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WO1990006949A2 - Derives de peptides - Google Patents

Derives de peptides Download PDF

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Publication number
WO1990006949A2
WO1990006949A2 PCT/EP1989/001448 EP8901448W WO9006949A2 WO 1990006949 A2 WO1990006949 A2 WO 1990006949A2 EP 8901448 W EP8901448 W EP 8901448W WO 9006949 A2 WO9006949 A2 WO 9006949A2
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WO
WIPO (PCT)
Prior art keywords
group
alkyl
hydrogen
somatostatin
peptide
Prior art date
Application number
PCT/EP1989/001448
Other languages
English (en)
Other versions
WO1990006949A3 (fr
Inventor
Rainer Albert
Eric P. Krenning
Steven W. J. Lamberts
Janos Pless
Original Assignee
Sandoz Ag
Sandoz-Patent-Gmbh
Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB888828364A external-priority patent/GB8828364D0/en
Priority claimed from GB898916115A external-priority patent/GB8916115D0/en
Priority claimed from GB898916761A external-priority patent/GB8916761D0/en
Application filed by Sandoz Ag, Sandoz-Patent-Gmbh, Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Sandoz Ag
Priority to DE893991505T priority Critical patent/DE3991505T1/de
Priority to DE3991505A priority patent/DE3991505B4/de
Publication of WO1990006949A2 publication Critical patent/WO1990006949A2/fr
Publication of WO1990006949A3 publication Critical patent/WO1990006949A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins
    • C07K14/6555—Somatostatins at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to polypeptides, process for their production, pharmaceutical preparations containing them and their use as a pharmaceutical, e.g. for treatment of somatostatin receptor positive tumors or as in vivo diagnostic imaging agents.
  • a somatostatin peptide bearing 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.
  • LIGANDS OF THE INVENTION possess one chelating group capable of reacting with a detectable element, e.g. a radionuclide, a radioopaque element or a paramagnetic ion, to form a complex and further are capable of binding to somatostatin receptors, e.g. expressed or overexpressed by tumors or metastases.
  • a detectable element e.g. a radionuclide, a radioopaque element or a paramagnetic ion
  • the chelating group is linked by a covalent bond to the amino group of the peptide.
  • the chelating group is preferably attached to the terminal N-amino group of the somatostatin peptide.
  • the chelating group may be attached either directly or indirectly, e.g. by means of a spacer group, to the amino group of the somatostatin peptide.
  • LIGANDS One group of LIGANDS is that wherein the chelating group is attached directly to the amino group of the somatostatin peptide.
  • LIGANDS Another group of LIGANDS is that wherein the chelating group is attached indirectly by a bridging or a spacer group to the amino group of the somatostatin peptide.
  • the chelating group is attached by an amide bond to the peptide.
  • somatostatin peptides includes the naturally occurring somatostatin (tetradecapeptide) and its analogues or derivatives.
  • derivatives or analogues as used herein is meant any straightchain or cyclic polypeptide derived from that of the naturally occurring tetradecapeptide somatostatin wherein one or more amino acid units have been omitted and/or replaced by one or more other amino acid radical(s) and/or wherein 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 several other isosteric groups.
  • the term covers all modified derivatives of a biologically active peptide which exhibit a qualitatively similar effect to that of the unmodified somatostatin peptide, e.g. they bind to somatostatin receptors and decrease hormone secretion.
  • Cyclic, bridge cyclic and straight-chain somatostatin analogues are known compounds. Such compounds and their preparation are described e.g. in European Patent Specifications EP-A-1295;
  • Preferred LIGANDS OF THE INVENTION are those derived from the following somatostatin analogues:
  • A is C 1-12 alkyl, C 7-10 phenylalkyl or a group of
  • RCO- whereby i) R is hydrogen, C 1-11 alkyl, phenyl or C 7-10- phenylakyl, or ii) RCO- is a) an L- or D-phenylalanine residue optionally ring-substituted by F, Cl, Br, NO 2 , NH 2 , OH, C 1-3 alkyl and/or C 1-3 alkoxy; b) the residue of a natural or synthetic ⁇ -amino acid other than defined under a) above or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above, the ⁇ -amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally mono- or di-C 1-12 alkylated or substituted by C 1-8 alkanoyl,
  • A' is hydrogen, C 1-12 alkyl or C 7-10 phenylalkyl, Y 1 and Y 2 represent together a direct bond or
  • each of Y 1 and Y 2 is independently hydrogen or a radical of formulae (1) to (5)
  • R a is methyl or ethyl
  • R b is hydrogen, methyl or ethyl
  • m is a whole number from 1 to 4
  • n is a whole number from 1 to 5
  • R c is (C 1-6 )alkyl
  • R d represents the substituent attached to the
  • Re is (C 1-5 )alkyl
  • Ra ' and R b ' are independently hydrogen, methyl or ethyl
  • R 8 and R 9 are independently hydrogen, halogen, (C 1-3 )alkyl or (C 1-3 )alkoxy
  • p 0 or 1
  • q 0 or 1
  • r is 0, 1 or 2
  • B is -Phe- optionally ring-substituted by halogen
  • NO 2 , NH 2 , OH, C 1-3 alkyl and /or C 1-3 alkoxy (including pentafluoroalanine), or ⁇ -naphthyl-Ala is (L)-Trp- or (D)-Trp- optionally ⁇ -N-methylated and optionally benzene-ring-substituted by halogen, NO 2 , NH 2 , OH, C 1-3 alkyl and/or C 1-3 alkoxy, is Lys, Lys in which the side chain contains O or S in ⁇ -position, ⁇ F-Lys or ⁇ F-Lys, optionally ⁇ -N-methylated, or a 4-aminocyclohexylAla or 4-aminocyclohexylGly residue is Thr, Ser, Val, Phe, lie or an ami ⁇ oisobutyric or aminobutyric acid residue is a group of formula
  • R 7 is hydrogen or C 1-3 alkyl
  • R 10 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester
  • R 11 is hydrogen, C 1- 3 alkyl, phenyl or C 7-10 phenylalkyl
  • R 12 is hydrogen, C 1-3 alkyl or a group of formula
  • R 13 is CH 2 OH, -(CH 2 ) 2 -OH, -(CH 2 ) 3 -OH, or -CH(CH 3 )OH or represents the substituent attached to the ⁇ -carbon atom of a natural or synthetic ⁇ -amino acid (including hydrogen) and is a group of formula -COOR 7 , -CH 2 OR 10 or
  • R 7 and R 10 have the meanings given above,
  • R 14 is hydrogen or C 1-3 alkyl
  • R 15 is hydrogen, C 1-3 alkyl, phenyl or C 7-10 phenylalkyl, and
  • R 16 is hydrogen or hydroxy, with the proviso that
  • R 12 when R 12 is -CH(R 13 )-X 1 then R 11 is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2-and 7-position and any residues Y 1 4) and Y 2 4) each independently have the (L)- or (D)- configuration.
