DE19632052A1 - New benzamide compounds which complex to technetium and/or rhenium - Google Patents

Abstract

Benzamide derivatives of formula Ar-Y-(CH2)n-ZR1R2 (I) are new. Ar = phenyl substituted by one or more X; X = a group which can complex to technetium or rhenium in an oxidation state of less than +7; Y = R'-CONH, R'-O, R'S(O)m, R'-SO2NH or R'-NHCO; m = 0 - 3; R' = bond, CH2 or CHPh; n = 1 - 4; Z = N, or another heteroatom such as O, S or P; R1, R2 = H, 1-6C alkyl, aryl or aralkyl. Also claimed are analogues (II) where X = NHNH2 and one CH of the benzene ring of Ar is optionally replaced by P or N: where (II) form TcO- or ReO- containing complexes, in which Tc and Re have oxidation state <+7. Also claimed is a kit for producing a radio-pharmaceutical for diagnosing and/or treating tumours, especially melanoma, which comprises a reducing agent and (I) or (II), which acts as a ligand for 99mTc, <186>Re and/or <188>Re.

Description

The invention relates to benzamide derivatives and their use for diagnosis and Treatment of tumors, especially melanoma.

The early localization of metastases is aggressive for the treatment of growing melanoma of particular importance. Nuclear medical research has a number of gamma-ray compounds in this context developed after intravenous injection in the primary tumor and in settled Should enrich melanoma metastases. The visual representation of the activity distribution and the possible accumulations in the tumors is then with a gamma camera made, anatomically assigned, assessed and documented.

At the beginning of nuclear medicine research, a number of radioactive ones labeled amino acids tested for their suitability as a means of detection. The first Studies on the selective enrichment of ³H- or ¹⁴C-labeled D, L-DOPA melanoma of the mouse was therefore more than 20 years ago (K. Hempel, M. Deimel :. Naunyn-Schmiedeberg’s Arch. Exp. Path. u. Pharmac. 246, 203- 214 (1963), M.S. Blois Jr., R.F. Kallman. Cancer Res. 24: 863-868 (1964)). Your Results show that radioactivity in can be enriched in the tumor cells - due to the involvement of the labeled DOPA molecules on the melanin biosynthesis and an associated Fixation of the radioisotopes in the cells - that, however, the previously achieved Enrichments for diagnostic purposes are too low.

Subsequent experiments attempted to scintigraphically diagnose melanomas with the help of 13 I-quinoline derivatives, but this marker also proved to be only slightly melanin affinity (W.H. Beierwaltes et al .: JAMA 206, 97-102 (1968)). Another attempt at selective enrichment of radioactivity in melanoma was based on the principle of incorporating so-called "false precursors" in melanin, e.g. B. 3- [1311] iodo-α-methyltyrosine (B. Bubeck et al .: Eur. J. Nucl. Med. 6, 227-233 (1981)) and ¹³¹I-thiouraeil derivatives (A. van Langevelde et al .: Eur. J. Nucl. Med. 8, 45- 51 (1983)). But even with this method, only little radioactivity could be found  Enrichments in melanoma can be achieved, so that this procedure for the clinical practice is not relevant.

Due to the known high affinity for other tumors neuroectodermal The enrichment of 131 I-MIBG (meta-iodine Benzylguanidine) was investigated in melanoma (B. Kimmig, M. Eisenhut, unpublished). The results also show little, for diagnostic purposes inadequate affinity of this radiopharmaceutical for melanotic tissue.

All of the aforementioned compounds show both in animal and in human Melanoma is too low an accumulation to be suitable for clinical use (especially in of diagnostics). In comparison, they are Enrichment values that have recently been identified with radioactively labeled monoclonal Has achieved antibodies against melanoma-associated cell membrane-associated antigens of greater importance (JF Eary, et al .: J. Nucl. Med. 30, 25-32 (1989)). But also this method is not suitable for clinical practice, mainly because because the contrast between the gamma radiation of the melanoma and that of the background is completely insufficient for a satisfactory scintigraphic representation.

