LU87633A1 - PEPTIDE DERIVATIVES - Google Patents

Description

PEPTIDE DERIVATIVES

The present invention relates to polypeptides, a process for their production, the pharmaceutical preparations containing them and their use as a pharmaceutical product, for example for treating tumors positive for somatostatin receptors or as in vivo diagnostic imaging agents.

In recent years, a high incidence of somatostatin receptors has been demonstrated in a variety of tumors in humans, for example, pituitary tumors, central nervous system tumors, breast tumors, gastroenteropancreatic tumors and their metastases. Some of them are small tumors or slow growing tumors which are difficult to locate with precision by conventional diagnostic methods.

In vitro visualization of somatostatin receptors was performed by autoradiography of tumor tissue using somatostatin or radioiodinated somatostatin analogs, for example [125j_Tyrll] somatostatin-14 (JE Taylor et al. Life Science (1988) ) _43, 421) or the (- * - 25j_Tyr3j sMS 201-995, also called [12 ^ I] 204-090 (JC Reubi et al., Brain Res. (1987) 406, 891; JC

Reubi et al., J. Clin. Endocr. Metab. (1987) 65, 1127; J.

C. Reubi et al., Cancer Res. (1987) 47, 551; J. C. Reubi et al., Cancer Res. (1987) A1, 5758).

We have now discovered new somatostatin peptides useful in therapy and which can be labeled for in vivo diagnosis and new therapeutic applications.

The subject of the invention is a somatostatin peptide carrying at least one chelating group for a detectable element, this chelating group being linked to an amino group of said peptide and this amino group having no significant binding affinity for the receptors of the somatostatin.

In the following, these compounds are called LIGANDS OF THE INVENTION. They have a chelating group capable of reacting with a detectable element, for example a radionuclide, a radiopaque element or a paramagnetic ion, to form a complex, and are further capable of binding to the somatostatin receptors, for example expressed or overexpressed by tumors or metastasis.

The chelating group is linked by a covalent bond to the amino group of the peptide.

The chelating group is preferably attached to the N-terminal amino group of the somatostatin peptide.

According to the invention, the chelating group can be attached directly or indirectly, for example by means of a spacer group, to the amino group of the somatostatin peptide.

One of the LIGANDS groups and one in which the chelating group is attached directly to the amino group of the somatostatin peptide.

Another LIGANDS group is that in which the chelating group is indirectly attached to the amino group of the somatostatin peptide by a bridging or spacer group.

Preferably, the chelating group is attached to the peptide by an amide bond.

The term "somatostatin peptides" includes naturally occurring somatostatin (tetradecapeptide) and its analogs or derivatives.

By derivatives or analogues, which are terms used herein, is meant any straight or cyclic chain polypeptide derived from tetradecapeptidic somatostatin of natural origin, in which one or more ami-noacid units have been deleted and / or replaced by one or more other amino acid radicals and / or in which one or more functional groups have been replaced by one or more other functional groups and / or one or more groups have been replaced by one or more other isosteric groups. In general, the term covers all the modified derivatives of a biologically active peptide which produces an effect qualitatively similar to that of the unmodified somatostatin peptide, for example those which bind to somatostatin receptors and decrease hormonal secretion.

Cyclic, cyclic bridged and straight chain somatostatin analogs are known compounds. These compounds and their preparation are described, for example, in European patents EP-A-1295, 29 579, 215 171, 203 031, 214 872, 298 732, 277 419.

The preferred LIGANDS OF THE INVENTION are those derived from the following somatostatin analogs:

A. Analogues of formula I

in which A is a C 1-6 alkyl phenylalkyl group or a group of the formula RCO-, in which i) R is hydrogen, a C 1-6 alkyl group, phenyl or phenylalkyl in £ · η- £ \ §Ι or ii) RCO- is a) a residue of L- or D-phenylalanine optionally substituted on the nucleus by F, Cl, Br, NO2, NH2, OH, C1-C3 alkyl and / or alkoxy in 0 ^ - 03; b) the residue of a natural or synthetic α-amino acid other than that defined in a) above or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid residues are identical or different and are chosen from those defined in a) and / or b) above, the α-amino acid group of the amino acid residues a) and b) and the N-terminal amino group of the dipeptide residues c) being optionally mono- or di-alkylated (C ^ -C ^) or substituted with a C ^ -Cg alkanoyl, A 'is hydrogen, a C3-C32 alkyl group or phenyl-Cy-C ^ Q / Y3 and Y2 and Y2 represent together a direct bond where each of the radicals Y ^ and Y2 is independently a hydrogen or a radical of formulas f1 to (5)

(4) (5) in which

Ra is a methyl or ethyl group

Rb is hydrogen, methyl or ethyl group m is an integer from 1 to 4 n is an integer from 1 to 5

Rc is a C ^ -Cg alkyl group R <j represents the substituent attached to the carbon atom a of a natural or synthetic α-amino acid (including hydrogen)

Re is a Cq-Cg alkyl group

Ra 'and R] -,' are each independently hydrogen, methyl or ethyl,

Rg and R9 are each independently hydrogen, halogen, C1-C6 alkyl or C2-C3 alkoxy, p is zero or equal to 1, q is zero or equal to 1, and 'r is zero, equal at 1 or 2, B is -Phe-, optionally substituted on the nucleus by a halogen, an NO2, NHg, OH group, C ^ -Cg alkyl and / or C ^ -Cg alkoxy (including pentafluoroalanine) , or the β-naphthyl-Ala C group is (L) -Trp- or (D) -Trp-, optionally α-Ν-methylated and optionally substituted on the benzene ring by a halogen, a NOg, NHg, OH group, C ^ -Cg alkyl and / or C ^ -Cg alkoxy, D is Lys, Lys in which the side chain contains 0 or S in position β, ftF-Lys or 6F-Lys, optionally aN-methylated, or a residue 4-aminocyclohexylAla or 4-ami-nocyclohexylGly E is Thr, Ser, Val, Phe, Ile or a residue of ami-noisobutyric acid or aminobutyric G is a group of formula

where R7 is hydrogen or a C3-C3 alkyl group, R3_q is a hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, Rq is hydrogen, a C1-C3 alkyl group, phenyl or phenylalkyl in C7-C10 / R ^ 2 is hydrogen, a C2-C3 alkyl group or a group of formula -CH (R ^ 3) -X ^, R13 is CH2OH, - (CH2) 2 “OH, - (CH2) 3-OH or -CH (CH3) OH, or represents the substituent attached to the carbon atom in a of a natural or synthetic α-amino acid (including a hydrogen) and X · ^ is a group of formula -COOR7 , -CH2OR2o or

where R7 and R10 have the meanings given above,

Rj_4 is hydrogen or O ^ -03 alkyl and R-j_5 is hydrogen, C ^ -C2 alkyl, phenyl or phenyl C7 -C30, and R] _g is hydrogen or hydroxy, provided that when R] _2 is -CH (R] _3) -X] _, R] _] _ is then hydrogen or a methyl group, where residues B, D and E have the L configuration, and the residues in position 2 and in position 7 and all the residues Y-j_ 4) and Y2 4) each independently have the configuration (L) or (D).

