FR2639947A1 - PEPTIDE DERIVATIVES - Google Patents

Abstract

The subject of the invention is somatostatin peptides carrying at least one chelating group for a detectable element, said chelating group being linked to an amino group of said peptide, and said amino group having no significant binding affinity for receptors for somatostatin, in free form or in salt form, complexed with a detectable element. These compounds are, as such, useful as pharmaceutical specialties, for example as radiopharmaceutical specialties, for in vivo imaging of tumors positive for somatostatin receptors, or for treatment.

Description

PEPTIDE DERIVATIVES

  The present invention relates to polypeptides, a

  process for their production, the pharmaceutical preparations

  ticks containing them and their use as a phar-

  maceuticals, for example to treat tumors positive for somatostatin receptors or as imaging agents

in vivo diagnostic group.

  In recent years, we have highlighted a strong

  incidence of somatostatin receptors in a va-

  riety of tumors in humans, for example small tumors

  tuitaries, tumors of the central nervous system, tu-

  breast dies, gastroenteropancreatic tumors and

  their metastases. Some of them are small tu-

  slowly developing tumors or tumors that are diffi-

  eyelashes to be precisely located by diagnostic methods

classic ticks.

  In vitro visualization of somatostatin receptors was performed by autoradiography of tumor tissue

  using somatostatin or somatostatin analogs-

  radioiodinated, for example [125I-Tyrll] somatostatin-14 (JE Taylor et al. Life Science (1988) 43, 421) or [125I-Tyr3] SMS 201-995, also called [125I] 204-090 (JC Reubi et al., Brain Res. (1987) 406, 891; JC Reubi et al., J. Clin. Endocr. Metab. (1987) 65, 1127; JC Reubi et al., Cancer Res. (1987) 47, 551; JC Reubi

  et al., Cancer Res. (1987) 47, 5758).

  We have now discovered new somatostatin peptides useful in therapy and which can be

  marked for in vivo diagnosis and new applications

therapeutic measures.

  The subject of the invention is a somatostatin peptide carrying

  as long as at least one chelating group for a detection element

  table, this chelating group being linked to an amino group of said peptide and this amino group having no binding affinity

  significant for somatostatin receptors.

  In the following, these compounds are called LIGANDS OF THE INVENTION. They have a chelating group capable of

  react with a detectable element, for example a radionu

  cleide, a radio-opaque element or a paramagnetic ion, to form a complex, and are further capable of

  bind to somatostatin receptors, e.g.

  més 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 fixed to the group

  N-terminal amino of the somatostatin peptide.

  According to the invention, the chelating group can be fixed 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

somatostatin peptide.

  Another group of LIGANDS is that in which the chelating group is indirectly attached to the amino group of

  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 soma-

  tostatin of natural origin (tetradecapeptide) and its ana-

logues or derivatives.

  By derivatives or analogues, which are terms used herein, is meant any straight or cyclic chain polypeptide derived from tetradecapeptide somatostatin

  of natural origin, in which one or more friendly motifs

  noacide have been removed and / or replaced by one or more

  other amino acid radicals and / or in which one or more

  if their functional groups have been replaced by one or more

  if 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 modified derivatives of a biologically active peptide that produces a

  qualitatively similar effect to that of the somato- peptide

  unmodified statin, for example those that bind to

  somatostatin receptors and decrease hormone secretion

monale.

  Cyclic, cyclic somatostatin analogs

  bridged and straight chain are known compounds. These com-

  laid 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. Analogs of Formula I

A 'CE2-S-Y1 Y2-S-CE2

AN-CH-C0-B-C-D-E-NH-CHG

  in which A is a C1-C12 alkyl group, a C7-C1o phenylalkyl group or a group of formula RCO-, in which i) R is a hydrogen, a C1-Cl1 alkyl group, phenyl or C7-C10 phenylalkyl group, or ii) RCO- est

  a) an optional L- or D-phenylalanine residue-

  ment substituted on the nucleus by F, C1, Br, NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy;

  b) the residue of a natural or synthetic α-amino acid

  tick other than that defined in a) above or a D-

  corresponding amino acid, or c) a dipeptide residue in which the individual amino acid residues are the same or different and are chosen from those defined in a) and / or b) above, the amino acid group of amino acid residues a) and b) and the amino group Nterminal of the dipeptide residues c)

  possibly being mono- or di-alkylated (Cl-Cl2) or substi-

killed by a C1-C8 alkanoyl,

  A 'is hydrogen, C1-C12 alkyl or phenyl-

  C7-C1o alkyl, Y1 and Y2 together represent a direct bond or each of the radicals Y1 and Y2 is independently a hydrogen or a radical of formulas (1) to (5) R.

R. CH2

-CO-C- (CH2) -H -CO-CHfi -CO-NHRó

Rh \ (CH2).

(1) (2) (3)

  Ra '-CO-NH-CH-COOR. -CO- (NH) p- RIl 2 r Rb-'Jq

(4) (5)

  in which Ra is a methyl or ethyl group Rb 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 C1-C6 alkyl group Rd represents the substituent attached to the carbon atom a of a natural or synthetic α-amino acid (including a hydrogen) Re is a C1-C5 alkyl group Ra 'and Rb' are each independently hydrogen, methyl or ethyl,

  R8 and R9 are each independently hydrogen, halo

  gene, C1-C3 alkyl or C1-C3 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 NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy (including pentafluoroalanine), or the group P-naphthyl-Ala C is (L) -Trp- or (D) -Trp, optionally aN-methylated and optionally substituted on the benzene ring with a halogen, a group NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, D is Lys , Lys in which the side chain contains O

  or S in position P, NF-Lys or 8F-Lys, possibly a-

  N-methylated, or a 4-aminocyclohexylAla or 4-amino residue

nocyclohexylGly

  E is Thr, Ser, Val, Phe, Ile or an amino acid residue

  noisobutyric or aminobutyric G is a group of formula R16 / RI I COOR7, -CH20R10, -CON or -CO-N XI o R7 is hydrogen or a C1-C3 alkyl group,