Only recently was radioiodinated N- (2-diethylaminoethyl) -4- iodobenzamide propagated as a melanoma-affine substance (J.M. Michelot et al .: J. Nucl. Med. 32: 17573-1580 (1991) and US-5,190,741) and also in a phase II study clinically tested ((J.M. Michelot et al .: J. Nucl. Med. 34: 1260-1266 (1993)). The described Results show significantly improved compared to the aforementioned methods Absolute creaming and cheaper melanoma / background conditions. Still points also this compound marked with ¹²³I some for clinical use very much unfavorable properties, namely (1) the still high underground activity and as a result, low-contrast representation especially in the internal organs and (2) the little or no affinity for amelanotic tumors. These properties are very disadvantageous for diagnostics, since metastases from melanotic primary tumors are very often appear amelanotic.  

By introducing polar groups on the phenyl residues of the radiohalogenated ones The applicant's working group has managed to overcome these disadvantages with benzamide derivatives eliminate or drastically reduce (B. Bubeck, M. Eisenhut, A. Mohammed, C. Nicholl German patent application 195 19 508.6-41). However, this still exists Problem that the radioiodinated benzamides cited due to the immense Manufacturing costs of ¹²³I are very expensive and because of the short physical Half-life of ¹²³I (13 hours) are insufficiently available.

It is therefore an object of the present invention to provide a radiopharmaceutical for the To provide diagnosis and treatment of tumors, in particular melanomas, whose affinity for tumor tissue is sufficiently large to be melanotic Melanomas also derived from but amelanotic metastases easily and safely, without detecting disruptive underground signals, and that in comparison to the previous ones known radiopharmaceuticals cheaper, more readily available and easier to handle.

This object is achieved by providing benzamide derivatives which have structural elements similar to the well-known, highly specific and highly sensitive radio-halogenated benzamide derivatives and can act as complex ligands for transition metals, in particular for technetium and rhenium, and above all for ^99m Tc or ¹⁸⁶Re or ¹⁸⁸Re.

The benzamide ligands according to the invention have the general structural formula:

in the

• - X represents one or more groups, the Technetium Tc or Rhenium Re in one Complex oxidation level <+7,
• - Y for one of the groups R ′ ′ ′ - CONH-, R ′ ′ ′ - O-, R ′ ′ ′ - S (O) _m - (m = 0, 1, 2 or 3), R ′ ′ ′ SO₂NH - or R ′ ′ ′ - NHCO-,
  where R '''represents a connection -CH₂- or -CHPh- or missing completely;
• - n stands for a number 1, 2, 3 or 4; and
• Z represents a nitrogen or other heteroatom such as O, S or P,
  wherein R₁ and R₂ are the same or different and each represents hydrogen, an alkyl group with C₁ to C₆, an aryl group or an aralkyl group.

The technetium ^{isotope 99m} Tc plays an outstanding role in nuclear medicine because of its comparatively low cost, its constant availability and favorable physical properties, especially because of its 141 keV γ energy, which is optimal for scintigraphy. In nuclear medicine laboratories, ^99m Tc is routinely obtained as sodium pertechnetate (Na ^99m TcO₄) from commercially available generators. For this purpose, the Na ^99m TcO₄ formed by Na₂⁹⁹MoO₄ decay is rinsed out with sterile physiological saline from a column filled with aluminum oxide. This generator eluate is with a reducing agent, for. B. a Sn (II) salt, reduced and then fed to a ligand that stabilizes the ^99m Tc by complex formation.

It has also long been a goal of nuclear medicine pharmaceutical research to replace known, clinically valuable, radiohalogenated radiopharmaceuticals with ligands for ^99m Tc that have similar or improved display options. For this purpose, complex ligands were designed and synthesized that contain similar structural elements (pharmacophore group) as are found in the known radiohalogenated radiopharmaceuticals. However, the transfer of such structural elements to ^99m Tc complex ligands has always been very difficult in the past, since the biological properties of the pharmacophoric group are normally lost due to the introduction of a ^99m Tc ligand.

With the present invention it is now possible for the first time to have one or more To provide radiopharmaceuticals, the one hand, one or more known to contain highly effective pharmacophoric group (s) and on the other hand Ligand structures for complex formation with transition metals, especially with  Technetium exhibit, and in which the biological properties of the Pharmacophoric group (s) are also preserved in the state of complex formation.

