-methyl-8α-amino- [8α-N- (thio-acetyl-sarkosyl-glycyl-glycyl)] ergoline,

6-N-methyl-8α-amino- [8α-N- (thio-acetyl-sarcosyl)] ergoline,

6-N-methyl-8β-hydroxymethylene- [O- (thio-acetyl-sarcosyl-glycyl-glycyl)] ergoline and

6-N-methyl-8β-hydroxymethylene- [O- (thio-acetyl-sarcosyl-glycyl] ergoline.

8. Metal chelate complexes of radioactive metal ions of the elements Tc, Re, Cu, Ga, Gd, Y and In with

Compounds of the general formula I

R ³ -S-CH ₂ -CO-NR ¹ - [CH ₂ -CO-NH] _n -CH ₂ -CO-R ² (I)

wherein

n represents a number 0, 1 or 2,

REPLACEMENT LEAF R ^{1 is} a straight-chain or branched alkyl radical having 1 to 20 carbon atoms, which is optionally interrupted or substituted by one to three oxygen atoms, and which optionally carries a terminal -COOH, -OH or -NH ₂ group, which may also be present Glycolic acid or glycolic acid esters or ethers is esterified or etherified, the esters or ethers being formed with carboxylic acids or alcohols having up to 18 carbon atoms, or a phenyl or cyclohexyl radical, which may be in the 4-position with a COOH -, NH ₂ - or OH group, which is optionally esterified, etherified or amidated or substituted with a halogen atom, with carboxylic acids or alcohols having up to 6 carbon atoms,

R ^{2 represents} a halogen atom, a halomethyl, methyl carboxyl, trifluoromethyl carboxyl group, an NH ₂ - or an OH group, the carboxyl group formed in the case of R ² = OH either directly or after esterification with an α, ω Hydroxycarboxylic acid with up to 8 carbon atoms via its terminal carboxyl group with a biomolecule, a steroid, an ergoline derivative, a benzodiazepine derivative, a cholecystokinin, a peptide, a protein, a proteohormone, an amino sugar, an endothelin, an endothelin

Derivative, an endothelin antagonist or an endothelin fragment is esterified or amidated,

a radical of the general formula II

REPLACEMENT LEAF

or the general formula II a

is where

R ^{8 represents} a hydrogen atom or a methyl group,

a radical of the general formula III

or the general formula III a

REPLACEMENT LEAF

represents what

R ^{5 is} an -NH-, -NH-CO-N <, -NH-CO-NH or methylene oxy group,

R ^{6 represents} a hydrogen atom, a halogen atom or a methyl group and

and their salts with pharmaceutically acceptable acids or bases.

Metal chelate complexes according to claim 8, characterized gekenn¬ characterized in that the radioactive metal ions are isotopes of the elements Tc and Re.

REPLACEMENT LEAF 10. Metal chelate complexes according to at least one of claims 8 and 9, characterized in that the radioisotope is technetium-99m.

11. Compounds according to claim 8, namely

[ ^99m Tc] -Mercaptoacetylsarcosine, [ ^99m Tc] -Mercaptoacetyl-Sarcosyl-Diglycin, [ ^99m Tc] -Mercaptoacetyl-Hexyglycyl-Diglycin and [" ^m Tc] -Mercaptoacetyl-N ¹ - [4-Bromophenyl] -glycyl-glycyl glycine.

12. Conjugates containing compounds of the general formula I or metal chelate complexes of radioactive metal ions of the elements Tc, Re, Cu, Ga, Gd, Y and In with compounds of the general formula I and substances which accumulate selectively in diseased tissues, with a there is a covalent bond and this in the case of substances containing carboxy or amino groups such as peptides, proteins, antibodies or their fragments, amidically or 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.

13. Conjugates according to claim 12, characterized in that the substances accumulating in the diseased tissue mean peptides such as endotheline, partial sequences of endothelin, endothelin analogues, endothelin derivatives or endothelin antagonists.

14. Conjugates according to claim 12, characterized in that the peptides have the following sequences

REPLACEMENT LEAF II

Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-1

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

I I

Cys-Ser-Cys-Ser-Ser-Trp-Leu-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,

-Tyr-

I I

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,

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

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

or the partial sequence

His-Leu-Asp-Ile-Ile-Trp

or the cyclic amino acid sequences

Cyclo- (DTrp-DAsp-Pro-DVal-Leu),

Cyclo- (DGlu-Ala-alloDIle-Leu-DTrp)

exhibit.

15. A process for the preparation of a compound of general formula I, characterized in that

a) a diketopiperazine derivative of glycine or b) glycine

with a halocarboxylic acid halide and then with an amine of the general formula VI

R ¹ - NH ₂ (VI)

wherein R ^{1 has} the meaning given in claim 1, reacted again with a halocarboxylic acid halide and then with a compound of the general formula IV

R ³ - SH (IV)

where R ^{3 has} the meaning given in claim 1,

REPLACEMENT LEAF implements

or a compound of the general formula V

NH ₂ -CH ₂ -CO-R ² (V)

wherein R ^{2 has} the meaning given in claim 1, with a halocarboxylic acid halide and then with an amine of the general formula VI

R ¹ - NH ₂ (VI),

R3 - SH (IV)

wherein R ^{3 has} the meaning given in claim 1, and that this compound is optionally converted into its salt with a pharmaceutically acceptable acid or base.

16. A process for the preparation of metal chelate complexes of radioactive metal ions of the elements Tc and Re with compounds 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 I

R ³ -S-CH ₂ -CO-NR ** - [CH ₂ -CO-NH] _n -CH ₂ -CO-R ² (I)

REPLACEMENT LEAF wherein R ¹ , R ² and R ^{3 have} the meaning given in claim 1 is implemented.

17. Kit for the production of radiopharmaceuticals, consisting of a compound of general formula I according to one of claims 1 to 7 or a conjugate according to one of claims 12 to 14, and a reducing agent and optionally an auxiliary ligand, which are in the dry state or in solution , as well as 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.

18. Radiopharmaceutical composition for the non-invasive in vivo presentation of receptors and tissue containing receptors and / or of atherosclerotic plaques and / or for kidney function testing, characterized in that it contains a compound according to one of claims 8 to 10 or a conjugate according to the egg ¬ nem of claims 12 to 14 and optionally with the additives customary in galenics, the compound being prepared in a kit according to claim 17 with technetium-99m or Re in the form of a pertechnetate solution or perrhenate solution.

REPLACEMENT LEAF