  R1o0 is hydrogen or the residue of a physiological ester-

  mentally acceptable, physiologically hydrolyzable, R11 is hydrogen, a C1-C3 alkyl group, phenyl or phenyl-C7-C10 alkyl, R12 is a hydrogen, a C1-C3 alkyl group or a group of formula -CH (R13) - X1,

  R13 is CH2OH, - (CH2) 2-OH, - (CH2) 3-OH or -CH (CH3) OH, or re-

  has the substituent attached to the carbon atom at C of a natural or synthetic camino acid (including hydrogen) and X1 is a group of formula -COOR7, -CH20Ro10 or / R14 -CO-N R15 o R7 and R10 have the meanings given above, R14 is a hydrogen or a C1-C3 alkyl group and R15 is a hydrogen, a C1-C3 alkyl group, phenyl or phenyl-C7-C10 alkyl, and R16 is a hydrogen or a hydroxy, provided that, when R12 is -CH (R13) -X1, R11 is then hydrogen or a methyl group,

  o the residues B, D and E have the configuration L, and the

  sidus in position 2 and in position 7 and all residues Y1 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

  -NH- terminal group capable of binding to a chelating agent

tor.

  In the compounds of formula I, the meanings are preferred.

  following cations, either individually or in combination

  its or as a sub-combination: 1. A is a C7-C10 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 C1-C1 alkyl group or phe-

  C7-C1O nylalkyl, in particular C7-C1O phenylalkyl, better still phenethyl, or RCO has the meanings a), b)

or c).

  1.2. When RCO has the meanings a), b) or c), the a-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 (C1-C12), in particular

  link alkylated (C1-C8), better still methylated. Any particular

  in general, the N-terminal group is non-alkylated.

  1.3. When RCO has the meaning a), it is preferable-

  ble a ') of a residue of L- or D-phenylalanine or of ty-

  rosin, possibly mono-N-alkylated (C1-C12). Any particular

  specifically, a ') is a residue of L- or D-phenylalanine.

  1.4. When RCO has the meaning b) -or c), the residue de-

  finished is preferably lipophilic. The preferred residues b) are thus b ′) α-amino acid residues comprising a

  hydrocarbon side chain, for example alkyl,

  as many as 3, preferably 4, carbon atoms, or more, for example up to 7 C atoms, a naphthyl-methyl group or

  heteroaryl, for example a residue of 3- (2- or 1-naphthyl) -

  alanine, pyridylmethyl or tryptophan, said residues having the L or D configuration, and residues c) preferred 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

especially 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 (E-Me), in particular

tie Lily.

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

  / Rl 6. G is G ', G' being a group of formula -CO-N / R11 R12 in particular a group of formula -CO-N

N CH (R13) -X1

  (in which case R11 = H or CH3). In the latter case, the group-

  ment -CH (R13) -X1 preferably has the configuration L.

  6.1. Rl1 is preferably hydrogen.

  6.2. As the substituent attached to the α atom of a natural amino acid (i.e. of formula H2N-CH (Rl3) -COOH), R13 is preferably -CH2OH, -CH (CH3) -OH, an isobutyl or butyl, or R13 is (CH2) 2-OH or - (CH2) 3-OH. These are in particular -CH2OH

or -CH (CH3) OH.

/ R14

  6.3. X1 is preferably a group of formula -CO-N R15 or -CH2-OR! 0, in particular of formula -CH2-OR10, and RO10

  is preferably hydrogen or has the meaning indicated

  quée in 7 below. In particular, R10 is a hy-

  drogenic. The following individual compounds are illustrative of the mixtures of formula I: H- (D) Phe-CYs-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol also known as octreotide (D) Phe-Cys -Thr- (D) Trp-Lys-Val-Cys-ThrNE2 (D) PheCys-Tyr- (D) Trp-Lys-Val-Cys-TrpNE2 (D) Trp-Cys-Phe- (D) Trp-Lys- Thr-CysThrNE2 (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-ThrNE2 3 3- (2-Naphthy) (DAaCysyr (D) TrpLys-Va-Cs-ThrNH 3_ (2_Naphthyl) _ ( D) AlaCysTyr- (D) TrpLy $ _ValCysThrNH2 3- (2-Naphthyl) - (D) Ala-Cys-Tyr- (D) Trp-Lys-Val-Cys-_Nal-NE2 3- (2-Naphthyl) - ( D) Ala-Cys-i-Nal- (D) Trp-Lys-Val-Cys-ThrNE (D) PheCys-Phe- (D) Trp-Lys-Thr-Cys - Nal-NE2 B. Analogues of formula II I! EH-CysPhe-Phe- (D) -Trp-Lys-Thr-Phe-Cys-olII [see Vale et al., Metabolism, 27, supp. 1, 139 (1978)] I H-Cys-His- Ris-Phe-Phe- (D) Trp-Lys-Thr-Phe-Thr-SerCys-OH III (see EP-A-200 188)

  The content of all of the above publications,

  closing specific compounds, is specifically cited

here for reference.

  The particularly preferred LIGANDS are those derived from

  H- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol.