The meanings of A and A ′ are preferably chosen in formula I so that the compound contains a terminal —NH- group capable of binding to a chelating agent.

In the compounds of formula I, the following meanings are preferred, either individually, or in combination or in sub-combination: 1. A is a C7-C1Q phenylalkyl group, in particular phenethyl, or a group of formula RCO. Preferably, A is a group of formula RCO.

1.1. Preferably, R is a C 1 -C 4 alkyl phenyl or C 1 -C 4 alkyl group, in particular phenyl C 1 -C 4 alkyl, more preferably phenethyl, or RCO has the meanings a), b) or c).

1.2. When RCO has the meanings a), b) or c), the α-amino group of the amino acid residues a) and b) and the N-terminal amino group of the dipeptide residues c) are preferably non-alkylated or monoalkylated / en particu lier alkylated (C ^ -Cg), better still methylated. In particular, the N-terminal group is non-alkylated.

1.3. When RCO has the meaning a), it is preferably a ') a residue of L- or D-phenylalanine or tyrosine, possibly mono-N-alkylated (C - ^ - C · ^) · Very particularly, a ') is a residue of L- or D-phenylalanine.

1.4. When RCO has the meaning b) or c), the residue defined is preferably lipophilic. The preferred residues b) are thus b ') α-amino acid residues comprising a hydrocarbon side chain, for example alkyl, comprising 3, preferably 4, carbon atoms, or more, for example up to 7 C atoms , a naphthyl-methyl or heteroaryl group, for example a residue of 3- (2- or 1-naphthyl) -alanine, pyridylmethyl or tryptophan, said residues having the L or D configuration, and the preferred residues c) are dipeptide residues in which the individual amino acid residues are identical or different and are chosen from those defined in a ') and b') above.

An example of residue c) is, for example, a residue of 3- (2-naphthyl) alanine.

1.5. In particular, RCO has the meaning a), in particular the meaning a ').

2. B is B ', B' being Phe or Tyr.

3. C is C ', C' being (D) Trp.

4. D is D ', D' being Lys, MeLys or Lys (£ -Me), in particular Lys.

5. E is E ', E' being Val or Thr, in particular Thr.

6. G is G1, G 'being a group of formula

in particular a group of formula

(in which case R13 = H or CH3). In the latter case, the group -CH (R] _3) -X] _ preferably has the configuration L.

6.1. is preferably hydrogen.

6.2. As a substituent attached to the α atom of a natural amino acid (ie of formula H2N-CH (R] _3) -COOH), R] _3 is preferably -CH2OH,

-CH (CHt) -OH, isobutyl or butyl, or R-i 3 is - (CH2) 2-OH or - (CH2) 3-OH. These are in particular -CK2OH or -CH (CH3) OH.

• 6.3. Xi is preferably a group of formula or -CH2-OR10 / in particular of formula -CH2-OR10, and R10 is preferably hydrogen or has the meaning indicated in 7 below. In particular, R ^ q is hydrogen.

The following individual compounds are illustrative of the comooses of formula I:

B. Analoques_de_. formula II

II

[see Vale et al., Metabolism, 27, supp. 1, 139 (1978)]

III

(see EP-A-200 188)

The content of all the above publications, containing the specific compounds, is specifically cited here for reference.

The particularly preferred LIGANDS are those derived from

Suitable chelating groups are physiologically acceptable chelating groups capable of complexing a detectable element. Preferably, the chelating group has an essentially hydrophilic character. Examples of chelating groups include, for example, iminodicarboxylic groups, polyaminopolycarboxylic groups, for example those derived from non-cyclic ligands, for example ethylenediaminetetraascetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-Ο, Ο'-bis (2-aminoethyl) -N, N, N ', N'-tetraacetic (EGTA), acid N, N'-bis (hydroxybenzyl) ethylenediami-ne-N, N'- diacetic acid (HBED) and triethylenetetramine hexaacetic acid (TTHA), those derived from substituted EDTA or substituted DTPA, for example p-isothiocyanatobenzyl-EDTA or -DTPA, those derived from macrocyclic ligands, for example-

pie acid 1, 4,7,10-tetra-azacyclododecane-N, N ', N ", N"' - tetraacetic (DOTA) and acid 1,4,8,11-tetra-azacyclo-tetradecane- Ν, Ν ', N ", N"' - tetraacetic (TETA), those derived from N-substituted or C-substituted macrocyclic amines, including also cyclams, for example those described in EP-A1-304 780 and in WO 89/01476-A, the groups of formula IV or V

IV

V

where each of the radicals Rj_, R2 and R3 is independently a Cq-Cg alkyl, Cg-Cg aryl or C7-Cg arylalkyl group, each being optionally substituted by OH, a 0 ^ -04 alkoxy group, COOH or SO3H , n 'is equal to 1 or 2, i is an integer from 2 to 6, and TT are independently a- or β-amino acids linked to each other by amide bonds,

groups derived from bis-aminothiol derivatives, for example the compounds of formula VI

VI

in which each of the radicals R20, R21, R22 and R23 is independently a hydrogen or a C1-C4 / X2 alkyl group is a group capable of reacting with the N-amino group of the peptide, and m 'is equal to 2 or 3 ,

groups derived from dithiasemicarbazone derivatives, for example the compounds of formula VII

VII

in which X2 is as defined above,

groups derived from propylene-amine oxime derivatives, for example the compounds of formula VIII

VIII

in which each of the radicals R24 / R25 / · R26 'R27' R28 and R29 is / independently, hydrogen or a C 1 -C 4 alkyl group; j_-C4, and X2 and m1 are as defined above,

groups derived from diamidedimercaptides, for example the compounds of formula IX

IX

in which X3 is a divalent radical optionally substituted and bearing a group capable of reacting with the N-amino group of the peptide, for example alkylene or phenylene bearing a group X2, and · Y5 is a hydrogen or CO2R30 / where R30 is a group <^ - 04 alkyl, or groups derived from porphyrins, for example N-benzyl-5,10,15,20-tetrakis- (4-carboxyphenyl) porphine or TPP carrying a group X2 as defined above.

The aryl group is preferably a phenyl group. The arylalkyl group is preferably a benzyl group.