In animal experiments for the diagnosis and treatment of tumors, in particular melanomas, it was surprisingly found that the benzamide derivatives according to the invention, despite their ( ^99m Tc) ligand structures and in the presence of the complex metal, are predominantly accumulated in the tumor tissue. With the compounds according to the invention it is thus possible to ensure high-contrast scintigraphic representations.

Instead of technetium, rhenium can also be used. The chemistry of rhenium and sodium perrhenate (NaReO₄) is related to that of technetium and the ligands that form stable complexes with ^99m Tc are also suitable for ¹⁸⁶Re and ¹⁸⁸Re for analogous complex formation. In addition, the use of ¹³⁶Re and ¹⁸⁸Re for therapeutic purposes is already known.

A first preferred group (type I) of benzamide derivatives according to the invention is characterized in that a second substituent X₂ is provided on the phenyl ring, and in that X₁ and X₂ are the same or different and each have a structure of the formula -Z ′ - (CR Represent '₂) _m -Z''-R''.

Z 'and Z' 'are the same or different and stand for groups that Tc or Re in an oxidation level <+7 complex, namely for: NH, PH, S, CONH, NHCO, COPH, or PHCO.

R ′ is an alkyl group with a carbon number from C₁ to C₆ or hydrogen,
m stands for 1, 2 or 3, and
R '' is an alkylidene group of the formula - (CH₂) _r - with r = 2, 3 or a benzyl, benzoyl, or acetyl group or hydrogen.

This type I of the benzamide derivatives according to the invention can be determined by the general formula

being represented.

In a particularly preferred embodiment of these type I benzamide derivatives the substituents and the variables are implemented as follows:

X₁ = X₂ = NH-CH₂-C (CH₃) ₂-SH
Y = CONH, n = 2, Z = N, R₁ = CH₂-CH₃, R₂ = R₁.

This benzamide derivative therefore has the specific structural formula:

and forms with Technetium a complex of the kind:

A second preferred group (type II) of benzamide derivatives according to the invention is characterized in that X is a structure of the formula

• a. Z ′ ′ ′ - (CH₂) _s -CH- [CH₂-Z ′ - (CR′₂) _m -Z ′ ′ - R ′ ′] ₂ or
• b. Z ′ ′ ′ - (CH₂) _s -CH [Z ′ - (CR′₂) _m -Z ′ ′ - R ′ ′] - CH₂-Z ′ - (CR′₂) _m -Z ′ ′ - R ′ ′ or
• c. Z ′ ′ ′ - (CH₂) _s -Z ′ ′ ′ ′ [(CR′₂) _m -Z ′ ′ - R ′ ′] - (CH₂) _t -Z ′ - (CR′₂) _m -Z ′ ′ -R ′ ′ represents

where Z 'and Z''are the same or different and stand for groups that Tc and / or
Complex Re in an oxidation state <+7, namely: NH, PH, S, CONH, NHCO, COPH or PHCO,
R ′ represents an alkyl group with a carbon number from C₁ to C₆ or hydrogen,
m = 1, 2 or 3,
R '' represents an alkylidene group of the formula - (CH₂) _r - with r = 2, 3 or a benzyl, benzoyl, acetyl group or hydrogen, and
Z ′ ′ ′ - (CH₂) _s - is a spacer that separates the benzamide and the ligand,
where Z '''= OCH₂-, CH₂-, or NH- and s = 0, 1, 2, 3 or 4.

In a particularly preferred embodiment of this benzamide derivative from Type II (a), the substituents and the variables are realized as follows:

X = O- (CH₂) ₄-CH [CH₂-NH-CH₂-C (CH₃) ₂SH] ₂
Y = CONH, n = 2, Z = N, R₁ = CH₂-CH₃, R₂ = R₁.

This benzamide derivative (type II a) therefore has the specific structural formula:

and forms with Technetium a complex of the kind:

In another, also particularly preferred embodiment of the Type II (b) benzamide derivatives, the substituents and the variables are as follows realized:

X = CH₂-CH [NH-CH₂-C (CH₃) ₂SH] -CH₂-NH-CH₂-C (CH₃) ₂SH
Y = CONH, n = 2, Z = N, R₁ = CH₂-CH₃, R₂ = R₁.