  Suitable chelating groups are groups

  physiologically acceptable chelators capable of

  plex. a detectable element. Preferably, the group ch-

  lator has an essentially hydrophilic character. Examples

  ples of chelating groups include, for example, groups

  iminodicarboxylic pes, polyaminopolycarboxy groups

  liques, for example those derived from non-cyclic ligands, for example ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), acid

  ethylene glycol-O, O'-bis (2-aminoethyl) -N, N, N ', N'-tetraaceous-

  tick (EGTA), N, N'-bis (hydroxybenzyl) ethylenediami-

  ne-N, N'-diacetic (HBED) and triethylenetetramine acid-

  hexaacetic (TTHA), those derived from substituted EDTA or substituted DTPA, for example p-isothiocyanatobenzyl-EDTA

  or -DTPA, those derived from macrocyclic ligands, for example-

  ple 1,4,7,10-tetra-azacyclododecane-N, N ', N ", N"' -

  tetraacetic acid (DOTA) and 1,4,8,11-tetra-azacyclo- acid

  tetradecane-N, N ', 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 89/01476A, the groups of formula IV or V o 0 0 I, tt t! Ri-C-S- (CH2) n.-C- (TT) i-CIV 0 o t, I R2-C-S- (CE2) n.-C-NE-CE2 0

CH-C- V

  R3-C-S- (CH2) n, -C-NE Il If o O O each of the radicals R1, R2 and R3 is independently a

  C1-C6 alkyl, C6-C8 aryl or C7- arylalkyl

  C9, each optionally substituted by OH, a C1C4 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 P-amino acids- linked to each other by amide bonds, the groups derived from bis-aminothiol derivatives, for example the compounds of formula VI, CH2 HN EfNH R) SHgSX VI in which in which each of the radicals R20, R21, R22 and R23 is independently a hydrogen or a C1-C4 alkyl group, X2 is a group capable of reacting with the N-amino group of the peptide, and m 'is equal to 2 or 3, the groups derived from dithiasemicarbazone derivatives, for example the compounds of formula VII NN pH VII PHH e> SH RS HH in which X2 is as defined above, groups derived from oxime derivatives of propylene amine, for example the compounds of formula VIII X rç 2

N NH

VIII

R úR8

R24

OR OH

in which '

  each of the radicals R24, R25, R26, R27, R28 and R29 is, in-

  depending on the case, hydrogen or C1-C4 alkyl, and X2 and m 'are as defined above, the groups derived from diamidedimercaptides, for example the compounds of formula IX

(X3 S

NH 0

Ix y X

H5C6C0 COC6.H

in which

  X3 is an optionally substituted divalent radical and carries

  as a group capable of reacting with the N-amino group of the peptide, for example C1-C4 alkylene or phenylene carrying a group X2, and Y5 is hydrogen or CO2R30, where R30 is a C1-C4 alkyl group,

  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 radicals of the formula - (X4) n.-X5, wherein X4 is C1-C6 alkylene; or a C1-C6 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 functional derivatives-

  nels, 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, - or = CH-CH = in place of a

hydrogen atom.

  The chelating group can be fixed, directly or indirectly.

  directly, 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 C1- alkylene group Cl ,, C2-Cll alkenylene

  or -CH (R ') -, in which R' is the residue fixed in a to an a-

  natural or synthetic amino acid, for example hydrogen, a C1-Cll alkyl group, benzyl, optionally substituted benzyl, naphthylmethyl, pyridylmethyl, Z is a functional group capable of reacting in a

  gon covalent 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 DTPA

  substituted. Particularly preferred are the

DTPA-derived readers.

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

  somatostatin peptide molecules.

  The LIGANDS OF THE INVENTION may exist, for example-

  ple, in free form or in salt form. The salts

  bent acid addition salts with, for example, acids

  organic, polymeric or mineral acids, for example hydrochlorides and acetates, and salt forms which can be obtained with the presence of groups

  carboxylic or sulfonic acids in the chela- group

  such as alkali metal salts such as so-

  dium or potassium, or substituted ammonium salts or

not substituted.

  The present invention also relates to a pro-

  assigned production of 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 the se-

  quence of amino acids desired, optionally followed by step a) of the process, or

  c) binding to each other of a chelating agent and pep-

  tide somatostatin desired in protected or unprotected form, so as to fix the chelating group on the

  desired N-amino group of the peptide, followed optionally-

  ment of step a), or d) elimination of a functional group from an unprotected or protected peptide 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

  killed 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 SS bridge and recovery of 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

  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, we can use, for functional groups

  who are not involved in the reaction, protective groups

  ters whose use is suitable in peptides or which are suitable for the desired chelating groups. The term

  protecting group can also include a poly-

  mother with 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 a 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 the

peptide chemistry.

  When you want to fix the chelating group to a group

  eg amino of a side chain of a peptide or of a peptide fragment used as starting material and that 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) by making

  act with the chelating agent the fragment of peptide

  providing 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

  bound to a peptide by reaction of a chelating agent

  mule IV 'or V' 0 o 0 IV 'IlV RL-C-S- (CE2) n, -C- (TT) i-C-X

* O O0

R2-C-S- (CH2), * - C-NH-CH2 0

t, Bt R3_CS_ (CE2) n._ CNH /

0 0

  o 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 processes

  known. The compound used is such that it allows intro

  duction of the desired chelating group on the somato- peptide

  statin, for example a polyaminopolycarboxylic acid such as

  as described, a salt or an anhydride thereof.

  In the above process, when in the amino-

  cides, peptide fragments or 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 (ul) as defined above, these amino acids, peptide fragments can be prepared or peptides by reacting, in a conventional manner, the corresponding amino acids or peptides, without bridging or spacer group, with a corresponding compound generating a bridging or spacer group, for example an acid or a reactive derivative of an acid comprising the group bridging or spacer, for example

  an acid of formula Z-R35-COOH or one of its reactive derivatives

  tifs, like an active ester. Examples of ester groups

  active or carboxy activating groups are the groups

  pes 4-nitrophenyl, pentachlorophenyl, pentafluorophenyl,

  succinimidyl or 1-hydroxybenzotriazolyle.