Examples of X2 include the radicals of formula - (X4) nii-X5, wherein X4 is C 1 -C 4 alkylene; or a C] _ ~ Cg alkylene optionally attached to the carbon atom by an oxygen atom or -NH-, n "is zero or equal to 1 and X5 is -NCS, a carboxy group or one of its derivatives functional, for example an acid halide, an anhydride or a hydrazide. It is understood that X2 is attached to one of the carbon atoms of ~ [CH2] m "" ou = CH-CH = instead of a hydrogen atom.

The chelating group can be attached, directly or indirectly, to the N-amino group of the somatostatin peptide. When it is attached indirectly, it is preferably attached via a bridging or spacer group, for example a group of formula (al) Z-R35-CO- (al) R35 is a C ^ alkylene group -C ^, alkenylene or -CH (R ') -, in which R' is the residue attached in a to a natural or synthetic a-amino acid, for example hydrogen, a C 1 -C 4 alkyl group, benzyl, optionally substituted benzyl, naphthylmethyl, pyridylmethyl, Z is a functional group capable of reacting covalently with a chelating agent.

Z can be, for example, a group which can form an ether, ester or amide bond with the chelating group. Z is preferably an amino.

The chelating groups, when they include carboxy, -SO3H and / or amino groups, can exist in free form or in salt form.

Preferred chelating groups are those derived from polyaminopolycarboxylic groups, for example those derived from EDTA, DTPA, DOTA, TETA or EDTA or substituted DTPA. Particular preference is given to chelating groups derived from DTPA.

In the LIGANDS OF THE INVENTION, the chelating group, when it is polyfunctional, may be linked either to a single molecule of somatostatin peptide, or to more than one molecule of somatostatin peptide, for example to two peptide molecules somatostatin.

The LIGANDS OF THE INVENTION may exist, for example, in free form or in the form of salt. The salts include acid addition salts with, for example, organic acids, polymeric acids or mineral acids, for example hydrochlorides and acetates, and salt forms which can be obtained with the presence of carboxylic or sulfonic acid groups in the chelating group, for example the alkali metal salts such as sodium or potassium, or the substituted or unsubstituted ammonium salts.

The present invention also relates to a process for producing the LIGANDS OF THE INVENTION. They can be produced by analogy with known methods.

The ligands of the invention can be produced, for example, in the following manner: a) elimination of at least one protecting group which is present in a somatostatin peptide carrying a chelating group, or b) binding to one other, by an amide bond, of two peptide fragments each containing at least one friend-noacid or an amino alcohol in protected or unprotected form and one of them containing the chelating group, the amide bond being such that one obtains the desired amino acid sequence, optionally followed by step a) of the process, or c) binding to one another of a chelating agent and of the desired somatostatin peptide in protected or unprotected form, so as to fix the chelating group on the desired N-amino group of the peptide, optionally followed by step a), or d) elimination of a functional group from an unprotected or protected peptide carrying a chelating group or its conversion into another group functional d e so as to obtain another unprotected or protected peptide carrying a chelating group, step a) of the process being carried out in the latter case, or

e) oxidation of a somatostatin peptide modified by a chelating group in which the mercapto groups of the Cys radicals exist in free form so as to produce an analog in which two Cys radicals are linked by an S-S bridge

and recovering the LIGAND thus obtained in free form or in the form of a salt.

The above reactions can be carried out by analogy with known methods, for example as described in the following examples, in particular methods a) and c). When the chelating group is attached by an amide bond, it can be done in a manner analogous to the methods used for the formation of an amide. If desired, in these reactions, protective groups may be used for functional groups which do not participate in the reaction, the use of which is suitable in peptides or which are suitable for the desired chelating groups. The term protecting group can also include a polymer resin having functional groups.

When it is desired to attach the chelating group to the N-amino terminal group of a peptide or of a peptide fragment used as starting material and comprising one or more amino groups on the side chains, these amino groups of the side chains are advantageously protected by a protective group, for example as used in peptide chemistry.

When it is desired to attach the chelating group to an amino group of a side chain of a peptide or of a peptide fragment used as starting material and the peptide comprises a free N-terminal amino group, the latter is preferably protected by a protecting group.

The peptide fragment carrying the chelating group and used in step b) can be prepared by reacting with the chelating agent the peptide fragment comprising at least one amino acid or one amino alcohol in a protected or unprotected form. The reaction can be carried out by analogy with step c).

The chelating groups of formula IV or V can be linked to a peptide by reaction of a chelating agent of formula IV or V

IV

V

where X is an activating group capable of forming an amide bond with the N-amino group of the peptide. The reaction can be carried out as described in EP-A1-247 866.

The chelating agent used in step c) of the process can be known or prepared by analogy with known processes. The compound used is such that it allows the introduction of the desired chelating group on the somatostatin peptide, for example a polyaminopolycarboxylic acid as described, a salt or an anhydride thereof.

In the above process, when, in the aminoacids, the peptide fragments or the peptides used as starting materials, the chelating group is attached to the peptide by a bridging or spacer group, for example a radical of formula (al ) as defined above, these amino acids, peptide fragments or peptides can be prepared by reacting, in a conventional manner, the corresponding amino acids or peptides, without bridging group or spacer, with a corresponding compound generating a bridging group or spacer , for example an acid or a reactive derivative of an acid comprising the bridging or spacer group, for example an acid of formula Z-R35-COOH or one of its reactive derivatives, such as an active ester. Examples of active ester groups or carboxy activating groups are 4-nitrophenyl, pentachlorophenyl, pentafluorophenyl, succinimidyl or 1-hydroxybenzotriazolyl groups.

Alternatively, the chelating agent may first be reacted with a compound generating a bridging or spacer group, in order to carry the bridging or spacer group, and then it may be reacted in a conventional manner with the peptide, the peptide fragment or 11 amino acid.

The LIGANDS OF THE INVENTION can be purified in a conventional manner, for example by chromatography. Preferably, the ligands of the invention contain less than 5% by weight of peptides free from chelating groups.

The LIGANDS OF THE INVENTION in free form or in the form of pharmaceutically acceptable salts are interesting compounds. According to another embodiment, the LIGANDS OF THE INVENTION can be complexed with a detectable element.

Consequently, the present invention also relates to the LIGANDS OF THE INVENTION as defined above complexed with a detectable element (hereinafter referred to as CHELATES OF THE INVENTION), in free form or in the form of salt, their preparation and their use for in vivo diagnosis and for therapeutic treatment.

An element is said to be detectable to denote an element, preferably a metal ion, having a detectable property in therapeutic or in vivo diagnostic techniques, for example a metal ion which emits detectable radiation or a metal ion which is capable to influence the relaxation properties in NMR.