  • a and A' in formula I are preferably selected so that the compound contains a terminal -NH- group capable of being linked to a chelating agent.
  • A is C 7-10 phenylalkyl, especially phenethyl, or a group of formula RCO.
  • A is a group of formula RCO.
  • R is C 1-11 alkyl or C 7-10 phenylalkyl, especially C 7-10 phenylalkyl, more especially phenethyl, or RCO has the meanings a), b) or c).
  • RCO has the meanings a), b) or c
  • the ⁇ -amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) is preferably non-alkylated or mono-C 1-1 2 alkylated, especially -C 1-8
  • alkylated more especially -methylated.
  • N-terminal is non-alkylated.
  • Vhen RCO has the meaning a) this is preferably a') an L- or D-phenylalanine or -tyrosine residue optionally mono-N-C 1-1 2 alkylated. More preferably a') is an L- or D-phenylalanine residue.
  • Vhen RCO has the meaning b) or c) the defined residue is preferably lipophilic.
  • Preferred residues b) are thus b') ⁇ -amino acid residues having a hydrocarbon side chain, e.g. alkyl with 3, preferably 4, or more C atoms, e.g. up to 7 C-atoms, naphthyl-methyl or heteroaryl, e.g.
  • 3-(2- or 1-naphthyl)-alanine, pyridyl-methyl or tryptophane residue, said residues having the L- or D-configuration, and preferred residues c) are dipeptide residues in which the individual amino acid residues are the same or different and are selected from those defined under a') and b') above.
  • Example of a residue c) is e.g. 3-(2-naphthyl)-alanine residue.
  • RCO has the meaning a) especially the meaning a').
  • B is B', where B' is Phe or Tyr.
  • C is C', where C' is (D)Trp. 4.
  • D is D' , where D' is Lys, MeLys or Lys( ⁇ -Me), especially Lys.
  • E is E', where E' is Val or Thr, especially Thr.
  • G is G', where G' is a group of formula
  • R 11 is preferably hydrogen.
  • R 13 is preferably -CH 2 OH, -CH(CH 3 )-OH, isobutyl or butyl, or R 13 is -(CH 2 ) 2 -OH or -(CH 2 ) 3 -OH. It is especially -CH 2 OH or
  • Xi is preferably a group of formula
  • R 10 is preferably hydrogen or has the meaning given under 7 below. Most preferably R 10 is hydrogen.
  • Suitable chelating groups are physiologically acceptable chelating groups capable of complexing a detectable element.
  • the chelating group has substantially a hydrophilic character.
  • chelating groups include e.g. iminodicarboxylic groups, polyaminopolycarboxylic groups, e.g. those derived from non cyclic ligands e.g.
  • ethylene diaminetetraacetic acid EDTA
  • diethylene triamine pentaacetic acid DTPA
  • EGTA ethylene glycol-0,0'-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid
  • HBED N,N'-bis(hydroxybenzyl)ethylenediamine-N,N'-diacetic acid
  • TTHA triethylenetetramine hexaacetic acid
  • each of R 1 , R 2 and R 3 independently is C 1-6 alkyl, C 6-8 aryl or
  • n' 1 or 2
  • i is an integer from 2 to 6
  • TT are independently ⁇ or ⁇ amino acids linked to each other by amide bonds, groups derived from bis-aminothiol derivatives, e.g. compounds of formula VI
  • each of R 20, R 21 , R 22 and R 23 independently is hydrogen or
  • X 2 is a group capable of reacting with the N-amino group of the peptide
  • n' is 2 or 3, groups derived from dithiasemicarbazone derivatives, e.g.
  • X 2 is as defined above, groups derived from propylene amine oxime derivatives, e.g. compounds of formula VIII
  • each of R 24 , R 25 , R 26 , R 27 , R 28 and R 29 independently are hydrogen or C 1-4 alkyl
  • X 2 and m' are as defined above, groups derived from diamide dimercaptides, e.g. compounds of formula IX wherein
  • X 3 is a divalent radical optionally substituted and bearing a group capable of reacting with the N-amino group of the peptide, e.g. C 1-4 alkylene or phenylene bearing a group X 2 , and
  • Y 5 is hydrogen or CO 2 R 30 , wherein R 30 is C 1-4 alkyl, or groups derived from porphyrins, e.g. N-benzyl-5, 10, 15,20-tetrakis-(4-carboxyphenyl)porphine or TPP bearing a group X 2 as defined above.
  • R 30 is C 1-4 alkyl, or groups derived from porphyrins, e.g. N-benzyl-5, 10, 15,20-tetrakis-(4-carboxyphenyl)porphine or TPP bearing a group X 2 as defined above.
  • Aryl is preferably phenyl.
  • Arylalkyl is preferably benzyl.
  • the chelating group may be attached either directly or indirectly to the N-amino group of the somatostatin peptide. Vhen it is attached indirectly, it is preferably linked through a bridging or spacer group, for example a group of formula ( ⁇ 1) Z-R 3 5 -CO- ( ⁇ 1 )
  • R 35 is C 1- 11 alkylene, C 2 -nalkenylene or -CH(R')- wherein R' is the residue attached in ⁇ to a natural or synthetic ⁇ -amino acid, e.g. hydrogen, C 1-11 alkyl, benzyl, optionally substituted benzyl, naphthyl-methyl, pyridyl-methyl,
  • Z is a functional moiety capable of covalently reacting with the chelating agent.
  • Z may be for example a group which can form an ether, ester or amide bonding with the chelating group. Z is preferably amino.
  • the chelating groups when comprising carboxy, -SO 3 H and/or amino groups may exist in free form or in salt form.
  • Preferred chelating groups are those derived from polyamino-polycarboxylic groups, e.g. those derived from EDTA, DTPA, DOTA, TETA or substituted EDTA or DTPA. Chelating groups derived from DTPA are most preferred.
  • the chelating group when polyfunctional, may be linked either to a single somatostatin peptide molecule or to more than one somatostatin peptide molecules e.g. to two somatostatin peptide molecules.
  • the LIGANDS OF THE INVENTION may exist e.g. in free or salt form.
  • Salts include acid addition salts with e.g. organic acids, polymeric acids or inorganic acids, for example hydrochlorides and acetates, and salt forms obtainable with the carboxylic or sulphonic acid groups present in the chelating group, e.g. alkali metal salts such as sodium or potassium, or substituted or unsubstituted ammonium salts.
  • the present invention also includes a process for the production of the LIGANDS OF THE INVENTION. They may be produced by analogy to known methods.