  Alternatively, the chested agent may first be reacted

  lator with a compound generating a bridging or space group

  heart, in order to carry the bridging or spacer group, then react it in a conventional manner with the peptide, the

  peptide fragment or amino acid.

  The LIGANDS OF THE INVENTION can be purified from a

  in a conventional manner, for example by chromatography. Befor-

  ference, 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 under

  form of pharmaceutically acceptable salts are compounds

  its interesting. According to another embodiment, the

  LIGANDS OF THE INVENTION may be complexed with an element

detectable.

  Consequently, the present invention also aims to

  jet 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

  salt, their preparation and their use for di-

  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 of influencing the relaxation properties in NMR.

  Suitable detectable metal ions include, for example, heavy elements or earth ions

  rare, for example those used in CT scans

  sorts (CAT = Computer axial tomography), the paramagnetic ions

  ticks, for example Gd3 +, Fe3 +, Mn2 + and Cr2 +, the metal ions

  fluorescent metallics, for example Eu3 +, and radionuclides

  cleides, for example e-emission radionuclides, P-emission radionuclides, a-emission radionuclides, positron emission radionuclides, for example 68Ga. Suitable e-emission radionuclides include those useful in diagnostic techniques. The e-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, techno-

  tium, ytterbium, rhenium and thallium, for example

  67Ga, 111In, 99mTc, 169yb and 186Re. Preferably, the e-ra-

  dionuclide is chosen according to the metabolism of LIGAND DE

  THE INVENTION or the somatostatin peptide used. Better in-

  core, the LIGAND OF THE INVENTION is chelated with an e-radio-

  nuclide with a half-life longer than the half-life of the

somatostatin peptide from the tumor.

  In addition, radionuclides suitable for use

  used in imaging are radionuclides with emission of

  sitons, for example like those mentioned above.

  Suitable P-emission radionuclides include those which are useful in therapeutic applications, e.g. 90y, 67CU, 186Re, 188Re, 169Er, 121Sn, 127Te, 143pr, 198Au, 109pd, 165Dy '32p, 142pr. The 5-radionuclide advantageously has a half-life of 2.3 hours to 14.3 days, from

  preferably 2.3 to 100 hours. Preferably, the radionu-

  emission key B is chosen so as to have a half

  life longer 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

example 211At and 212Bi.

  The CHELATES OF THE INVENTION can be prepared by making

  react LIGAND with a compound giving an element of detection

  corresponding table, for example a metal salt, of pre-

  ference a water-soluble salt. The reaction can be carried out by analogy with known methods, for example as described in Perrin, Organic Ligand, Chemical Data Series 22,

  NY Pergamon Press (1982); Krejcarit and Tucker, Biophys. Organic-

  chem. Res. Com. 77, 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

  intermediate chelating agent is 4,5-dihydroxy-l acid, 3-

  benzenedisulfonic (Tiron). In such a process, the element

  detectable is exchanged with the ligand.

  The CHELATES OF THE INVENTION can also be produced by linking 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 an ion

  metal detectable, then the metal ion can be replaced

  placed, in the resulting complexed peptide, by the element

detectable desired.

  The CHELATES OF THE INVENTION can also be produced by binding together a chelating agent complexed with

  the detectable element and a peptide fragment of somatosta-

  tine comprising at least one amino acid in protected or unprotected form, then 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 a non-detectable metal and this metal can then be replaced

  by the detectable element in the somatostatin peptide

resulting plex.

  When the chelating group is attached to the somato- peptide

  statin by a bridging or spacer group, for example by

  a radical of formula (al) defined above, this group p-

  as long or as a spacer can be carried by the peptide or the frag-

  somatostatin peptide or by the chelating agent.

  The above reactions can be carried out by analogy to known methods. Depending on the celelator 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 pertechnetate

  of Tc-99m, which can be complexed under reduced conditions

trices.

  Advantageously, the above reactions can be carried out.

  ted in conditions avoiding any trace of contamination

  tion. Preferably, demineralized distilled water is used.

  of ultra-pure reagents, radioactivity for chelating

  tion, etc., to reduce the effects of traces of metals.

  The CHELATES OF THE INVENTION may exist, for example-

  ple, in free form or in salt form. The salts

  bent acid addition salts with, for example, acids

  organic, polymeric or mineral acids,

  for example hydrochlorides and acetates, and the

  my salt that can be obtained with acid groups

  carboxylic present in the molecule and which does not partici-

  cannot lead to the formation of the chelate, for example the alkali metal salts such as sodium or potassium, or the salts

  of substituted or unsubstituted ammonium.

  The CHELATES OF THE INVENTION and their pharmaceutical salts

  only acceptable have a pharmaceutical activity and are therefore useful as imaging agents, for example of visualization of tumors and metastases positive to somatostatin receptors, when they are complex with a paramagnetic ion, a metal ion with emission or a radionuclide with positron emission, or as a radiopharmaceutical specialty for the in vivo treatment of tumors and metastases positive for receptors of the

  somatostatin, when complexed with an a- or an f-

  radionuclide, as indicated by standard tests.

  In particular, the CHELATES OF THE INVENTION have

  an affinity for somatostatin receptors expressed

  més or overexpressed by tumors and metastases, as

  indicate standard in vitro binding assays.

  A somatostatin receptor positive tumor

  from the human gastrointestinal system is reti-

  rée on a patient and immediately placed on ice and, within a maximum of 30 minutes, is frozen at -80 C. To then submit it to an autoradiography, this frozen material is cut on a cryostat (Leitz 1720) in sections of 10 gn, they are mounted on prewashed microscope slides and stored at -200C for at least 3 days to improve the adhesion of the tissue to the slide. The sections are preincubated in Tris-HCl buffer (50mN, pH 7.4), containing CaCl2 (2mM) and KCl (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 ml, pH 7.4), containing bovine serum albumin (10 g / l), bacitracin. (40 mg / l) and MgCl2 (5mM),

  to inhibit endogenous proteases. We determine the links

  nonspecific sounds by adding the unlabeled, unmodified, corresponding somatostatin peptide in a concentration

  l1M. The cups are washed twice for 5 minutes.

  cubed, 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 films of [3H] -LKB. After an exposure period 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 tissues

  healthy surrounding, when added in a concen-

tration of about 10-10 to 10-3 M.