Suitable detectable metal ions include, for example, heavy elements or rare earth ions, for example those used in computed tomography (CAT = Computer axial tomography), paramagnetic ions, for example Gd8 +, Fe8 +, Mn ^ + and Cr ^ +, fluorescent metal ions, for example Eu3 +, and radionuclides, for example radionuclides with emission radionuclides with β emission, radionuclides with emission a, radionuclides with emission of positrons, for example 68Ga.

Suitable j-emitting radionuclides include those useful in diagnostic techniques. The $ emission radionuclides advantageously have a half-life from 1 hour to 40 days, preferably from 5 hours to 4 days, better still from 12 hours to 3 days. Examples are the radionuclides derived from gallium, indium, technetium, ytterbium, rhenium and thallium, for example 6 ^ Ga, ü ^ ln, 99mTc, •! -69Yb and 186Re. Preferably, the fr-radionuclide is chosen according to the metabolism of the LIGAND OF THE INVENTION or of the somatostatin peptide used. Most preferably, the LIGAND OF THE INVENTION is chelated with a ^ -radionuclide having a longer half-life than the half-life of the tumor somatostatin peptide.

In addition, the radionuclides suitable for use in imaging are positron emission radionuclides, for example like those mentioned above.

Suitable β-emitting radionuclides include those useful in therapeutic applications, for example 8 (^ Y, 6 ^ Cu, ^ 86Re, ^ 88Re, ^ 89Er, 121Sn, - * - 2 ^ Te, 143pr, 109pd, ^ ^ Dy, 32p ^ 142pr> The β-radionuclide advantageously has a half-life of 2.3 hours to 14.3 days, preferably 2.3 to 100 hours. Preferably, the radionuclide with β emission is chosen so to have a longer half-life than the half-life of the somatostatin peptide on the tumor.

Suitable radionuclides with emission are those which are used in the therapeutic treatments, for example 211At and 2 ^ 2Bi.

The CHELATES OF THE INVENTION can be prepared by reacting the LIGAND with a compound giving a corresponding detectable element, for example a metal salt, preferably a water-soluble salt. The reaction can be carried out by analogy with known methods, for example as described by Perrin, Organic Ligand, Chemical Data Sériés 22, NY Pergamon Press (1982); Krejcarit and Tucker, Biophys. Bio-chem. Res. Corn. ΊΊ_, 581 (1977); and Wagner and Welch, J. Nucl. Med. 20, 428 (1979).

Preferably, the complexation of LIGAND takes place at a pH at which the LIGAND OF THE INVENTION is physiologically stable.

Alternatively, the detectable element can also be brought into the solution in the form of a complex with an intermediate chelating agent, for example a chelating agent which forms a complex chelate which makes the element soluble at the physiological pH of LIGAND, but which is less thermodynamically stable than CHELATE. An example of such an intermediate chelating agent is 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron). In such a method, the detectable element is exchanged with the ligand.

The CHELATES OF THE INVENTION can also be produced by binding together a chelating agent complexed with the detectable element and a somatostatin peptide, in protected or unprotected form, and optionally by eliminating at least one protective group. present. The same reaction can be carried out with a chelating agent complexed with a detectable metal ion, then the metal ion can be replaced, in the resulting complexed peptide, by the desired detectable element.

The CHELATES OF THE INVENTION can also be produced by linking together a chelating agent complexed with the detectable element and a peptide fragment of somatostatin comprising at least one amino acid in protected or unprotected form, then by continuing the peptide synthesis step by step until the final peptide sequence is obtained, and optionally by eliminating at least one protective group present. Instead of being complexed with the detectable element, the chelating agent can be complexed with an undetectable metal and this metal can then be replaced by the detectable element in the resulting complexed somatostatin peptide.

When the chelating group is attached to the somatostatin peptide by a bridging or spacer group, for example by a radical of formula (al) defined above, this weighting or spacer group can be carried by the peptide or the peptide fragment of somatostatin or by 11 chelating agent.

The above reactions can be carried out by analogy to known methods. Depending on the chelating group present, the labeling yield may approach 100%, so that no purification is necessary. Radionuclides such as, for example, technetium 99m, can be used in oxidized form, for example in the form of Tc-99m pertechnetate, which can be complexed under reducing conditions.

The above reactions can advantageously be carried out under conditions avoiding any trace of contamination. Preferably, demineralized distilled water, ultrapure reagents, radioactivity for chelation, etc. are used to reduce the effects of traces of metals.

The CHELATES OF THE INVENTION may exist, for example, in free form or in the form of salt. Salts include acid addition salts with, for example, organic acids, polymeric acids or mineral acids, for example hydrochlorides and acetates, and salt forms obtainable with acid groups carboxylic acids present in the molecule and which do not participate in the formation of the chelate, for example the alkali metal salts such as sodium or potassium, or the substituted or unsubstituted ammonium salts.

The CHELATES OF THE INVENTION and their pharmaceutically acceptable salts exhibit pharmaceutical activity and are therefore useful as imaging agents, for example for visualizing tumors and metastases positive for somatostatin receptors, when they are complexed with a paramagnetic ion, a metal ion with y emission or a radionuclide with positron emission, or as a radiopharmaceutical specialty for the in vivo treatment of tumors and metastases positive to somatostatin receptors, when they are complexed with an a- or a β-radionuclide, as indicated by standard tests.

In particular, the CHELATES OF THE INVENTION have an affinity for the somatostatin receptors expressed or overexpressed by tumors and metastases, as indicated by standard in vitro binding assays.

A somatostatin receptor positive tumor from the human gastrointestinal system is removed from a patient and immediately placed on ice and, within 30 minutes at most, is frozen at -80 ° C. To then submit it to an autoradiography, this frozen material is cut on a cryostat (Leitz 1720) in 10 μιη sections, it is mounted on prewashed microscope slides and it is stored at -20 ° C for at least 3 days to improve the adhesion of the tissue to the blade. The sections are pre-incubated in Tris-HCl buffer (50mN, pH 7.4), containing CaCl2 (2mM) and KC1 (5mM), for 10 min at room temperature, then washed twice for 2 min in the same buffer, without addition of additional salts.

The sections are then incubated with a CHELATE OF THE INVENTION for 2 hours at room temperature in Tris-HCl buffer (170 mM, pH 7.4), containing bovine serum albumin (10 g / 1), bacitracin. (40 mg / 1) and MgCl2 (5mM), to inhibit endogenous proteases. The non-specific bonds are determined by adding the corresponding unlabelled, unmodified, corresponding somatostatin peptide in a concentration of ΙμΜ. The incubated sections are washed twice for 5 minutes in cold incubation buffer containing 0.25 g / l of BSA. After a brief soaking in distilled water to remove excess salts, the sections are quickly dried and placed on [^ H] -LKB films. After an exposure time of approximately 1 week in x-ray cassettes, it is observed that the CHELATES OF THE INVENTION, for example a radionuclide CHELATE, give very good results for the labeling of tumor tissue, without labeling the surrounding healthy tissue, when added in a concentration of about 10 ~ 10 to 10 "3 M.