  • the LIGANDS OF THE INVENTION may be produced for example as follows: a) removing at least one protecting group which is present in a somatostatin peptide bearing a chelating group, or b) linking together by an amide bond two peptide fragments each of them containing at least one amino acid or amino alcohol in protected or unprotected form and one of them containing the chelating group, wherein the amide bond is in such a way that the desired amino acid sequence is obtained, and stage a) of the process is then optionally effected, or c) linking together a chelating agent and the desired somatostatin peptide in protected or unprotected form in such a way that the chelating group is fixed on the desired N-amino group of the peptide, and stage a) is then optionally effected or, d) removing a functional group of an unprotected or a protected peptide bearing a chelating group or converting it into another functional group so that another unprotected
  • the above reactions may be effected in analogy with known methods, e.g. as described in the following examples, in particular processes a) and c).
  • Vhen the chelating group is attached by an amide bond this may be carried out analogously to the methods used for amide formation.
  • protecting groups which are suitable for use in peptides or for the desired chelating groups may be used for functional groups which do not participate in the reaction.
  • the term protecting group may also include a polymer resin having functional groups.
  • Vhen it is desired to attach the chelating group to the terminal N-amino group of a peptide or peptide fragment used as starting material, and which comprises one or more side chain amino groups, these side chain amino groups are conveniently protected with a protecting group , e.g. as used in peptide chemistry.
  • Vhen it is desired to attach the chelating group to a side chain amino group of a peptide or peptide fragment used as starting material, and the peptide comprises a free terminal N-amino group, the latter is preferably protected with a protecting group.
  • the peptide fragment bearing the chelating group and used in stage b) may be prepared by reacting the peptide fragment comprising at least one amino acid or amino alcohol in protected or unprotected form with the chelating agent.
  • the reaction may be performed in analogy with stage c).
  • the chelating groups of formula IV or V may be linked to a peptide by reacting a chelating agent of formula IV' or V'
  • X is an activating group capable of forming an amide bond with the N-amino group of the peptide.
  • the reaction may be performed as disclosed in EP 247,866 A1.
  • the chelating agent used in process step c) may be known or prepared in analogy with known procedures.
  • the compound used is such that it allows the introduction of the desired chelating group on the somatostatin peptide, e.g. a polyaminopolycarboxylic acid as disclosed, a salt or anhydride thereof.
  • the chelating group is attached through a bridging or spacer group to the peptide, e.g. a radical of formula ( ⁇ 1 ) as defined above
  • a bridging or spacer group to the peptide
  • such amino-acids, peptide fragments or peptides may be prepared by reacting in conventional manner the corresponding amino-acids or peptides free of bridging or spacer group with a corresponding bridgingor spacer-yielding compound, for example an acid or reactive acid derivative comprising the bridging or spacer group, e.g. an acid of formula Z-R 35 -COOH or a reactive acid derivative thereof such as an active ester.
  • active ester groups or carboxy activating groups are e.g. 4-nitrophenyl, pentachlorophenyl, pentafluorophenyl, succinimidyl or 1-hydroxy-benzotriazolyl.
  • the chelating agent may first be reacted with a bridging or spacer group-yielding compound, in order to bear the bridging or spacer group and then be reacted in conventional manner with the peptide, peptide fragment or amino-acid.
  • the LIGANDS OF THE INVENTION may be purified in conventional manner, e.g. by chromatography.
  • the LIGANDS OF THE INVENTION contain less than 5% by weight of peptides free of chelating groups.
  • the LIGANDS OF THE INVENTION can be complexed with a detectable element.
  • the present invention also provides the LIGANDS OF THE INVENTION as defined above which are complexed with a detectable element (hereinafter referred to as CHELATES OF THE INVENTION), in free form or in salt form, their preparation and their use for in vivo diagnostic and therapeutic treatment.
  • CHELATES OF THE INVENTION a detectable element
  • detectable element any element, preferably a metal ion which exhibits a property detectable in therapeutic or in vivo diagnostic techniques, e.g. a metal ion which emits a detectable radiation or a metal ion which is capable of influencing NMR relaxation properties.
  • Suitable detectable metal ions include for example heavy elements or rare earth ions, e.g. as used in CAT scanning (Computer axial tomography), paramagnetic ions, e.g. Gd 3+ , Fe 3+ , Mn 2+ and Cr 2+ , fluorescent metal ions, e.g. Eu 3+ , and radionuclides, e.g.
  • ⁇ -emitting radionuclides ⁇ -emitting radionuclides, ⁇ -emitting radionuclides, positron-emitting radionuclides e.g. 68 Ga.
  • Suitable ⁇ -emitting radionuclides include those which are useful in diagnostic techniques.
  • the ⁇ -emitting radionuclides advantageously have a half-life of from 1 hour to 40 days, preferably from 5 hours to 4 days, more preferably from 12 hours to 3 days. Examples are radionuclides derived from Gallium, Indium, Technetium, Ytterbium, Rhenium and Thallium e.g. 67 Ga, 111 In, 99m Tc, 169 Yb and 186 Re.
  • the ⁇ -radionuclide is selected depending on the metabolism of the LIGAND OF THE INVENTION or somatostatin peptide used. More preferably the LIGAND OF THE INVENTION is chelated with a ⁇ -radionuclide having a longer half-life than the half-life of the somatostatin peptide on the tumor.
  • radionuclides suitable for use in imaging are positronemitting radionuclides, e.g. as mentioned above.
  • Suitable ⁇ -emitting radionuclides include those which are useful in therapeutic applications, for example 90 Y, 67 -Cu, 186 Re, 188 Re, 169 Er, 121 Sn, 127 Te, 143 Pr, 198 Au, 109 Pd, 165 Dy, 32 P, 142 pr.
  • the ⁇ -radionuclide advantageously have a half-life of from 2.3 hrs to 14.3 d, preferably from 2.3 to 100 hrs.
  • the ⁇ -emitting radionuclide is selected in order to have a longer half-life than the half-life of the somatostatin peptide on the tumor.
  • Suitable ⁇ -emitting radionuclides are those which are used in therapeutic treatments, e.g. 211 At, 212 Bi.
  • the CHELATES OF THE INVENTION may be prepared by reacting the LIGAND with a corresponding detectable element yielding compound, e.g. a metal salt, preferably a water-soluble salt.
  • a detectable element yielding compound e.g. a metal salt, preferably a water-soluble salt.
  • the reaction may be carried out by analogy with known methods, e.g. as disclo sed in Perrin, Organic Ligand, Chemical Data Series 22. NY Pergamon Press (1982) ⁇ in Krejcarit and Tucker, Biophys. Biochem. Res. Com. 77: 581 (1977) and in Wagner and Welch, J. Nucl. Med. 20: 428 (1979).
  • the complexing of the LIGAND is effected at a pH at which the LIGAND OF THE INVENTION is physiologically stable.
  • the detectable element may also be provided to the solution as a complex with an intermediate chelating agent, e.g. a chelating agent which forms a chelate complex that renders the element soluble at the physiological pH of the LIGAND but is less thermodynamically stable than the CHELATE.