  The affinity of the CHELATES OF THE INVENTION for receptors

  somatostatin can also be demonstrated in in vivo tests. Somatostatin receptor positive transplantable pancreatic exocrine tumor rats treated with intravenous injection of 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 we control the

  tribution of radioactivity at various time intervals.

  We can also determine the biodistribution of the ra-

  dioactivity by serial sacrifice of a certain 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 emission Y, in a dose of 1 to 5 lg / 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 tuberculosis

  death or metastasis positive to soma receptors

  tostatin, which includes a) administering to the subject a

  CHELATE OF THE INVENTION and b) registration of the location

  sation of the receptors targeted by said CHELATE.

  The CHELATES OF THE INVENTION usable in the in vivo detection method of the invention are the CHELATES which

  are complexed with a radioactive emission radionuclide

  positron emission nuclide or a para-metallic ion

  magnetic, 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 on LIGAND and the type of element

  detectable ment used, for example the radionuclide. A suitable dose to be injected is in the interval allowing imaging by known photobay procedures.

  in the technique. When using an INVENTIVE CHELATE-

  TION radiolabelled, it can advantageously be administered by

  a dose with a radioactivity of 0.1 to 50 mCi, preferably

  rence from 0.1 to 30 mCi, better still from 0.1 to 20 mCi. A po-

  indicated sology can be from 1 to 200 gg of LIGAND labeled

  with 0.1 to 50 mCi, preferably 0.1 to 30 mCi, for example-

  pl of 3. to 15 mCi, e-emission radionuclide, depending on the e-emission radionuclide used. For example, with In, we prefer to use radioactivity at the bottom of the range, while with Tc, we prefer to use radioactivity

at the top of the range.

  The enrichment by CHELATES in tumo- sites

  rigene can be followed by cor-

  respondents, for example using an imaging device

  nuclear medical, such as a scanner, a camera 1, a camera

  rotary mera, -each one being preferably assisted by or-

  computer, positron emission tomography (PET) scanner, MRI equipment or

  computed tomography (CAT) equipment.

  CHELATES OF INVENTION, for example the major

  part of the CHELATES with emission f, are essentially ex-

  excreted by the kidneys and hardly accumulates

in the liver.

  2. A method of treatment in vivo, in a necessary subject

  situating such treatment, tumors and metastases po-

  somatostatin receptor receptors, which includes

  the administration to said subject of a therapeutic quantity-

  ment of a CHELATE OF THE INVENTION.

  The CHELATES OF THE INVENTION usable in the process

  of in vivo treatment of the invention are the CHELATES

  plexed with an a- or a P-radionuclide as defined above.

  The dosages used in the implementation of the

  therapeutic assignments of the present invention will vary, although

  sure, depending, for example, on the particular affection to be treated

  ter, for example the volume of the tumor, the particular CHELATE

  link employee, for example the half-life of CHELATE in the

  meur, 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-

  ple, CHELATE can be administered in a posolo-

  A gic having a radioactivity of 0.1 to 3 mCi / kg of body weight, for example from 1 to 3 mCi, preferably from 1 to 1.5 mCi / kg of body weight. A daily dosage range indicated is 1 to 200 gg 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, emission radionuclide a. or P, before-

  carefully administered in several doses (up to 4 per day). The CHELATES OF THE INVENTION with a or P 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 administered

  advantageously administered by infusion, for example by

  fusion from 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

  The administration chosen depends on the dissociation speed of the

  CHELATE used and speed of excretion.

  CHELATES OF THE INVENTION Can Be Administered

  in free form or in a pharmaceutically acceptable form

  table. These salts can be prepared in a conventional manner and have the same order of reactivity as the free compounds.

  It is advantageous to prepare the CHELATES OF IN-

  VENTION usable in the process of the present invention

  shortly before administering them to a subject, i.e.

  say to carry out radiolabelling with the metal ion detected

  desired table, in particular the radionuclide a, f or,

  shortly before administration.

  The CHELATES OF THE INVENTION may suit the ima-

  or for the treatment of tumors such as pituitary, gastroenteropancreatic, central nervous system, breast, prostate, ovary or colon tumors,

  small cell lung cancer, paragan-

  gliomas, neuroblastomas, pheochromocytomas, car-

  medullary thyroid cinomas, 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 K emission. Groups of five mice are used. We inject in

  each mouse, intravenously, through a vein

  dale, 0.1 ml containing 1 mCi of a CHELATE OF THE INVENTION. 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. We perform system imagery

  uropoietic using the habitual imaging technique

  tuelle. In this test, the CHELATES OF THE INVENTION emitted-

  improve imaging of renal excretion,

  that they are administered in doses of 0.1 to 30 mCi.

  Consequently, the present invention also aims to

  a method of in vivo evaluation in a subject of renal function, which comprises administration to said subject

  of an effective amount of an emission CHELATE and the

kidney function record.

  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 phar-

  maceutically acceptable, 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 pre-

  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 in the form of a two-component package, that is to say in the form of a single package containing separate unit doses.

  LIGAND and detectable metal ion, with ins-

  instructions for mixing and administering the CHELATE.

  A diluent or a vehicle may be present in the forms

unit dosage.