The affinity of the CHELATES OF THE INVENTION for somatostatin receptors can also be demonstrated in in vivo tests.

Somatostatin receptor positive transplantable exocrine pancreatic tumor rats are treated with an intravenous injection of a CHELATE OF THE INVENTION. The injection site is the vein of the penis. Immediately after administration, the animals are placed on the collimator of a gamma camera and the distribution of the radioactivity is monitored at various time intervals.

The biodistribution of radioactivity can also be determined by serial sacrifice of a number of these treated rats and determination of the radioactivity of the organ.

After having administered a CHELATE OF THE INVENTION, for example a CHELATE radionuclide, for example in CHELATE with tf emission, in a dose of 1 to 5 μg / kg of LIGAND labeled with 0. 1 to 2 mCi of radionuclide, one begins to detect the site of the tumor as well as the organs where essentially the excretion takes place.

Consequently, in a series of specific or other embodiments, the present invention also relates to: 1. A method of in vivo detection in a subject of somatostatin receptor positive tumors or metastases, which comprises a) 1 administration to said subject of a CHELATE OF THE INVENTION and b) recording the location of the receptors targeted by said CHELATE.

The CHELATES OF THE INVENTION usable in the in vivo detection method of the invention are CHELATES which are complexed with an emission radionuclide, a positron emission radionuclide or a paramagnetic metal ion, for example as indicated above.

The CHELATES OF THE INVENTION which can be used as imaging agents in method (1) can be administered parenterally, preferably intravenously, for example in the form of solutions or injectable suspensions, preferably in a single injection. The appropriate dosage will, of course, depend, for example, on LIGAND and the type of detectable element used, for example, the radionuclide. A suitable dose for injection is in the interim allowing imaging by photobay procedures known in the art. When using a radiolabelled CHELATE OF THE INVENTION, it can advantageously be administered in a dose having a radioactivity of 0.1 to 50 mCi, preferably from 0.1 to 30 mCi, better still from 0.1 to 20 mCi. A poology indicated may be from 1 to 200 μg of LIGAND labeled with 0.1 to 50 mCi, preferably from 0.1 to 30 mCi, for example from 3 to 15 mCi, of emission radionuclide depending on the emission radionuclide ÿ used. For example, with In, we prefer to use radioactivity at the bottom of the range, while with Te, we prefer to use radioactivity at the top of the range.

The enrichment by CHELATES in tumoregene sites can be followed by the corresponding imaging techniques, for example by means of a nuclear medical imaging device, such as a scanner, a camera, a rotating camera, each being preferably computer assisted, a positron emission tomometric scanner (PET = positron emission tomography), an MRI apparatus or a tomodensitometry apparatus (CAT).

The CHELATES OF THE INVENTION, for example most of the Y-emission CHELATES, are essentially excreted by the kidneys and hardly accumulate in the liver.

2. A method of treating in vivo, in a subject requiring such treatment, tumors and metastases positive to somatostatin receptors, which comprises the administration to said subject of a therapeutically effective amount of a CHELATE OF THE INVENTION .

The CHELATES OF THE INVENTION which can be used in the in vivo treatment process of the invention are the CHELATES complexed with an a- or a β-radionuclide as defined above.

The dosages used in the implementation of the therapeutic process of the present invention will vary, of course, depending, for example, on the particular condition to be treated, for example the volume of the tumor, the particular CHELATE employed, for example half -life of CHELATE in the tumor, and the treatment sought. In general, the dose is calculated based on the distribution of radioactivity in each organ and the target fixation observed. For example, CHELATE can be administered in a dosage range having a radioactivity of 0.1 to 3 mCi / kg body weight, for example 1 to 3 mCi, preferably 1 to 1.5 mCi / kg body weight . A daily dosage range indicated is from 1 to 200 µg of LIGAND labeled with 0.1 to 3 mCi / kg of body weight, for example 0.1 to 1.5 mCi / kg of body weight, of radionuclide with a or β emission , advantageously administered in several doses (up to 4 per day).

The CHELATES OF THE INVENTION with a or β emission can be administered by any suitable route, in particular parenteral, for example in the form of solutions or injectable suspensions. They can also be advantageously administered by infusion, for example by infusion of 30 to 60 minutes. Depending on the site of the tumor, they can be administered as close as possible to the site of the tumor, for example by means of a catheter. The mode of administration chosen depends on the speed of dissociation of the CHELATE used and the speed of excretion.

The CHELATES OF THE INVENTION can be administered in free form or in a pharmaceutically acceptable form. These salts can be prepared in a conventional manner and have the same order of reactivity as the free compounds.

The CHELATES OF THE INVENTION which can be used in the process of the present invention can advantageously be prepared shortly before administering them to a subject, that is to say carrying out radiolabelling with the desired detectable metal ion, in particular the radionuclide α, β or Jf, shortly before administration.

The CHELATES OF THE INVENTION may be suitable for imaging or treating tumors such as pituitary, gastroenteropancreatic, central nervous system, breast, prostate, ovarian or colon tumors, small lung cancers cells, paragangliomas, neuroblastomas, pheochromocytomas, medullary carcinomas of the thyroid, myelomas, etc., and their metastases.

According to another embodiment of the invention, it is also possible to use, as imaging agent for evaluating renal function, the CHELATES OF THE INVENTION with emission

Groups of five mice are used. 0.1 ml containing 1 mCi of a CHELATE OF THE INVENTION is injected into each mouse, intravenously, into a tail vein. The mice are then placed in metabolic cages to collect the excreted urine. After 10 or 120 minutes after the injection, the urethra are ligated and the mice are anesthetized with chloroform. Imaging of the uropoietic system is performed using the usual imaging technique. In this trial, the emission CHELATES OF THE INVENTION improve the imaging of renal excretion, when administered in doses of 0.1 to 30 mCi.

Consequently, the present invention also relates to a method of in vivo evaluation in a subject of renal function, which comprises the administration to said subject of an effective quantity of an emission CHELATE and the recording of kidney function.

According to another aspect, the subject of the invention is also: i. a pharmaceutical composition comprising a LIGAND OF THE INVENTION in free form or in the form of a pharmaceutically acceptable salt, as well as one or more pharmaceutically acceptable vehicles or diluents thereof; ii. a pharmaceutical composition comprising a CHELATE according to the invention in free form or in the form of a pharmaceutically acceptable salt, as well as one or more pharmaceutically acceptable vehicles or diluents thereof.