This benzamide derivative (type II b) therefore has the specific structural formula:

and forms with Technetium a complex of the kind:

In yet another, also very preferred embodiment of the benzamide derivative of type II (c) the substituents and the variables are realized as follows:

X = CH₂-N [CH₂-C (CH₃) ₂SH] - (CH₂) ₂-NH-CH₂-C (CH₃) ₂SH
Y = CONH, n = 2, Z = N, R₁ = CH₂-CH₃, R₂ = R₁.

This benzamide derivative (type IIc) therefore has the specific structural formula:

and forms with Technetium a complex of the kind:

A third preferred group (type III) of benzamide derivatives according to the invention is characterized in that X = NH₂-NH, and that a carbon atom of the phenyl ring is substituted by an N, P, O, or S (generally X ') and together with the Hydrazino group ("NH₂-NH-") TcO and / or ReO-containing complexes in which Tc or Re with an oxidation state <+7 can bind.

These type III benzamide derivatives can be represented by the general structural formula

being represented

In a particularly preferred embodiment of these benzamide derivatives from Type III, the substituents and the variables are implemented as follows:

X = NH₂-NH, X ′ = N ′ Y = CONH, n = 2, Z = N, R₁ = CH₂-CH₃, R₂ = R₁.

This benzamide derivative therefore has the concrete structural formula

and forms with Technetium a complex of the kind:

where as ligand gluconate, tricin or the like are suitable.

A fourth preferred group (type IV) of benzamide derivatives according to the invention is characterized in that X is a PH₂ or SH and with complexes in which Tc or Re with an oxidation state <+7 can bind.

These type IV benzamide derivatives can be represented by the general structural formula:

being represented.

In a particularly preferred embodiment of these benzamide derivatives from Type IV, the substituents and the variables are realized as follows:

X = SH, Y = CONH, n = 2, Z = N, R₁ = CH₂-CH₃, R₂ = R₁.

This benzamide derivative therefore has the specific structural formula:

and forms with Technetium a complex of the kind:

The invention also relates to the use of the various aforementioned Compounds for the manufacture of a radiopharmaceutical for diagnostics and / or therapeutic treatment of tumors, especially melanomas. she thus of course also includes all pharmaceutical agents, one or contain several of the compounds of the invention.

The invention also relates to a kit for the manufacture of a pharmaceutical for the diagnosis and / or therapeutic treatment of tumors, in particular melanoma, which comprises a ligand for ^99m Tc and / or ¹⁸⁶Re and / or ¹⁸⁸Re and a reducing agent, and in which the ligand comprises one of the benzamide derivatives according to the invention is implemented.

In order to explain the invention in more detail, some production examples are given below and given an application example:

Example 1: Preparation of a Type I benzamide ligand and ^99m Tc complex formation

2 g of 3,4-diaminobenzoic acid (13.2 mmol) is mixed with 5.72 g (t-BOC) ₂O (26.4 mmol) implemented at room temperature for 20 hours. The on the amino groups with BOC Groups protected 3,4-diaminobenzoic acid is then treated with 2-diethylamino protected ethylamine in the presence of 1-hydroxy-7-azabenzotriazole in the BOC Benzamide transferred. By pouring HCl into a BOC dioxane solution  Protected benzamids split off the BOC groups. The crystals that precipitate are recrystallized from ethyl acetate. 3.14 g (83% yield) are pure Obtain N- (2-diethylaminoethyl) -3,4-diaminobenzamide.

3 g of the N- (2-diethylaminoethyl) -3,4-diaminobenzamide (10.5 mmol) is added equimolar amounts of dialdehyde, OHC-C (CH₃) ₂-S-S-C (CH₃) ₂-CHO in 300 ml of ethanol put together and converted under reflux into the cyclic diimine. The subsequent reduction with 1.5 times the molar amount of NaB₄ gives one 10-membered heterocycle, which is almost quantitative with dithiothreitol in a benzamide general formula I with the following concrete structural formula Ia:

MS: m / z 426 ([M⁺], 8). Elemental analysis as HCl salt: Theoretical (% by weight) C 47.05, H 7.71, N 10.45; Found (wt%) C 46.96, H 7.61, N 10.30.