  In the following examples, all the temperatures are in OC 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-Cvs-Phe-DTrp-Lys-ThrCys-Thr-ol

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

  Cys-Thr-ol as free base (lmM) in 5 liters of

  dioxane / H20 1/1 (v / v) and reacted with 5 g of NaHCO3.

  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 column of silica gel, the following products are isolated

  vants: 230 mg of DTPA-DPhe-Cs-Phe-DTrp-Lys (-Boc) -Thr-Cys-

  Thr-ol and 500 mg of the corresponding dimer DTPA- (DPhe-Cys-Phe-

DTrp-Lys (ú-Boc) -Thr-Cys-Thr-ol) 2.

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

  Phe-DTrp-Lys (E-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, which gives 150 mg of the title compound: [cL] D20

= -26.6 (c = 1, 95% AcOH).

  The starting material can be prepared as follows. a) H-DPheCys-Phe-DTrp-Lys (Boc) -Thr-Cys-Thr-ol 2.25 g of dissolved di-t-butyl pyrocarbonate is added slowly, at room temperature

  in 30 ml of DMF, to a solution of 10 g of H- acetate

  DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol in 100 ml of DMF. After two hours at room temperature, the

  solvent under vacuum and 200 ml of diethyl ether are added to the residue

  sopropyl. The deposit thus formed is separated by filtra-

  tion, washed with diisopropyl ether and dried. The pro-

  raw product is purified by chromatography on si- gel

  lice (eluent: CH2Cl2 / MeOH 9/1) and is then isolated under

form of an amorphous white powder.

  [a] D20 = 29.8 (c = 1.28 in the DMF) -.

  EXAMPLE 2: DTPA- (DPhe-Cys-Phe-DTrp-Lys-Thr-Cvs-Thr-ol) 2

* The fraction containing the intermediate product is treated

  diary DTPA- (DPhe-Cys-Phe-DTrp-Lys (e-Boc) -Thr-Cys-Thr-ol) 2

  obtained in Example 1, as above for the mono- form

  corresponding mother, eliminating the protected Boc groups

  teurs, to obtain the title compound:

  [aLD20 = -24.50 (c = 0.55 95% AcOH).

  EXAMPLE 3 H2N- (CH2) 5-CO-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-

ol

  at. 0.56 g of H-DPhe-Cys-Phe-DTrp-Lys (Boc) -Thr- is dissolved

  Cys-Thr-ol, 0.5 mmol of Fmoc-ú-aminocaproic acid and 115 mg of hydroxybenzotriazole in 10 ml of DMF and cooled to -30 "C. To this solution, a solution of 115 mg of dicyclohexylcarbodiimide in 5 ml DMF (cooled to

-10 C).

  After a reaction time of 24 hours, during

  from which the mixture heats up to the am-

  biante, the resulting dicyclohexylurea is filtered off

  aunt and dilute the filtrate with water to 10 times its volume. The precipitated reaction product is filtered, washed and dried over phosphorus pentoxide. The gross 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 it is

  then mix with 100 ml of diisopropyl ether. The pro-

  reaction product which then precipitates is separated by filtration

  tion, washed and dried. This raw product is used in other

  purification in the next step.

  vs. Cleavage of Boc 300 mg of the crude product obtained in (1.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 deposit is separated by filtration

  resulting, it is washed and dried under a high vacuum.

  The final product is purified by chromatography on silica gel (CHCl3 / MeOH / H2O / AcOH 7/3 / 0.5 / 0.5), followed by desalting on Duolite (gradient: H2O / AcOH 95/5 ) - '

H20 / dioxane / AcOH 45/50/5).

  The title compound is obtained in the form of acetate.

(white lyophilisate).

  [t] D20 = -32 (c = 0.5, 95% AcOH).

  The resulting compound can be used to make it

  act 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-PAla-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Throl.

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

  EXAMPLE 5 DTPA-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol labeled with l-lIn

  1 mg of DTPA-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys- is dissolved

  Thr-ol in 5 ml of 0.01M acetic acid. The resulting solution is passed through a 0.22 l Millex-GV filter, it is divided into 0.1 ml portions and it is stored at -20 C. IlInCl3 (Amersham, 1 mCi / 100l1) is prediluted in a

  equal volume of 0.5M sodium acetate and the

  by mixing the ligand with the InC13 solution and

  by homogenizing it in a gentle manner at the am-

biante.

  HEPES buffer, pH 7.4, is then added to prepare

rer a 10-6M solution.

  EXAMPLE 6 DTPA-DPhe-Cys-Phe-DTrp-Lys-Thr-C s-Thr-ol labeled at 90y

  90y is obtained from a radio generator-

  cleides 90Sr-90Y. The construction of the generator, its elution and the transformation of [90Y] EDTA into acetate complex are carried out according to the method described by M. Chinol et, D. J. Hnatowitch, in J. Nucl. Med. 28, 1465-1470 (1987). We

  allows to warm to room temperature 1 mg of DTPA-

  DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol dissolved in 5 ml of 0.01M acetic acid and 1.0 mCi of 90Y is added in 50 g1 of sterile 0.5M acetate. The mixture is then left to stand for 30 minutes to 1 hour to obtain the maximum

of chelation.

  A group of LIGANDS OF THE INVENTION is made up of

  somatostatin peptides, for example somato analogs

  statin, which contain, on at least one of the reasons for friend-

  noacides, a chelating group which is attached to said friendly group

  no by an amide bond, in free form or in the form of

salt.

  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

salt form.

  In the above chelating and chelating can designate indifferently

remment The adjective chelating.