These compositions can be produced in a conventional manner.

A composition according to the invention can also be presented in a separate package with instructions for mixing the LIGAND with the metal ion and for administering the resulting CHELATE. It can also be presented as a two-component package, i.e. as a single package containing separate unit doses of LIGAND and detectable metal ion, with instructions for mixing them and to administer CHELATE. A diluent or carrier may be present in the unit dosage forms.

In the following examples, all the temperatures are in ° C and the values of [a] D20 are not corrected. The following abbreviations are used:

Boc t-butoxycarbonyl TFA trifluoroacetic acid DTAP diethylenetriaminepentaacetic acid EXAMPLE 1: DTPA-DPhe-Cys-Phe-DTrp-Lys-Thr-Cvs-Thr-ol

1.1 g of DPhe-Cys-Phe-DTrp-Lys (ε-Boc) -Thr- * - are dissolved.

Cys-Thr-ol in the form of free base (ImM) in 5 liters of dioxane / H20 1/1 (v / v) and reacted with 5 g of NaHCOj. 520 mg of DTPA dianhydride is added slowly, with stirring. The reaction mixture is stirred for a further 30 minutes and lyophilized. The residue is dissolved in 250 ml of water and the pH is adjusted to 2.5 with concentrated HCl. The precipitated product is separated by filtration, washed and dried over phosphorus pentoxide. After chromatography on a silica gel column, the following products are isolated: 230 mg of DTPA-DPhe-cÿs-Phe-DTrp-Lys (£.-Boc) -Thr-Cys-Thr-ol and 500 mg of the dimer DTPA- correspondent (DPhe-Cys-Phe-DTrp-Lys (£ -Boc) -Thr-Cys-Thr-ol) 2 ·

3 ml of TFA are mixed with 200 mg of DTPA-DPhe-Cys - r

Phe-DTrp-Lys (£ -Boc) -Thr-Cys-Thr-ol. After 5 minutes at room temperature, the mixture is precipitated with diisopropyl ether, separated by filtration and dried. The residue is desalted on Duolite and lyophilized, this mistletoe gives 150 mg of the title compound: [a] D20 = -26.6 ° (c = 1, 95% AcOH).

The starting material can be prepared as follows.

1-1 a) H-DPhe-Cys-Phe-DTrp-Lys (Boc) -Thr-Cys-Thr-ol

2.25 g of di-t-butyl pyrocarbonate, dissolved in 30 ml of DMF, are slowly added dropwise at room temperature to a solution of 10 g of Hi-1 DPhe-Cys- acetate. Phe-DTrp-Lys-Thr-Cys-Thr-ol in 100 ml of DMF. After two hours at room temperature, the solvent is removed in vacuo and 200 ml of diisopropyl ether are added to the residue. The deposit thus formed is separated by filtration, washed with diisopropyl ether and dried. The crude product is purified by chromatography on silica gel (eluent: OH ^ C ^ / MeOH 9/1) and is then isolated in the form of an amorphous white powder.

[a] n20 = 29.8 ° (c = 1.28 in the DMF).

u I-1 EXAMPLE 2: DTPA- (DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol)

The fraction containing the intermediate product-1 -—- 1 diary DTPA- (DPhe-Cys-Phe-DTrp-Lys (£ -Boc) -Thr-Cys-Thr-ol) 2 treated in Example 1 is treated as above for the corresponding single mother form, eliminating the protective Boc groups, to obtain the title compound: [a] D20 = -24.5 ° (c = 0.55 AcOH at 95%).

EXAMPLE 3: H? N- (CH?) Σ-CO-DPhe-cÿs-Phe-DTrp-Lys-Thr-Cys-Thr-ol a. 0.56 g of H-DPhe-Cys-Phe-DTrp-Lys (Boc) -Thr-Cys-Thr-ol, 0.5 mmol of Fmoc- £ -aminocaproic acid and 115 mg of hydroxybenzotriazole are dissolved in 10 ml of DMF and cooled to -30 ° C. To this solution is added a solution of 115 mg of dicyclohexylcarbodiimide in 5 ml of DMF (cooled to -10 ° C).

After a reaction time of 24 hours, during which the mixture warms up to room temperature, the resulting dicyclohexylurea is filtered off and the filtrate is diluted with water to 10 times its volume. The precipitated reaction product is filtered, washed and dried over phosphorus pentoxide. The crude product is used without further purification for the next step.

b. Cleavage of Fmoc

0.5 g of the crude product of the coupling reaction (a) is treated for 10 minutes at room temperature with 5 ml of DMF / piperidine 4/1 in v / v (clear solution) and then mixed with 100 ml diisopropyl ether. The reaction product which then precipitates is separated by filtration, washed and dried. This crude product is used in further purification in the next step.

vs. Boc cleavage

300 mg of the crude product obtained in (l.b) are treated for 5 minutes at room temperature with 5 ml of 100% TFA (fully dissolved) and then mixed with 50 ml of diisopropyl ether. After adding 2 ml of HCl / diisopropyl ether, the resulting deposit is filtered off, washed and dried under high vacuum.

The final product is purified by chromatography on silica gel (CHC ^ / MeOH / ^ O / AcOH 7/3 / 0.5 / 0.5), followed by desalting on Duolite (gradient: H ^ O / AcOH 95/5) -> H20 / dioxane / Ac0H 45/50/5).

The title compound is obtained in the form of acetate (white lyophilisate).

[a] D20 = -32 ° (c = 0.5, 95% AcOH).

The resulting compound can be used to react it with DTAP according to the procedure of Examples 1 and 2.

EXAMPLE 4:

Following the procedure described in Examples 1 and 3, the following LIGAND can be prepared: DTPA-3Ala-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol.

[a] D20 = -14.8 ° (c = 0.5, 95% AcOH).

i-1 EXAMPLE 5: DTPA-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol mark at XXXln i --—- 1

1 mg of DTPA-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol is dissolved in 5 ml of 0.01M acetic acid. The resulting solution is passed through a 0.22 μ Millex-GV filter, it is divided into 0.1 ml portions and it is stored at -20 ° C. One predilutes l- ^ ïnCl3 (Amersham, 1 mCi / ΙΟΟμΙ) in an equal volume of 0.5M sodium acetate and the labeling is carried out by mixing the ligand with the solution of InCl3 and by homogenizing it in a gentle manner with ambient temperature.

HEPES buffer, pH 7.4, is then added to prepare a 10% solution.