  • an intermediate chelating agent e.g. a chelating agent which forms a chelate complex that renders the element soluble at the physiological pH of the LIGAND but is less thermodynamically stable than the CHELATE.
  • an intermediate chelating agent is 4,5-dihydroxy-l,3-benzene-di-sulfonic acid (Tiron).
  • Tiron 4,5-dihydroxy-l,3-benzene-di-sulfonic acid
  • the CHELATES OF THE INVENTION may also be produced by linking together a chelating agent complexed with the detectable element, and a somatostatin peptide in protected or unprotected form and if desired removing at least one protecting group which is present. The same reaction may be performed with a chelating agent complexed with a non detectable metal ion and then in the resulting complexed peptide the metal ion may be replaced by the desired detectable element.
  • the CHELATES OF THE INVENTION may also be produced by linking together a chelating agent complexed with the detectable element, and a somatostatin peptide fragment comprising at least one amino acid in protected or unprotected form and. then continuing the peptide synthesis step by step until the final peptide sequence is obtained and if desired removing at least one protecting group which is present.
  • the chelating agent may be complexed with a non detectable metal and this metal may then be replaced by the detectable element in the resulting complexed somatostatin peptide.
  • the chelating group is attached through a bridging or spacer group to the somatostatin peptide, e.g. through a radical of formula ( ⁇ i) as defined above, either the somatostatin peptide or peptide fragment or the chelating agent may bear said bridging or spacer group.
  • Radionuclides such as for example Technetium-99m may be used in oxidized form, e.g. Tc-99m pertechnetate, which may be complexed under reducing conditions.
  • the above mentioned reactions are conveniently effected under conditions avoiding trace metal contamination.
  • distilled de-ionized water, ultrapure reagents, chelation-grade radioactivity etc. are used to reduce the effects of trace metal.
  • the CHELATES OF THE INVENTION may exist e.g. in free or salt form.
  • Salts include acid addition salts with e.g. organic acids, polymeric acids or inorganic acids, for example hydrochlorides and acetates, and salt forms obtainable with the carboxylic acid groups present in the molecule which do not participate to the chelate formation, e.g. alkali metal salts such as sodium or potassium, or substituted or unsubstituted ammonium salts.
  • the CHELATES OF THE INVENTION and their pharmaceutical acceptable salts exhibit pharmaceutical activity and are therefore useful either as an imaging agent, e.g. visualisation of somatostatin receptor positive tumors and metastases when complexed with a paramagnetic, a ⁇ -emitting metal ion or a positron-emitting radionuclide, or as a radiopharmaceutical for the treatment in vivo of somatostatin receptor positive tumors and metastases when complexed with a ⁇ - or ⁇ -radionuclide, as indicated by standard tests.
  • an imaging agent e.g. visualisation of somatostatin receptor positive tumors and metastases when complexed with a paramagnetic, a ⁇ -emitting metal ion or a positron-emitting radionuclide
  • radiopharmaceutical for the treatment in vivo of somatostatin receptor positive tumors and metastases when complexed with a ⁇ - or ⁇ -radi
  • the CHELATES OF THE INVENTION possess affinity for somatostatin receptors expressed or overexpressed by tumors and metastases, as indicated in standard in vitro binding assays.
  • a somatostatin receptor positive tumor originating from the human gastro intestinal tract is removed from a patient and immediately put on ice and within a maximal delay of 30 min frozen at
  • this frozen material is cut on a cryostat (Leitz 1720) in 10 ⁇ m sections, mounted on precleaned microscope slides and stored at - 20 ° C for at least 3 days to improve adhesion of the tissue to the slide.
  • the sections are preincubated in Tris-HCl buffer (50 mM, pH 7.4), containing CaCl 2 (2mM) and KCl (5mM), for 10 min at ambient temperature and then washed twice for 2 min in the same buffer without additional salts added.
  • the sections are then incubated with a CHELATE OF THE INVENTION for 2 hours at ambient temperature in Tris-HCl buffer (170 mM, pH 7.4), containing bovine serum albumin (10 g/l), bacitracin (40 mg/1) and MgCl 2 (5 mM) to inhibit endogenous proteases.
  • Non-specific binding is determined by adding the corresponding non-labelled, non-modified somatostatin peptide at a concentration of 1 ⁇ M.
  • Incubated sections are washed twice for 5 min in cold incubation buffer containing 0.25 g/l BSA. After a brief dip in distilled water to remove excess salts, the sections are dried quickly and apposed to [ 3 H]-LKB films.
  • the CHELATES OF THE INVENTION e.g. a radionuclide CHELATE
  • the CHELATES OF THE INVENTION give very good results in labeling the tumoral tissue without labeling the surrounding healthy tissue when added at a concentration of about 10 -10 to 10 -3 M.
  • the affinity of the CHELATES OF THE INVENTION for somatostatin receptors can also be shown by in vivo testing.
  • Rats bearing transplantable exocrine pancreatic somatostatin receptor positive tumors are treated with an intravenous injection of a CHELATE OF THE INVENTION. Injection site is the penis vein. Immediately after administration, the animals are positioned on the collimator of a gamma-camera and the distribution of radioactivity is monitored at various time intervals.
  • Biodistribution of radioactivity may also be determined through serial sacrifice of a number of such treated rats and determination of the organ radioactivity.
  • a CHELATE OF THE INVENTION e.g. a radionuclide CHELATE, for example a ⁇ -emitting CHELATE
  • a dosage of from 1 to 5 ⁇ g/kg of LIGAND labeled with 0.1 to 2 mCi radionuclide the tumor site becomes detectable together with the organs where excretion essentially takes place.
  • the present invention also provides:
  • a subject which comprises a) administering a CHELATE OF THE INVENTION to said subject and b) recording the localisation of the receptors targeted by said CHELATE.
  • CHELATES OF THE INVENTION for use in the in vivo detection method of the invention are the CHELATES which are complexed with, a ⁇ -emitting radionuclide, a positron-emitting radionuclide or a paramagnetic metal ion, e.g. as indicated above.
  • the CHELATES OF THE INVENTION for use as an imaging agent in method (1) may be administered parenterally, preferably intravenously, e.g. in the form of injectable solutions or suspensions, preferably in a single injection.
  • the appropriate dosage will of course vary depending upon, for example, the LIGAND and the type of detectable element used, e.g. the radionuclide.
  • a suitable dose to be injected is in the range to enable imaging by photoscanning procedures known in the art.
  • Vhen a radiolabeled CHELATE OF THE INVENTION is used, it may advantageously be administered in a dose having a radioactivity of from 0.1 to 50 mCi, preferably 0.1 to 30 mCi, more preferably 0.1 to 20 mCi.