Claims (30)

R E V E N D I C A T IONS   1. Somatostatin peptide carrying at least one chelating group   tor for a detectable element, this chelating group being linked to an amino group of said peptide, in free form or in salt form.   2. Somatostatin peptide carrying at least one chelating group   tor 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 the form salt.   3. Somatostatin peptide according to claim 1 or 2, characterized in that the chelating group is attached to the group   N-terminal amino of the somatostatin peptide.   4. Somatostatin peptide according to any one of the claims   above, characterized in that the group ch-   lator is attached directly or indirectly to the amino group of said peptide.   5. Somatostatin peptide according to any one of the claims   above, in which the chelating group is   attached to said peptide by an amide bond.   6. Somatostatin peptide carrying at least one chelating group   tor 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 A 'CH2-S-Y1 Y2-S-CE2 N-CH-CO-B-C-D-E-NH-CH-G   AX in which A is a C1-C12 alkyl group, a C7-C1O phenylalkyl group or a group of formula RCO-, in which i) R is a hydrogen, a C1-Cl1 alkyl group, phenyl or a C7-C1O phenylalkyl group , or ii) RCOest   a) an optional L- or D-phenylalanine residue-   ment substituted on the nucleus with F, Cl, Br, NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy;   b) the residue of a natural or synthetic α-amino acid   tick other than that defined in a) above or a D-   corresponding amino acid, or c) a dipeptide residue in which the individual amino acid residues are the same or different and are chosen from those defined in a) and / or b) above, the amino acid group of amino acid residues a) and b) and the amino group Nterminal of the dipeptide residues c)   possibly being mono- or di-alkylated (C1-C12) or sub- formed by a Cl-C8 alkanoyl,   A 'is hydrogen, C1-C12 alkyl or phenyl-   C7-C10 alkyl Y1 and Y2 together represent a direct bond or each of the radicals Y1 and Y2 is independently a hydrogen or a radical of formulas (1) to (5) R, / CH2 -CO-C- (CH2) 5-H -C0- -C0-NHRc (CH2) ,. (1) (2) (3) -CO-NH-CE-COOR. -C - ((C2) r (R ( Rd R (4) (5)   in which Ra is a methyl or ethyl group Rb 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 C1-C6 alkyl group Rd represents the substituent attached to the carbon atom at a of a natural or synthetic α-amino acid (including hydrogen) Re is a C1-C5 alkyl group Ra 'and Rb' are each independently hydrogen, methyl or ethyl ,   R8 and R9 are each independently hydrogen, halo   gene, C1-C3 alkyl or C1-C3 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 NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy (including pentafluoroalanine), or the group P-naphthyl-Ala C is (L) -Trp- or (D) -Trp, optionally aN-methylated and optionally substituted on the benzene ring by a halogen, a group NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, D is Lys , Lys in which the side chain contains O   or S in position P, rF-Lys or 8F-Lys, possibly a-   N-methylated, or a 4-aminocyclohexylAla or 4-amino residue nocyclohexylGly   E is Thr, Ser, Val, Phe, Ile or an amino acid residue   noisobutyric or aminobutyric G is a group of formula R16 rCOOR7, CH20R1o, -C0Nz or -CO-N XI o R7 is hydrogen or a C1-C3 alkyl group,   R10 is hydrogen or the residue of a physiological ester-   mentally acceptable, physiologically hydrolyzable, Rl1 is hydrogen, C1-C3 alkyl, phenyl or phenylC7-C1Oalkyl, - R12 is hydrogen, C1-C3 alkyl group or a group of formula -CH (R13) -X1,   R13 is CH2OH, - (CH2) 2-OH, - (CH2) 3-OH or -CH (CH3) OH, or re-   has the substituent attached to the carbon atom at a of a natural or synthetic amino acid (including hydrogen) and Xi is a group of formula -COOR7, -CH20R10 or R14 -CO-N   R15 o R7 and R10 have the meanings given above, R14 is hydrogen or C1-C3 alkyl and R15 is hydrogen, C1-C3 alkyl, phenyl or C7-C10 phenylalkyl, and R16 is hydrogen or hydroxy, provided that when R12 is -CH (R13) -Xl, Rli is then hydrogen or a methyl group,   o the residues B, D and E have the configuration L, and the   sidus in position 2 and in position 7 and all residues Y1 4) and Y2 4) each independently have the configuration (L) or (D).   7. Somatostatin peptide according to claim 6, charac-   terized 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 o R13 is -CH2OH, CH (CH3) -OH, - (CH2 ) 2-OH, - (CH2) 3-OH, an isobutyl or butyl group, and X1 is -CO-NR14R15 or -CH2OR10, where R10, R14 and R15 are   as defined in claim 5.   9. Somatostatin peptide according to any one of the claims   above, characterized in that the peptide so-   matostatin is derived from the H- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol also known under the name of octreotide.   10. Somatostatin peptide according to any one of the claims   above, characterized in that the group ch-   reader is chosen from the group made up of the groups   iminodicarboxylics, polyaminopolycarboxy groups   lics, groups derived from macrocyclic amines, groups of formula IV or V 0 0 0   I! II if R1 -C-S- (CH2) X, -C- (TT) i-C- IV 0 0 * t - t, R2-C-S- (CH2). -C-NE-CE2. 0 CH-C- V   R3-C-S- (CH2) n, -C-NH / IlIt o each of the radicals R1, R2 and R3 is independently a   C1-C6 alkyl, C6-C8 aryl or C7- arylalkyl   C9, each optionally substituted by OH, a C1C4 alkoxy group, COOH or SO3H, is equal to 1 or 2, i is an integer from 2 to 6, and TT are independently ac- or 3-amino acids linked to each other by amide bonds, the groups derived from bis-aminothiol derivatives, dithiasemicarbazone derivatives, oxime derivatives of propyleneamine, diamide-dimercaptides or porphyrins, in free form or in the form of salt.   11. Somatostatin peptide according to claim 10, charac-   terized in that the chelating group is derived from acid   ethylenediaminetetraacetic (EDTA), diethylene acid-   triaminepentaacetic acid (DTPA), ethylene glycol-   O, O'-bis (2-aminoethyl) -N, N, N ', N'-tetraacetic (EGTA), from   N, N'-bis (hydroxybenzyl) ethylenediamine-N, N'-diacid- acid   tick (HBED), triethylenetetraminehexaacetic