This benzamide Ia can act as a ligand for ^99m Tc (or also for ¹⁸⁶Re or ¹⁸⁸Re). The ^99m Tc marking takes place at room temperature with 0.5 mg benzamide Ia in the presence of 0.1 molar equivalents of SnCl₂ and 1 GBq ^99m TcO₄-. The labeling yield is <93%.

Example 2: Preparation of a benzamide ligand of type II (a) and ^99m Tc complex formation

50 mg of a heterobifunctional NHS-BAT ester [= N-hydroxysuccinimide ester of 6- (4 ′ - (4 ′ ′ - carboxyphenoxy) butyl) -2,10-dimercapto-2,10-dimethyl-4,8-d-iazaundecane] (M. Eisenhut et al., J. Nucl. Med. 37: 362-370, 1996) is reacted almost quantitatively in acetonitrile with an equimolar amount of 2-diethylaminoethylamine to give a benzamide of the general formula II. This benzamide is precipitated as the hydrochloride salt in diethyl ether and recrystallized from ethyl acetate. It can act as a ligand for ^99m Tc (or also for ¹⁸⁶Re or ¹⁸⁸Re) and has the following specific structural formula:

MS: m / z 540 ([M⁺], 5). Elemental analysis as HCl salt: Theoretical (% by weight) C 51.72, H 8.53, N 8.62; Found (wt%) C 51.55, H 8.61, N 8.50.

The ^99m Tc marking is carried out at room temperature with 0.5 mg of type II (a) benzamide in the presence of 0.1 molar equivalents of SnCl₂ and 1 GBq of ^99m TcO₄-. The labeling yield is <93%.

Example 3: Preparation of a benzamide ligand of the type in and ^99m Tc complex formation

100 mg of the N-hydroxysuccinimide ester of 6- [2- (t-butoxycarbonyl) hydrazino] pyridine-3-carboxylic acid (MJ Abrams et al., J. Nucl. Med. 31: 2022-2028, 1990; DA Schwarz et al ., Bioconjugate Chem. 2: 333-336, 1991) are reacted with an equimolar amount of 2-diethylaminoethylamine in acetonitrile to give the amide. Acid hydrolysis of the BOC groups with trifluoroacetic acid gives a benzamide of the general formula III, namely N- (2-diethylaminoethyl) -6-hydrazinopyridine-3-carboxamide. This benzamide can act as a ligand for ^99m Tc (or also for ¹⁸⁶Re or ¹⁸⁸Re) and has the following specific structural formula:

MS: m / z 251 ([M⁺], 16). Elemental analysis as HCl salt: Theoretical (% by weight) C 44.45, H 7.15, N 21.60; Found (% by weight) C 44.18, H 7.01, N 21.48.

The ^99m Tc labeling is carried out at room temperature with 0.1 mg of this benzamide III in the presence of the previously prepared ^99m Tc-tricin complex. After a reaction time of 30 minutes, the labeling yield is <90%.

Example 4: Preparation of a benzamide ligand of type IV and ^99m Tc complex formation

200 mg of 4-mercaptobenzoic acid is dissolved in acetonitrile and converted into a benzamide of the general formula IV with a 1.1-fold molar excess of 2-diethylaminoethylamine in the presence of the uronium salt of 1-hydroxy-7-azabenzotriazole (HATU). The product is isolated chromatographically and recrystallized from ethyl acetate. The benzamide obtained can act as a co-ligand for ^99m Tc (or also for ¹⁸⁶Re or ¹⁸⁸Re) and has the following specific structural formula:

MS: m / z 252 ([M⁺], 24). Elemental analysis as HCl salt: Theoretical (% by weight) C 54.06, H 7.33, N 9.70; Found (% by weight) C 53.86, H 7.20, N 9.45.