  • An indicated dosage range may be of from 1 to 200 ⁇ g LIGAND labeled with 0.1 to 50 mCi, preferably 0.1 to 30 mCi, e.g. 3 to 15 mCi, ⁇ -emitting radionuclide, depending on the ⁇ -emitting radionuclide used.
  • it is preferred to use a radioactivity in the lower range whereas with Tc, it is preferred to use a radioactivity in the upper range.
  • the enrichment in the tumorigenic sites with the CHELATES may be followed by the corresponding imaging techniques, e.g. using nuclear medicine imaging instrumentation, for example a scanner, ⁇ -camera , rotating ⁇ -camera, each preferably computer assisted; PET-scanner (Positron emission tomography); MRI equipment or CAT scanning equipment.
  • nuclear medicine imaging instrumentation for example a scanner, ⁇ -camera , rotating ⁇ -camera, each preferably computer assisted; PET-scanner (Positron emission tomography); MRI equipment or CAT scanning equipment.
  • the CHELATES OF THE INVENTION e.g. a major part of the ⁇ -emitting CHELATES is substantially excreted through the kidneys and does not significantly accumulate in the liver.
  • a method for in vivo treatment of somatostatin receptor positive tumors and metastases in a subject in need of such a treatment which comprises administering to said subject a therapeutically effective amount of a CHELATE OF THE INVEN TION.
  • CHELATES OF THE INVENTION for use in the in vivo treatment method of the invention are the CHELATES complexed with a ⁇ - or ⁇ -radionuclide as defined above.
  • Dosages employed in practising the therapeutic method of the present invention will of course vary depending e.g. on the particular condition to be treated, for example the volume of the tumor, the particular CHELATE employed, for example the half-life of the CHELATE in the tumor, and the therapy desired.
  • the dose is calculated on the basis of radioactivity distribution to each organ and on observed target uptake.
  • the CHELATE may be administered at a daily dosage range having a radioactivity of from 0.1 to 3mCi/kg body weight, e.g. 1 to 3 mCi, preferably 1 to 1.5 mCi/kg body weight.
  • An indicated daily dosage range is of from 1 to 200 ⁇ g LIGAND labeled with 0.1 to 3 mCi/kg body weight, e.g. 0.1 to 1.5/kg body weight ⁇ - or ⁇ -emitting radionuclide, conveniently administered in divided doses up to 4 times a day.
  • the ⁇ - or ⁇ -emitting CHELATES OF THE INVENTION may be administered by any conventional route, in particular parenterally, e.g. in the form of injectable solutions or suspensions. They may also be administered advantageously by infusion, e.g. an infusion of 30 to 60 min. Depending on the site of the tumor, they may be administered as close as possible to the tumor site, e.g. by means of a catheter.
  • the mode of administration selected may depend on the dissociation rate of the CHELATE used and the excretion rate.
  • the CHELATES OF THE INVENTION may be administered in free form or in pharmaceutically acceptable form.
  • Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
  • the CHELATES OF THE INVENTION for use in the method of the present invention may preferably be prepared shortly before the administration to a subject, i.e. the radiolabeling with the desired detectable metal ion, particularly the desired ⁇ -, ⁇ - or ⁇ - radionuclide, may be performed shortly before the administration.
  • the CHELATES OF THE INVENTION may be suitable for imaging or treating tumors such as pituitary, gastroenteropancreatic, central nervous system, breast, prostatic, ovarian or colonic tumors, small cell lung cancer, paragangliomas, neuroblastomas, pheochromocytomas, medullary thyroid carcinomas, myelomas, etc. and metastases thereof.
  • tumors such as pituitary, gastroenteropancreatic, central nervous system, breast, prostatic, ovarian or colonic tumors, small cell lung cancer, paragangliomas, neuroblastomas, pheochromocytomas, medullary thyroid carcinomas, myelomas, etc. and metastases thereof.
  • r-emitting CHELATES OF THE INVENTION may also be used as imaging agent for the evaluation of the kidney function.
  • mice Groups of five mice are used. Each mouse is injected intravenously through a tail vein with 0.1 ml containing 1 mCi of a CHELATE OF THE INVENTION. The mice are then placed in metabolic cages for the collection of excreted urine. At 10 or 120 min. post-injection, the urethras are ligated and the mice anesthetized with chloroform. Imaging of the uropoietic system is carried out using the usual imaging technique. In this test, the ⁇ -emitting CHELATES OF THE INVENTION improves imaging of renal excretion when administered at a dosage of from 0.1 to 30 mCi.
  • the present invention also provides a method for in vivo evaluation of the kidney function in a subject which comprises administering to said subject an effective amount of a r-emitting CHELATE and recording the kidney function.
  • a pharmaceutical composition comprising a LIGAND OF THE
  • compositions may be manufactured in conventional manner.
  • a composition according to the invention may also be presented in separate package with instructions for mixing the LIGAND with the metal ion and for the administration of the resulting CHELATE. It may also be presented in twin-pack form, that is, as a single package containing separate unit dosages of the LIGAND and the detectable metal ion with instructions for mixing them and for administration of the CHELATE. A diluent or carrier may be present in the unit dosage forms.
  • the starting material may be produced as follows: a)
  • the end product is purified by chromatography on silica gel (CHCl 3 /MeOH/H 2 O/AcOH 7/3/0.5/0.5), with subsequent de-salting over Duolite (gradient: H 2 O/AcOH 95/5)---H 2 O/dioxane/AcOH 45/50/5),
  • the title compound is obtained as an acetate (white lyophilisate).
  • the resulting compound may be used for reaction with DTPA in accordance with the procedure of Examples 1 and 2.
  • 111 InCl 3 (Amersham, 1 mCi/100 ⁇ l) is prediluted in an equal volume of 0.5M sodium acetate and labeling is carried out by mixing the ligand with the InCl 3 solution and gentle homogenisation at room temperature.
  • HEPES buffer pH 7.4
  • HEPES buffer pH 7.4
  • 90 Y is obtained from a 90 Sr- 90 Y radionuclide generator.
  • the construction of the generator, its elution and the conversion of the [ 90 Y]EDTA to the acetate complex are performed in accordance with the method disclosed by M.Chinol and D.J. Hnatowich in J. Nucl.
  • somatostatin peptides e.g. somatostatin analogues , which contain at least on one of the amino acid units a chelating group which is attached to said amino group by an amide bond, in free form or in salt form.
  • CHELATES OF THE INVENTION are the LIGANDS just mentioned above complexed with a detectable element, e.g. a metal ion, in free form or in salt form.
  • a detectable element e.g. a metal ion

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Abstract

On forme un complexe de peptides de somatostatine portant au moins un groupe de chélation destiné à un élément détectable, ledit groupe de chélation étant lié à un groupe amino dudit peptide, et ledit groupe amino n'ayant pas d'affinité de liaison vis-à-vis de récepteurs de somatostatine, sous forme libre ou de sel, avec un élément détectable, lesquels sont utiles comme produit pharmaceutique, par exemple comme produit radiopharmaceutique pour l'imagerie in vivo de tumeurs à réaction positive aux récepteurs de somatostatine, ou en thérapie.