acid (TTHA), substituted EDTA or substituted DTPA, 1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic   (DOTA) and 1,4,8,11-tetra-azacyclotetradecane- acid   N, N ', N ", N"' - tetraacetic (TETA), in free form or in acid form.   12. Somatostatin peptide according to claim 11, charac-   terized 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 claims   above, which is DTPA- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-CysThr-ol   in free form or in salt form.   14. Somatostatin peptide according to any one of the claims   dications 1 to 12, characterized in that the chelating group   is attached to said peptide through a space group   heart of formula cl Z-R35-CO- (c1) R35 is a C1-Cll alkylene group, C2-Cl alkenylene   or -CH (R ') -, in which R' is the residue fixed in a to a c- natural or synthetic amino acid,   Z is a functional group capable of reacting in a   covalent lesson with a chelating agent.   15. Method for producing a somatostatin peptide according to claim 1, in free form or in salt form, characterized in that it comprises - a) the elimination of at least one protective group which is present in a peptide somatostatin 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 se-   quence of amino acids desired, 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) the elimination of a functional group from a non-protected or protected peptide carrying a chelating group or its conversion into a another functional group so as to obtain another unprotected or protected peptide carrying   a chelating group, step a) of the process being carried out   killed in the latter case, or e) the 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 a bridge SS and recovery of the compound thus obtained in free form or in the form of a salt.   16. Somatostatin peptide according to any one of the claims   Dications 1 to 14, in free form or in the form of a pharmaceutically acceptable salt, usable as a pharmaceutical specialty.   17. Pharmaceutical composition comprising a soma- peptide   tostatin according to any one of claims 1 to 14,   in free form or in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutical carrier or diluent. 18. Somatostatin peptide taken from the group comprising the peptides having the following sequences: lu DTPA-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol DTPA (DPhe-Cys-Phe-DTrp-Lys-Thr- Cys-Thr-ol) 2 H2N- (CH2) 5-CO-DPhe-Cys-Phe-DTrpLys-Thr-Cys-Thr-ol DTPA- / pAla-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys- Thr-ol   19. Somatostatin peptide according to any one of the claims   Dications I to 14, in free form or in salt form,   usable 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   ficative for somatostatin receptors, this somatostatin peptide being complexed with a detectable element, in free form or in the form of a pharmaceutically salt acceptable.   21. Chelate according to claim 20, characterized in that   the somotostatin peptide is according to any of the vendications 3 to 14.   22. Chelate according to claim 20 or 21, characterized in that the detectable element is an emission radionuclide '.   23. Chelate according to claim 22, characterized in that   the detectable element is llin or 99mTc.   24. DTPA- (D) Phe-Cys-Phe (D) Trp-Lys-Thr-Cys-Thr-ol labeled with   lllln, in free form or in salt form.   25. Chêlate according to any one of claims 20 to   24, in free form or in the form of a pharmaceutical salt-   acceptable, usable as a pharmaceutical specialty.   26. Chêlate according to any one of claims 20 to   24. in free form or in the form of a pharmaceutical salt-   acceptable, usable as an imaging agent   death or metastasis positive to soma receptors   tostatin. 27.Pharmaceutical composition comprising a chelate   according to any one of claims 20 to 24, in form   me free or in the form of a pharmaceutically acceptable salt   ble, in combination with a pharmaceutical carrier or diluent. 28. In or Tc-labeled somatostatin peptide taken from the group comprising the peptides having the following sequences: -DTPA-DPhe-C ysPhe-DTrp-Lys-Thr-Cys-Thr-ol -DTPA- (DPhe-tys -Phe-DTrp-Lys-Thr-Cys-Thr-ol) 2 -H2N- (CH2) 5-CO-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol -DTPA-BAla-DPhe- CysPhe-DTrp-Lys-Thr-ys-Thr-ol   29. Chelate according to claim 20 or 21, character-   risé in that the detectable element is an emission radionuclide or S. 30. Chelate according to claim 29, characterized   in that the detectable element is 90Y.   31.DTPA- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol mark a 90 y, in free form or in the form of a salt pharmaceutically acceptable.   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   , 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 to somatostatin receptors. 34. 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 combination with a pharmaceutical carrier or diluent. 35. Y-labeled somatostatin peptide taken from the group comprising the peptides having the following sequences: -DTPA-DPhe-ys-Phe-DTrp-Lys-Thr-Cys-Thr-ol DTPA-DPhe-Cys-Phe-DTrp-Lys -Thr-Cys-Thr-ol) 2 -DTPA- (DPhe-ys-Phe-DTrp-LysThr-Cys-Thr-ol) 2 -DTPA-BAla-DPhe-ys-Phe-DTrp-Lys-Thr-tys- Thr-ol 36. Method for producing a chelate according to one   any of claims 20 to 26, 28 to 33 and 35, charac-   terized in that it includes the reaction of a soma- peptide   tostatin according to claim 1, in free form or in   salt form, with a compound generating a detectable element   corn. 37. Method for producing a chelate according to one   any of claims 20 to 26, 28 to 33 and 35, charac-   terized in that it comprises the bonding to one another of a chelating agent complexed with a detectable agent and of a somatostatin peptide according to claim 1, in protected or unprotected form, and optionally the elimination   at least one protecting group present.   38.Packaged presentation containing unit doses of a somatostatin peptide according to any one   claims 1 to 14 and 18 and a detectable element,   with instructions for mixing and using them   as an imaging or therapeutic agent.