The ^99m Tc marking is carried out at room temperature by mixing 20 ul of a 10 mM solution of the benzamide ligand IV, 20 ul of the 10 mM diethylenetriamine as auxiliary ligand solution, SnCl₂ and ^99m TcO₄-. After 5 minutes, <90% of the desired complex has formed.

Example 5: Distribution of radioactivity in the test animal

The type II (a) benzamide derivative prepared according to Example 2 was C 57 B16 Mice with subcutaneously transplanted B16 melanoma intravenously in a tail vein injected and dissected after 60 or 360 minutes. The radioactivity measurements of the Organ samples were taken after organ removal and tissue weighing. The recording the radioactivity accumulated in the organs was then injected onto the Activity quantity related and standardized to one gram. This resulted in the so-called "relative organ activity value". In Table 1 below, the results are as Percentage dose injected per gram of melanoma or organ tissue (% ID / g Melanoma). The values given are average values (medians) of each three animals for each time. For the sake of clarity, the deviations omitted.

The results show a clear accumulation of the ^99m Tc complex according to the invention in the melanoma tissue after only 60 minutes. Compared to muscle and blood, which usually form the background from which a melanoma or a settled metastasis should be scintigraphically distinguished, the accumulation is 5 to 10 times. After 360 minutes, the concentration is still many times higher and is at least 5 times higher than that of other important underground organs such as the heart, lungs, spleen and brain. Only in the liver and kidneys, the central organs of metabolism, which are also responsible for the breakdown of endogenous and foreign metabolic waste products, is there a greater accumulation than in the melanoma.

In contrast, the connection according to the invention enables in all other areas of the body a clear scintigraphic representation of even poorly developed melanoma or metastases. It stands with respect to the known iodinated benzamide derivatives is practically equivalent to the quality of detection, but also offers the essential advantages of the significantly cheaper production and the simpler technical handling, causing health risks to the user drastically are reduced.

Table 1

(Radioactivity certificate)

Claims (17)

1. Benzamide derivative of the general formula in the

• X represents one or more groups which complex technetium Tc or rhenium Re in an oxidation state <+7,
• - Y for one of the groups R ′ ′ ′ - CONH-, R ′ ′ ′ - O-, R ′ ′ ′ - S (O) _m - (m = 0, 1, 2 or 3),
  R ′ ′ ′ SO₂NH- or R ′ ′ ′ - NHCO-,
  where R '''represents a connection -CH₂- or -CHPh- or missing completely;
• - n stands for a number 1, 2, 3 or 4; and
• - Z represents a nitrogen or other heteroatom such as O, S or P, where R₁ and R₂ are the same or different and each represents hydrogen, an alkyl group with C₁ to C₆, an aryl group or an aralkyl group.

2. Benzamide derivative according to claim 1, characterized in
that a second substituent X₂ is provided on the phenyl ring,
and that X₁ and X₂ are identical or different from one another and each represent a structure of the formula -Z ′ - (CR′₂) _m -Z ′ ′ - R ′ ′,
where Z ′ and Z ′ ′ are the same or different and stand for groups which complex Tc or Re in an oxidation state <+7, namely: NH, PH, S, CONH, NHCO, COPH, or PHCO,
R ′ represent an alkyl group with a carbon number from C₁ to C₆ or hydrogen,
m = 1, 2 or 3, and
R '' represents an alkylidene group of the formula (CH₂) _r - with r = 2, 3 or a benzyl, benzoyl, or acetyl group or hydrogen. 3. Benzamide derivative according to claim 2, characterized in that the substituents and the variables are realized as follows: X₁ = NH-CH₂-C (CH₃) ₂-SH
X₂ = X₁
Y = CONH
n = 2
Z = N
R₁ = CH₂-CH₃
R₂ = R₁and that the benzamide derivative has the following specific structural formula: 4. Use of a compound according to claim 1, 2 or 3 for diagnosis and Treatment of tumors, especially melanoma. 5. Benzamide derivative according to claim 1, characterized in that

