WO1992021383A1 - Radiolabelled somatostatin derivatives, their preparation and use - Google Patents
Radiolabelled somatostatin derivatives, their preparation and use Download PDFInfo
- Publication number
- WO1992021383A1 WO1992021383A1 PCT/US1992/004559 US9204559W WO9221383A1 WO 1992021383 A1 WO1992021383 A1 WO 1992021383A1 US 9204559 W US9204559 W US 9204559W WO 9221383 A1 WO9221383 A1 WO 9221383A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino acid
- group
- trp
- phe
- lys
- Prior art date
Links
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/083—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being octreotide or a somatostatin-receptor-binding peptide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- the invention relates to a metal radionuclide-labelled polypeptide intended for diagnostic or therapeutic applications.
- Radionuclide-labelled compounds may be used for diagnostic examinations, for example, into deviations in shape and functions of internal organs and into the presence and location of pathological processes in the body.
- a composition in which the radioactive compound is present is administered to the patient, for example, in the form of an injection liquid.
- a suitable detection apparatus for example, a gamma camera
- images of, for example, the organ or the pathological process in which the active compound is incorporated can be obtained by detecting the emitted radiation ("scanning") .
- Radioactive-labelled biological acromolecules in particular polypeptides, present interesting perspectives for diagnostic applications.
- Certain polypeptides have a very large target organ specificity and, after having been introduced into the body of the patient, can react very selectively with biological macromolecules present therein.
- Binding studies have demonstrated that certain endocrine- related tumours comprise large numbers of binding sites with a high affinity to somatostatin and somatostatin-related polypeptides. Examples of such tumours having large numbers of somatostatin-receptors are pituitary tumours, tumours of the central nervous system, malignant breast tumours, gastro entero-pan ⁇ reatic tumours, and metastases hereof.
- tumour-selective polypeptides may successfully be used for controlling tumours and hence form a powerful tool in radiotherapy.
- the polypeptides used hence serve as vehicles to transport the desired radiation dose, viz. the metal radionuclide, to the tumour to be exposed to the radiation.
- the direct labelling of a polypeptide with a metal radionuclide has two disadvantages.
- the biologically active site of the peptide necessary for a good target organ specificity or selectivity is easily blocked by this reaction, so that the normal behaviour of the biological macro olecule is disturbed.
- the affinity between metal-radionuclide and macromolecule often is unsatisfactory, so that the formed bond is not sufficiently stable to remain intact under physiological conditions.
- the administered material then is no longer useful - neither as a diagnostic -it cannot be detected any more how the polypeptide behaves in the body - nor as a therapeutic - the radiation dose is no longer transported to the desired target but causes an undesired radiation burden elsewhere!
- Both the commercially available somatostatin, and the octreotide described in Patent Application WO 90/06949 mentioned hereinbefore, comprise cystine bridges, formed by oxidation from two cysteine amino acid radicals. It is the object of the present invention to provide an easily accessible radioactive-technetium-labelled or radio ⁇ active-rhenium-labelled polypeptide for the selective detection/localisation or for the selective therapeutic treatment of tumours with somatostatin receptors, which is sufficiently stable for in vivo application. This object can be achieved with a labelled polypeptide which according to the present invention is characterised by the general formula
- R-j_ is a hydrogen atom or a ⁇ -C ⁇ alkylcarbonyl group
- R 2 is an amino group, a hydroxy group or a C ⁇ -C ⁇ , alkoxy group
- Ai and A5 each independently are Phe, MePhe, EtPhe,
- a 2 is Phe, MePhe, EtPhe, Tyr, Trp or Nal
- A3 is Lys, MeLys or (£-Me)Lys
- A4 is Thr or Val
- S ⁇ is an amino acid sequence of 1 to 6 amino acids, selected from the group consisting of Ala, cys, Asn, Phe, MePhe, EtPhe, Tyr, Trp, Nal, Gly, Lys, MeLys, (£-Me)Lys, Thr, Val, Asn and Ser, and
- S is an amino acid sequence of 0 to 3 amino acids, selected from the group mentioned sub S lf with the proviso that the polypeptide comprises two cysteine amino acid radicals, the metal-radionuclide being selected from a radioactive Tc- isotope or Re-isotope which as a cation is bound covalently to the mercapto groups of the cysteine amino acid radicals.
- Nal naphthylalanyl
- the labelled polypeptide can simply be prepared and is sufficiently stable in vivo for performing the desired examinations and the desired therapeutic treatment, respectively. It has been established that the labelled compound remained stable at least one hour after injection. The selectivity is not adversely influenced by the labelling with radioactive technetium or rhenium.
- Tc-99m-labelled polypeptide according to the invention is bound specifically to somatostatin receptor- sites.
- Suitable labelled polypeptides according to the invention are derived from the previously mentioned octreotide and analogues thereof, and may then be represented by the general formula
- R ⁇ , R 2 , A 2 , A3 and A4 have the meanings given hereinbefore, and A 6 is Phe, MePhe, EtPhe, Tyr, Trp or Nal, the metal radionuclide being selected from the group consisting of Tc-99m, Re-186 and Re-188 which as a cation is bound covalently to the mercapto groups of the cysteine amino acid radicals.