PCT/EP1989/001448 1988-12-05 1989-11-30 Derives de peptides WO1990006949A2 (fr)

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DE893991505T DE3991505T1 (de) 1988-12-05 1989-11-30 Peptidderivate
DE3991505A DE3991505B4 (de) 1988-12-05 1989-11-30 Somatostatinpeptide, deren Analoga oder Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen

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GB898916115A GB8916115D0 (en) 1989-07-13 1989-07-13 Improvements in or relating to organic compounds
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992021383A1 (fr) * 1991-06-03 1992-12-10 Mallinckrodt Medical, Inc. Derives de somatostatine radiomarques, leur preparation et utilisation
WO1993018797A1 (fr) * 1992-03-25 1993-09-30 Mallinckrodt Medical, Inc. Procede pour detecter et localiser de façon peroperatoire des tissus tumoraux
WO1994000489A2 (fr) * 1992-06-23 1994-01-06 Diatech, Inc. Peptides derives de la somatostatine et marques de maniere radioactive pour imagerie et utilisations therapeutiques
WO1995000553A1 (fr) * 1993-06-23 1995-01-05 Diatech, Inc. Peptides radiomarques derives de la somatostatine et utilises dans des procedes d'imagerie et therapeutiques
WO1995003330A1 (fr) * 1993-07-21 1995-02-02 Diatech, Inc. Derives de somatostatine et leurs produits radiomarques
US5556939A (en) * 1994-10-13 1996-09-17 Merck Frosst Canada, Inc. TC or RE radionuclide labelled chelate, hexapeptide complexes useful for diagnostic or therapeutic applications
US5632969A (en) * 1994-10-13 1997-05-27 Merck & Co., Inc. N3 S2 chelating ligands optionally radiolabelled with Tc or Re, useful for diagnostic or therapeutic applications
WO1998028336A1 (fr) * 1996-12-20 1998-07-02 Map Medical Technologies Oy Derives de polysaccharide-peptide
US5804157A (en) * 1995-06-07 1998-09-08 Mallinckrodt Medical, Inc. Peptide compositions and method of radiolabeling
US5849261A (en) * 1991-02-08 1998-12-15 Diatide, Inc. Radiolabeled vasoactive intestinal peptides for diagnosis and therapy
US5871711A (en) * 1992-06-23 1999-02-16 Diatide, Inc. Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses
US6017509A (en) * 1991-11-27 2000-01-25 Diatide, Inc. Radiolabeled somatostatin receptor-binding peptides
US6017512A (en) * 1992-06-23 2000-01-25 Diatide, Inc. Radiolabeled peptides
US6051206A (en) * 1994-06-03 2000-04-18 Diatide, Inc Radiolabeled somatostatin-derived peptides for imaging and therapeutic uses
WO2000061194A2 (fr) * 1999-04-09 2000-10-19 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin Conjugues de colorants ayant des peptides a courte chaine utilises comme agents de contraste pour le diagnostic optique
US6630570B1 (en) 1999-04-09 2003-10-07 Insitut für Diagnostikforschung GmbH Short-chain peptide-dye conjugates as contrast media for optical diagnosis
US7175953B2 (en) 1999-04-09 2007-02-13 Institute Fuer Diagnostik Forschung Short-warp peptide-dye conjugate as contrast agent for optical diagnostic
US7589061B2 (en) 2001-04-23 2009-09-15 Mallinckrodt Inc. Tc and Re labeler radioactive glycosylated octreotide derivatives

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3822557C2 (de) * 1987-07-10 1998-07-02 Ciba Geigy Ag Arzneimittel, enthaltend Somatostatine
AU639371B2 (en) * 1987-07-10 1993-07-22 Novartis Ag Method of treating breast cancer
GB9111199D0 (en) * 1991-05-23 1991-07-17 Sandoz Ltd Improvements in or relating to organic compounds
US5460785A (en) * 1989-08-09 1995-10-24 Rhomed Incorporated Direct labeling of antibodies and other protein with metal ions
US5443816A (en) * 1990-08-08 1995-08-22 Rhomed Incorporated Peptide-metal ion pharmaceutical preparation and method
US5985240A (en) * 1989-08-09 1999-11-16 Rhomed Incorporated Peptide radiopharmaceutical applications
US5700444A (en) * 1992-02-20 1997-12-23 Rhomed Incorporated Chemotactic peptide pharmaceutical applications
GB9004017D0 (en) * 1990-02-22 1990-04-18 Krenning Eric P Improvements in or relating to organic compounds
US5382654A (en) * 1992-02-05 1995-01-17 Mallinckrodt Medical, Inc. Radiolabelled peptide compounds
ATE181240T1 (de) * 1991-02-08 1999-07-15 Biomeasure Inc Verwendung von somatostatinanalogen zur behandlung von melanomen
US7238340B1 (en) 1991-11-27 2007-07-03 Cis Bio International Monoamine, diamide, thiol-containing metal chelating agents
WO1993004702A1 (fr) * 1991-08-29 1993-03-18 Mallinckrodt Medical, Inc. Utilisation de l'acide gentisique ou de l'alcool gentisyle pour stabiliser des peptides et proteines radiomarques
US5225180A (en) * 1991-09-10 1993-07-06 Diatech, Inc. Technetium-99m labeled somatostatin-derived peptides for imaging
US5783170A (en) * 1991-11-27 1998-07-21 Diatide, Inc. Peptide-metal chelate conjugates
WO1993012819A1 (fr) * 1992-01-03 1993-07-08 Rhomed Incorporated Applications pharmaceutiques a base d'ions metalliques-proteines et peptides
US5738838A (en) * 1992-02-20 1998-04-14 Rhomed Incorporated IKVAV peptide radiopharmaceutical applications
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US5371184A (en) * 1992-02-05 1994-12-06 Mallinckrodt Medical, Inc. Radiolabelled peptide compounds
JPH08504166A (ja) * 1992-02-05 1996-05-07 マリンクロッド・メディカル・インコーポレイテッド 放射標識ペプチド化合物
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US5650134A (en) * 1993-01-12 1997-07-22 Novartis Ag (Formerly Sandoz Ltd.) Peptides
NZ250653A (en) * 1993-01-12 1995-12-21 Sandoz Ltd Somatostatin derivatives and pharmaceutical or diagnostic imaging compositions
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US5879657A (en) * 1993-03-30 1999-03-09 The Dupont Merck Pharmaceutical Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
US5932189A (en) * 1994-07-29 1999-08-03 Diatech, Inc. Cyclic peptide somatostatin analogs