• - X is a structure of the formula
• a. Z ′ ′ ′ - (CH₂) _s -CH- [CH₂-Z ′ - (CR′₂) _m -Z ′ ′ - R ′ ′] ₂ or
• b. Z ′ ′ ′ - (CH₂) _s -CH [Z ′ - (CR′₂) _m -Z ′ ′ - R ′ ′] - CH₂-Z ′ - (CR′₂) _m -Z ′ ′ - R ′ ′ or
• c. Z ′ ′ ′ - (CH₂) _s -Z ′ ′ ′ ′ [(CR′₂) _m -Z ′ ′ - R ′ ′] - (CH₂) _t -Z ′ - (CR′₂) - _m Z ′ ′ -R ′ ′ represents

where Z ′ and Z ′ ′ are identical or different and stand for groups which complex Tc and / or Re in an oxidation state <+7, namely: NH, PH, S, CONH, NHCO, COPH or PHCO,
R ′ represents an alkyl group with a carbon number from C₁ to C₆ or hydrogen,
m = 1, 2 or 3,
R '' represents an alkylidene group of the formula - (CH₂) _r - with r = 2, 3 or a benzyl, benzoyl, acetyl or hydrogen group, and
Z ′ ′ ′ - (CH₂) _s - is a spacer that separates the benzamide and the ligand,
where Z '''= OCH₂-, CH₂-, or NH- and s = 0, 1, 2, 3 or 4. 6. Benzamide derivative according to claim 5, characterized in that the substituents and the variables are realized as follows: X = O- (CH₂) ₄-CH [CH₂-NH-CH₂-C (CH₃) ₂SH] ₂
Y = CONH
n = 2
Z = N
R₁ = CH₂-CH₃
R₂ = R₁and that the benzamide derivative has the following specific structural formula: 7. Benzamide derivative according to claim 5, characterized in that the substituents and the variables are realized as follows: X = CH₂-CH [NH-CH₂-C (CH₃) ₂SH] -CH₂-NH-CH₂-C (CH₃) ₂SH
Y = CONH
n = 2
Z = N
R₁ = CH₂-CH₃
R₂ = R₁and that the benzamide derivative has the following specific structural formula: 8. Benzamide derivative according to claim 5, characterized in that the substituents and the variables are realized as follows: X = CH₂-N [CH₂-C (CH₃) ₂SH] - (CH₂) ₂-NH-CH₂-C (CH₃) ₂SH
Y = CONH
n = 2
Z = N
R₁ = CH₂-CH₃
R₂ = R₁and that the benzamide derivative has the following specific structural formula: 9. Use of a compound according to one of claims 5 to 8 for diagnosis and treatment of tumors, especially melanomas.   10. Benzamide derivative according to claim 1, characterized in that

• - X = NH₂-NH, and that
• - A CH group in the phenyl ring can be substituted by an N or P (generally X ') and with a hydrazino group ("NH₂-NH-") TcO- and / or ReO-containing complexes in which Tc or Re with an oxidation state <+7 can bind.

11. Benzamide derivative according to claim 10, characterized in that the substituents and the variables are realized as follows: X = NH₂-NH
the C atom on the phenyl ring is substituted by N.
Y = CONH
n = 2
Z = N
R₁ = CH₂-CH₃
R₂ = R₁and that the benzamide derivative has the following specific structural formula: 12. Use of a compound according to claim 10 or 11 for diagnosis and Treatment of tumors, especially melanoma. 13. Benzamide derivative according to claim 1, characterized in that X is a PH₂, or SH and with complexes in which Tc or Re with a Oxidation level <+7 are present, can bind.   14. Benzamide derivative according to claim 13, characterized in that the substituents and the variables are realized as follows: X = SH
Y = CONH
n = 2
Z = N
R₁ = CH₂-CH₃
R₂ = R₁and that the benzamide derivative has the following specific structural formula: 15. Use of a compound according to claim 13 or 14 for diagnosis and Treatment of tumors, especially melanoma. 16. Kit for the production of a radiopharmaceutical for the diagnosis and / or therapeutic treatment of tumors, in particular melanomas, characterized in that it comprises a ligand for ^99m Tc and / or ¹⁸⁶Re and / or ¹⁸⁸Re and a reducing agent, and that the ligand is a Benzamide derivative according to one of claims 1, 2, 3, 5-8, 10, 11, 13 or 14.