EXAMPLE 6 DTPA-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol labeled with_— X

The ^ 0γ ^ is obtained from a 9 ° Sr-9 () Y radionuclide generator. When the generator is constructed, its elution and the transformation of the [90Y] EDTA into an acetate complex are carried out according to the method described by M. Chinol etyD. J. Hnatowitch, in J. Nucl. Med. 2_8, 1465-1470 (1987). 1 mg of DTPA-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol dissolved in 5 ml of acetic acid Ο, laisse is allowed to warm to room temperature and 1.0 mCi of in 50 μΐ of sterile 0.5M acetate. The mixture is then left to stand for 30 minutes to 1 hour to obtain the maximum chelation.

A group of LIGANDS OF THE INVENTION consists of somatostatin peptides, for example of somatostatin analogs, which contain, on at least one of the amino-noid motifs, a chelating group which is attached to said ami-no group by a amide bond, in free form or in salt form.

A group of CHELATES OF THE INVENTION consists of the above-mentioned LIGANDS complexed with a detectable element, for example a metal ion, in free form or in the form of salt.

Claims (38)

1. Somatostatin peptide carrying at least one chelating group for a detectable element, this chelating group being linked to an amino group of said peptide, in free form or in the form of salt. 2. Somatostatin peptide carrying at least one chelating group for a detectable element, this chelating group being linked to an amino group of said peptide, and this amino group having no significant binding affinity for somatostatin receptors, in free form or in salt form. 3. Somatostatin peptide according to claim 1 or 2, characterized in that the chelating group is attached to the N-terminal amino group of the somatostatin peptide. 4. Somatostatin peptide according to any one of the preceding claims, characterized in that the chelating group is attached directly or indirectly to the amino group of said peptide. 5. Somatostatin peptide according to any one of the preceding claims, in which the chelating group is attached to said peptide by an amide bond. 6. Somatostatin peptide carrying at least one chelating group for a detectable element, this chelating group being linked to an amino group of said peptide, and this amino group having no significant binding affinity for somatostatin receptors, in free form or in salt form, characterized in that the somatostatin peptide is derived from a compound of formula I

in which A is a C 1 -C 4 alkyl group> C 7 -C 20 phenylalkyl or a group of formula RCO-, in which i) R is hydrogen, a C 1 -C 4 alkyl group, phenyl or phenylalkyl in C7-C20, or ii) RCO- is a) a residue of L- or D-phenylalanine optionally substituted on the nucleus with F, Cl, Br, NO2, NH2, OH, C1-C3 alkyl and / or alkoxy in C ^ -Cg; b) the residue of a natural or synthetic α-amino acid other than that defined in a) above or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid residues are identical or different and are chosen from those defined in a) and / or b) above, the α-amino acid group of the amino acid residues a) and b) and the N-terminal amino group of the dipeptide residues c) being optionally mono- or di-alkylated or substituted by a C 1 -C 6 alkanoyl, A ′ is hydrogen, a C 1 -C 4 alkyl group 0x1 phenyl O 1 -C 6 phenylalkyl, Y 1 and Y 2 together represent a direct bond or each of the radicals Y-j_ and Y2 is independently hydrogen or a radical of formulas (1) to (5)

(4) (5) in which Ra is a methyl or ethyl group R] -, is a hydrogen, a methyl or ethyl group m is an integer from 1 to 4 n is an integer from 1 to 5 Rc is a group C ^ -Cg alkyl R ^ represents the substituent attached to the carbon atom in a of a natural or synthetic α-amino acid (including a hydrogen) Re is an alkyl group in 0 ^ -05 Ra 'and Rjj' are each independently hydrogen, methyl or ethyl, R3 and Rg are each independently hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 3 alkoxy, p is zero or equal to 1, q is zero or equal to 1, and r is zero, equal to 1 or 2, B is -Phe-, optionally substituted on the nucleus by a halogen, a group NO2, NH2, OH, alkyl in 0 ^ -03 and / or alkoxy in C1-C3 (including pentafluoroalanine), or the β-naphthyl-Ala C group is (L) -Trp- or (D) -Trp-, optionally α-Ν-methylated and optionally substituted on the benzene ring with halogè ne, NO2, NH2, OH, 0 - ^ - 03 alkyl and / or 0 ^ -03 alkoxy, D is Lys, Lys in which the side chain contains O or S in position β, ÿF-Lys or ôF -Lys, optionally aN-methylated, or a 4-aminocyclohexylAla or 4-ami-nocyclohexylGly E residue is Thr, Ser, Val, Phe, Ile or a ami-noisobutyric or aminobutyric acid residue G is a group of formula

where r * 7 is hydrogen or a 0 ^ -03 alkyl group, R ^ q is a hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R] _2 is hydrogen, an 0 ^ alkyl group - 03 ,. phenyl or phenyl C7 “C10, Rj_2 is hydrogen, a C] _- C3 alkyl group or a group of formula -CHCR ^ JX ^, R13 is CH2OH, - (CH2) 2 ~ OH, - (CH2) 3 -OH or -CB (CH3) OH, or represents the substituent attached to the carbon atom in a of a natural or synthetic α-amino acid (including a hydrogen) and is a group of formula -COOR7, -CH2OR20 or or

R7 and R ^ q have the meanings given above, R * L4 is hydrogen or a C1-C3 alkyl group and R15 is hydrogen, a 0 - ^ - 03 alkyl group, phenyl or C ^ - phenylalkyl C ^ q, and R ^ g is hydrogen or hydroxy, provided that when R ^ 2 is -CH (Ri3) -X] _, then either hydrogen or methyl, where residues B, D and E have the configuration L, and the residues in position 2 and in position 7 and all the residues Y] _ 4. and Y2 4) each independently have the configuration (L) or (D). 7. Somatostatin peptide according to claim 6, characterized in that, in formula I, A is RCO and A 'is hydrogen. 8. Somatostatin peptide according to claim 6 or 7, characterized in that, in formula I, G is -CO-NH-CH (R13) -X1 where R13 is -CH2OH, -CH (CH3) -OH, ~ { CK2) 2 ~ OR '- (CH2) 3 “OH, an isobutyl or butyl group, and is -CCHMR14RX5 or -GE ^ OR ^ q, where R] _0' r14 and R15 are as defined in claim 5. 9. Somatostatin peptide according to any one of the preceding claims, characterized in that the so-matostatin peptide is derived from_H- (D) Phe-Cys-Phe -, (D) Trp-Iiys-Thr-Cys-Thr -ol also known as octreotide. 10. Somatostatin peptide according to any one of the preceding claims, characterized in that the chelating group is chosen from the group consisting of iminodicarboxylic groups, polyaminopolycarboxylic groups, groups derived from macrocyclic amines, groups of formula IV or V