CA2190727C (fr) * 1994-05-19 2006-07-18 Sudhakar Kasina Ligands d'atomes donneurs d'azote et de soufre pontes et substitues par amines aromatiques, utilises en imagerie
GB9417873D0 (en) 1994-09-06 1994-10-26 Sandoz Ltd Organic compounds
GB9708265D0 (en) 1997-04-24 1997-06-18 Nycomed Imaging As Contrast agents
US6685914B1 (en) 1999-09-13 2004-02-03 Bristol-Myers Squibb Pharma Company Macrocyclic chelants for metallopharmaceuticals
WO2005018682A2 (fr) 2003-08-20 2005-03-03 The Regents Of The University Of California Analogues de somatostatine a activite inhibitrice de liberation d'hormone de croissance
AU2004273911B2 (en) * 2003-09-17 2010-04-15 Board Of Regents, The University Of Texas System Mechanism-based targeted pancreatic beta cell imaging and therapy
EP2067786A1 (fr) 2007-12-07 2009-06-10 ITALFARMACO S.p.A. Nouveaux analogues non sélectifs de somatostatine
US9480759B2 (en) 2012-11-21 2016-11-01 Serene, Llc Tin-117m somatostatin receptor binding compounds and methods
CN119708199A (zh) 2023-09-27 2025-03-28 钱杭江医药科技(嘉兴)有限公司 生长抑素肽类类似物、螯合物及其应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0150844A2 (fr) * 1984-01-30 1985-08-07 Enzo Biochem, Inc. Méthode pour le marquage radioactif d'agents diagnostiques et thérapeutiques contenant un groupe de chélation
DE3511206A1 (de) * 1985-03-28 1986-10-09 Sandoz-Patent-GmbH, 7850 Lörrach Neue polypeptidderivate, ihre herstellung und pharmazeutische praeparate, welche diese polypeptidderivate enthalten
EP0233619A1 (fr) * 1986-02-14 1987-08-26 Nihon Medi-Physics Co., Ltd. Composés aminés de haut poids moléculaire et leur utilisation
EP0247866A1 (fr) * 1986-05-29 1987-12-02 Mallinckrodt, Inc. (a Delaware corporation) Agents de couplage pour la préparation de protéines marquées par la radioactivité
EP0248506A1 (fr) * 1986-03-05 1987-12-09 Mallinckrodt, Inc. (a Delaware corporation) Marquage de molécules de support par les ions métalliques
WO1989004666A1 (fr) * 1987-11-18 1989-06-01 The Administrators Of The Tulane Educational Fund Traitement du cancer avec de la somatostatine et avec des analogues de celle-ci

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1222691A (fr) * 1981-12-29 1987-06-09 Wilhelmus T. Goedemans Methode de preparation de proteines marquees par un radionucleide, notamment des anticorps ou des fragments d'anticorps
US4652519A (en) * 1983-02-03 1987-03-24 Yeda Research And Development Company Limited Bifunctional chelating agents and process for their production
HUT42101A (en) * 1985-01-07 1987-06-29 Sandoz Ag Process for preparing stomatostatine derivatives and pharmaceutical compositions containing such compounds
DE3522638A1 (de) * 1985-06-25 1987-01-08 Diamalt Ag Neue somatostatin-derivate
US4678667A (en) * 1985-07-02 1987-07-07 501 Regents of the University of California Macrocyclic bifunctional chelating agents
HU906341D0 (en) * 1986-10-13 1991-04-29 Sandoz Ag Process for producing peptonic derivatives modified with sugar and pharmaceutical preparatives containing these compounds as active substance
CH679045A5 (fr) * 1987-06-29 1991-12-13 Sandoz Ag
BE1003762A3 (fr) * 1988-11-11 1992-06-09 Sandoz Sa Nouvelle utilisation therapeutique de la somatostatine et de ses analogues et derives.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0150844A2 (fr) * 1984-01-30 1985-08-07 Enzo Biochem, Inc. Méthode pour le marquage radioactif d'agents diagnostiques et thérapeutiques contenant un groupe de chélation
DE3511206A1 (de) * 1985-03-28 1986-10-09 Sandoz-Patent-GmbH, 7850 Lörrach Neue polypeptidderivate, ihre herstellung und pharmazeutische praeparate, welche diese polypeptidderivate enthalten
EP0233619A1 (fr) * 1986-02-14 1987-08-26 Nihon Medi-Physics Co., Ltd. Composés aminés de haut poids moléculaire et leur utilisation
EP0248506A1 (fr) * 1986-03-05 1987-12-09 Mallinckrodt, Inc. (a Delaware corporation) Marquage de molécules de support par les ions métalliques
EP0247866A1 (fr) * 1986-05-29 1987-12-02 Mallinckrodt, Inc. (a Delaware corporation) Agents de couplage pour la préparation de protéines marquées par la radioactivité
WO1989004666A1 (fr) * 1987-11-18 1989-06-01 The Administrators Of The Tulane Educational Fund Traitement du cancer avec de la somatostatine et avec des analogues de celle-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Life Sciences, Vol. 43, No. 5, 1988 J.E. Taylor et al: "High affinity binding of (125I-Tyr11)somatostatin-14 to human small cell lung carcinoma (NCI-H69) ", *

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US5849261A (en) * 1991-02-08 1998-12-15 Diatide, Inc. Radiolabeled vasoactive intestinal peptides for diagnosis and therapy
AU657770B2 (en) * 1991-06-03 1995-03-23 Mallinckrodt Medical, Inc. Radiolabelled somatostatin derivatives, their preparation and use
WO1992021383A1 (fr) * 1991-06-03 1992-12-10 Mallinckrodt Medical, Inc. Derives de somatostatine radiomarques, leur preparation et utilisation
US6017509A (en) * 1991-11-27 2000-01-25 Diatide, Inc. Radiolabeled somatostatin receptor-binding peptides
WO1993018797A1 (fr) * 1992-03-25 1993-09-30 Mallinckrodt Medical, Inc. Procede pour detecter et localiser de façon peroperatoire des tissus tumoraux
US5871711A (en) * 1992-06-23 1999-02-16 Diatide, Inc. Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses
US6017512A (en) * 1992-06-23 2000-01-25 Diatide, Inc. Radiolabeled peptides
EP1094074A3 (fr) * 1992-06-23 2002-01-09 Diatide, Inc. Peptides dérivés de la somatostatine et marques de manière radiactive pour imagerie et utilisations thérapeutiques
EP1094074A2 (fr) * 1992-06-23 2001-04-25 Diatide, Inc. Peptides dérivés de la somatostatine et marques de manière radiactive pour imagerie et utilisations thérapeutiques
US5716596A (en) * 1992-06-23 1998-02-10 Diatide, Inc. Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses
WO1994000489A2 (fr) * 1992-06-23 1994-01-06 Diatech, Inc. Peptides derives de la somatostatine et marques de maniere radioactive pour imagerie et utilisations therapeutiques
WO1994000489A3 (fr) * 1992-06-23 1994-03-31 Diatech Inc Peptides derives de la somatostatine et marques de maniere radioactive pour imagerie et utilisations therapeutiques
US5814298A (en) * 1992-06-23 1998-09-29 Diatide, Inc. Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses
US5820845A (en) * 1992-06-23 1998-10-13 Diatide, Inc. Somatostatin-derived peptides for imaging and therapeutic uses
US5843401A (en) * 1992-06-23 1998-12-01 Diatide, Inc. Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses
US5833942A (en) * 1992-06-23 1998-11-10 Diatide, Inc. Technetium-99m labeled somatostatin-derived peptides for imaging and therapeutic uses
EP1092726A2 (fr) * 1993-06-23 2001-04-18 Diatide, Inc. Peptides dérivés de la somatostatine et marques de manière radioactive pour imagerie et utilisations thérapeutiques
WO1995000553A1 (fr) * 1993-06-23 1995-01-05 Diatech, Inc. Peptides radiomarques derives de la somatostatine et utilises dans des procedes d'imagerie et therapeutiques
EP1099707A3 (fr) * 1993-06-23 2002-01-09 Diatide, Inc. Peptides derives de la somatostatine et marques de maniere radioactive pour imagerie et utilisations therapeutiques
EP1092726A3 (fr) * 1993-06-23 2002-01-09 Diatide, Inc. Peptides dérivés de la somatostatine et marques de manière radioactive pour imagerie et utilisations thérapeutiques
EP1099707A2 (fr) * 1993-06-23 2001-05-16 Diatide, Inc. Peptides derives de la somatostatine et marques de maniere radioactive pour imagerie et utilisations therapeutiques
WO1995003330A1 (fr) * 1993-07-21 1995-02-02 Diatech, Inc. Derives de somatostatine et leurs produits radiomarques
US6241965B1 (en) 1993-07-21 2001-06-05 Diatide, Inc. Somatostatin derivatives and their radiolabelled products
US6051206A (en) * 1994-06-03 2000-04-18 Diatide, Inc Radiolabeled somatostatin-derived peptides for imaging and therapeutic uses
US5556939A (en) * 1994-10-13 1996-09-17 Merck Frosst Canada, Inc. TC or RE radionuclide labelled chelate, hexapeptide complexes useful for diagnostic or therapeutic applications
US5632969A (en) * 1994-10-13 1997-05-27 Merck & Co., Inc. N3 S2 chelating ligands optionally radiolabelled with Tc or Re, useful for diagnostic or therapeutic applications
US5830431A (en) * 1995-06-07 1998-11-03 Mallinckrodt Medical, Inc. Radiolabeled peptide compositions for site-specific targeting
US5804157A (en) * 1995-06-07 1998-09-08 Mallinckrodt Medical, Inc. Peptide compositions and method of radiolabeling
US6455025B1 (en) 1996-12-20 2002-09-24 Map Medical Technologies Oy Polysaccharide-peptide derivatives
WO1998028336A1 (fr) * 1996-12-20 1998-07-02 Map Medical Technologies Oy Derives de polysaccharide-peptide
WO2000061194A3 (fr) * 1999-04-09 2001-11-08 Diagnostikforschung Inst Conjugues de colorants ayant des peptides a courte chaine utilises comme agents de contraste pour le diagnostic optique
WO2000061194A2 (fr) * 1999-04-09 2000-10-19 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin Conjugues de colorants ayant des peptides a courte chaine utilises comme agents de contraste pour le diagnostic optique
EP1281405A2 (fr) * 1999-04-09 2003-02-05 INSTITUT FÜR DIAGNOSTIKFORSCHUNG GmbH AN DER FREIEN UNIVERSITÄT BERLIN Conjugués de peptides à courte chaíne avec des colorants comme agent de contraste pour le diagnostique optique
EP1281405A3 (fr) * 1999-04-09 2003-02-12 INSTITUT FÜR DIAGNOSTIKFORSCHUNG GmbH AN DER FREIEN UNIVERSITÄT BERLIN Conjugués de peptides à courte chaíne avec des colorants comme agent de contraste pour le diagnostique optique
US6630570B1 (en) 1999-04-09 2003-10-07 Insitut für Diagnostikforschung GmbH Short-chain peptide-dye conjugates as contrast media for optical diagnosis
US7175953B2 (en) 1999-04-09 2007-02-13 Institute Fuer Diagnostik Forschung Short-warp peptide-dye conjugate as contrast agent for optical diagnostic
US7589061B2 (en) 2001-04-23 2009-09-15 Mallinckrodt Inc. Tc and Re labeler radioactive glycosylated octreotide derivatives

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NL8902981A (nl) 1990-07-02
ES2023533A6 (es) 1992-01-16
IE893866L (en) 1990-06-05
DE3991505B4 (de) 2006-04-20
SE508799C2 (sv) 1998-11-09
MY106120A (en) 1995-03-31
DK175338B1 (da) 2004-08-30
FI102540B1 (fi) 1998-12-31
PT92487A (pt) 1990-06-29
GB8927255D0 (en) 1990-01-31
SA96160495B1 (ar) 2006-08-23
CH678329A5 (fr) 1991-08-30
FI102540B (fi) 1998-12-31
GB2225579A (en) 1990-06-06
PT92487B (pt) 1996-01-31
JPH02184698A (ja) 1990-07-19
IE62091B1 (en) 1994-12-14
KR900009697A (ko) 1990-07-05
FR2639947A1 (fr) 1990-06-08
LU87633A1 (fr) 1991-09-18
WO1990006949A3 (fr) 1990-07-26
AU4587189A (en) 1990-06-14
BE1002296A5 (fr) 1990-11-20
SE8904087L (sv) 1991-06-05
NL194828C (nl) 2003-04-03
JPH1095737A (ja) 1998-04-14
HUT53375A (en) 1990-10-28
ATA901789A (de) 1997-07-15
HU211468A9 (en) 1995-11-28
DK612689D0 (da) 1989-12-05
IL92534A (en) 1994-06-24
CA2004532C (fr) 2000-02-22
JP2726320B2 (ja) 1998-03-11
KR0156541B1 (ko) 1998-10-15
NL194828B (nl) 2002-12-02
FR2639947B1 (fr) 1995-04-21
DK612689A (da) 1990-06-06
HU896359D0 (en) 1990-02-28
JP3686503B2 (ja) 2005-08-24
AT403476B (de) 1998-02-25
CA2004532A1 (fr) 1990-06-05
GB2225579B (en) 1993-03-17
AU633859B2 (en) 1993-02-11
FI895809A0 (fi) 1989-12-04
HK189995A (en) 1995-12-29
SE8904087D0 (sv) 1989-12-04

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