IV V where each of the radicals R3, R3 and R3 is independently a C 1 -C 6 alkyl group, C 5 -C 3 aryl or C 7 -C 9 arylalkyl, each being optionally substituted by OH, a C 1 -C 4 alkoxy group , COOH or S03H, n 'is equal to 1 or 2, i is an integer from 2 to 6, and TT are independently a- or β-amino acids linked to each other by amide bonds, groups derived from derivatives bis-aminothiols, dithiasemicarbazone derivatives, oxime derivatives of propyleneamine, diamide-dimercaptides or porphyrins, in free form or in salt form. 11. Somatostatin peptide according to claim 10, characterized in that the chelating group is derived from ethylenediaminetetraacetic acid (EDTA), diethylene triaminepentaacetic acid (DTPA), ethylene glycol-0,0'-bis acid (2-aminoethyl) -N, N, Ν ', N'-tetraacetic (EGTA), N, N'-bis (hydroxybenzyl) ethylenediamine-N, N'-diacetic (HBED) acid, l triethylenetetraminehexaacetic acid (TTHA), substituted EDTA or substituted DTPA, 1,4,7,10-tetra-azacyclododecane-N, N ', N ", N"' - tetraacetic acid (DOTA) and 1,4,8,11-tetra-azacyclotetradecane-Ν, Ν ', N ", N" 1-tetraacetic acid (TETA), in free form or in acid form. 12. Somatostatin peptide according to claim 11, characterized in that the chelating group is derived from diethylenetriaminepentaacetic acid (DTAP), in free form or in the form of salt. 13. Somatostatin peptide according to any one of the preceding claims, which is DTPA- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol in free form or in salt form. 14. Somatostatin peptide according to any one of claims 1 to 12, characterized in that the chelating group is attached to said peptide by means of a spacer group of formula a Z-R35-CO- (al) R35 is a C ^ alkylene-C2-alkenylene group or -CH (R ') -, in which R' is the residue attached in a to a natural or synthetic a-amino acid, Z is a functional group capable of reacting covalently with a chelating agent. 15. A method of producing a somatostatin peptide according to claim 1, in free form or in the form of a salt, characterized in that it comprises a) the elimination of at least one protective group which is present in a somatostatin peptide carrying a chelating group, or b) the connection to one another, by an amide bond, of two peptide fragments · each containing at least one amino acid or one amino alcohol in protected or unprotected form and one of them containing the chelating group, the amide bond being such that the desired amino acid sequence is obtained, optionally followed by step a) of the process, or c) the binding to one another of a chelating agent and of the desired somatostatin peptide in protected or unprotected form, so as to fix the chelating group on the desired N-amino group of the peptide, optionally followed by step a), or d) elimination of a functional group d an unprotected or protected peptide ge carrying a chelating group or its conversion into another functional group so as to obtain another unprotected or protected peptide carrying a chelating group, step a) of the process being carried out in the latter case, or e) the oxidation d a somatostatin peptide modified by a chelating group in which the mercapto groups of the Cys radicals exist in free form so as to produce an analog in which two Cys radicals are linked by an SS bridge and the recovery of the compound thus obtained in free form or in form of a salt. 16. Somatostatin peptide according to any one of claims 1 to 14, in free form or in the form of a pharmaceutically acceptable salt, usable as a pharmaceutical specialty. 17. A pharmaceutical composition comprising a somatostatin peptide according to any one of claims 1 to 14, in free form or in the form of a pharmaceutically acceptable salt, in association with a pharmaceutical vehicle or diluent. 18. Somatostatin peptide essentially as described above in any one of Examples 1 to 4. 19. A somatostatin peptide according to any one of claims 1 to 14, in free form or in the form of a salt, which can be used to prepare a detectable chelate. 20. Chelate which comprises a somatostatin peptide carrying at least one chelating group for a detectable element, this chelating group being linked to an amino group of said peptide, and this amino group having no significant binding affinity for somatostatin receptors, somatostatin peptide being complexed with a detectable element, in free form or in the form of a pharmaceutically acceptable salt. 21. Chelate according to claim 20, characterized in that the somatostatin peptide is according to any one of claims 3 to 14. 22. Chelate according to claim 20 or 21, characterized in that the detectable element is an emitting radionuclide · 23. Chelate according to claim 22, characterized in that the detectable element is · * ·· ^ Ιη or ^ mTc. 24. DTPA- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol labeled at min ’/ in free form or in salt form. 25. Chelate according to any one of claims 20 to 24, in free form or in the form of a pharmaceutically acceptable salt, usable as a pharmaceutical specialty. 26. Chelate according to any one of claims 20 to 24, in free form or in the form of a pharmaceutically acceptable salt, usable as an agent for imaging tumors or metastases positive for somatostatin receptors. 27. A pharmaceutical composition comprising a chelate according to any one of claims 20 to 24, in free form or in the form of a pharmaceutically acceptable salt, in association with a pharmaceutical carrier or diluent. 28. In or Te labeled somatostatin peptide essentially as defined above and described in any of the examples. 29. Chelate according to claim 20 or 21, characterized in that the detectable element is an a or β emission radionuclide. 30. Chelate according to claim 29, characterized in that the detectable element is ^ 0γ, _ 31. DTPA- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol labeled with 90γ, in free form or in the form of a pharmaceutically acceptable salt. 32. Chelate according to any one of claims 20, 21 and 29 to 31, in free form or in the form of a pharmaceutically acceptable salt, usable as a radiopharmaceutical specialty. 33. Chelate according to any one of claims 20, 21 and 29 to 31, in free form or in the form of a pharmaceutically acceptable salt, usable in radiotherapy of tumors or metastases positive for somatostatin receptors. 34. A pharmaceutical composition comprising a chelate according to any one of claims 20, 21 and 29 to 31, in free form or in the form of a pharmaceutically acceptable salt, in association with a pharmaceutical carrier or diluent. 35. Somatostatin peptide labeled with Y, essentially as defined and described above in any of the examples. 36. Method for producing a chelate according to any one of claims 20 to 26, 28 to 33 and 35, characterized in that it comprises the reaction of a somatostatin peptide according to claim 1, in free form or in salt form, with a compound generating a detectable element. 37. A method of producing a chelate according to any one of claims 20 to 26, 28 to 33 and 35, characterized in that it comprises the bonding to one another of a chelating agent complexed with a detectable agent and a somatostatin peptide according to claim 1, in protected or unprotected form, and optionally the elimination of at least one protective group present. 38. Packaged presentation containing unit doses of a somatostatin peptide according to any one of claims 1 to 14 and 18 and of a detectable element, with instructions for mixing them and for using them as an imaging agent or therapeutic agent .