- labelled polypeptides according to the invention are derived from somatostatin and analogues thereof, and may be represented by the general formula
- A'I and A'5 each independently represent Phe, MePhe, EtPhe, Tyr, Trp or Nal,
- S' ⁇ is an amino acid sequence of 1 to 6 amino acids, preferably of 5 amino acids, selected from the group consisting of Ala, Cys, Asn, Phe, MePhe, EtPhe, Tyr, Trp, Nal, Gly, Lys, MeLys, ( ⁇ -Me)Lys, Thr, Val, Asn and Ser, with the proviso that S' ⁇ comprises a cysteine amino acid radical, and
- S' is an amino acid sequence of 1 to 3 amino acids, preferably of 2 amino acids, selected from the group mentioned sub S- ⁇ 1 , with the proviso that S 2 ' comprises a cysteine amino acid radical, the metal radionuclide being selected from the group consisting of Tc-99m, Re-186 and Re- 188 which as a cation is bound covalently to the mercapto groups of the cysteine amino acid radicals.
- a labelled polypeptide is preferred of the general formula
- the metal radionuclide being selected from the group consisting of Tc-99m, Re-186 and Re-188 which as a cation is bound covalently to the mercapto groups of the cysteine amino acid radicals.
- the invention also relates to a method of preparing a metal- radionuclide-labelled polypeptide according to the invention by starting from a cyclised polypeptide, in which the cysteine amino acid radicals together are oxidised to a cystine group.
- cyclised polypeptides are the already mentioned somatostatin commercial product and analogues thereof.
- Analogues are to be understood to mean polypeptides having corresponding biological activity, i.e. specific so atostatin-receptor binding affinity, but with modifications in the amino acid sequence. It has been found that the said cyclised polypeptides can be excellently reduced and may then be labelled under reducing conditions without the polypeptide molecule being attacked.
- reducing agent are preferably chosen zinc ions or metallic zinc, the latter, for example, in the form of zinc powder, because such reducing agents are suitable both for the preparation of the polypeptide from the cyclised material, and also for the reduction of pertechnetate or perrhenate.
- metallic zinc powder in the so-called SPED (Solid Phase Electron Donor) technique, in which the cyclised polypeptide is incubated by means of zinc powder, for example, on a 0.22 ⁇ filter, after which addition of a Tc-99m pertechnetate solution immediately provides a solution of the pure, Tc- 99m-labelled polypeptide in the filtrate.
- Metallic zinc may also be provided excellently as a zinc mirror on the inner wall of a tube or other reaction vessel and thus produce the desired conversions in the tube or reaction vessel.
- the invention further relates to a pharmaceutical composition which comprises the metal-radionuclide-labelled polypeptide according to the invention, and to the use of the said composition for diagnostic or therapeutic purposes.
- a pharmaceutical composition which comprises the metal-radionuclide-labelled polypeptide according to the invention, and to the use of the said composition for diagnostic or therapeutic purposes.
- the active substance should be labelled with radioactive technetium, for therapeutic purposes, the active substance should be labelled with radioactive rhenium. All this is defined in more detail in Claims 8 and 9.
- the invention finally relates to a kit for preparing a radiopharmaceutical composition, comprising, in an optionally dry condition, a cyclised polypeptide, as defined hereinbefore, a reducing agent, preferably metallic zinc or zinc ions, and directives for reacting the ingredients of the kit and of the resulting product with Tc-99m pertechnetate or with Re-186 or Re-188 perrhenate.
- a kit for preparing a radiopharmaceutical composition comprising, in an optionally dry condition, a cyclised polypeptide, as defined hereinbefore, a reducing agent, preferably metallic zinc or zinc ions, and directives for reacting the ingredients of the kit and of the resulting product with Tc-99m pertechnetate or with Re-186 or Re-188 perrhenate.
- a kit for preparing a radiopharmaceutical composition comprising, in an optionally dry condition, a cyclised polypeptide, as defined hereinbefore, a reducing agent, preferably metallic zinc or zinc ions
- somatostatin is treated for 30 minutes at a pH of 8 on a 0.22 ⁇ filter by means of the so-called SPED technique as described hereinbefore. A freshly eluted sodium pertechnetate solution is then added and the mixture is incubated at room temperature for 15 minutes.
- the labelled polypeptide may be obtained as a filtrate. Precipitate and liquid can be separated without a filter by decanting and extracting the liquid by means of a syringe. A labelling efficiency of 90% is obtained. Free technetium is bound to the SPED and cannot contaminate the product. Labelling is confirmed by means of thin-layer chromatography and ion exchange column chromatography. The labelled compound is stable in vitro up to 4 hours.
- tumour take-up reaches a maximum at approximately 4 minutes after injection. During the determination period no significant activity reduction from the tumour can be observed.
- the labelled compound is stable in vivo during the whole of the determination period, as appears from the absence of thyroid gland and stomach activities. Scintigrams of the tumours are made four minutes after injection.
- the uptake ratios tumourimuscle tissue are favourable, namely 5:1.
- tumour accummulation of technetium is related to the somatostatin binding to receptors in the tumour has been checked by treating one group of experimental animals having tumours prior to administration of the labelled compound with Sursamine® to block the receptor sites. No tumour uptake is observed in these animals, so that it is confirmed that the binding takes place at somatostatin receptors in the tumour.
- a group of adult female rats were implanted with CC531 Colon Carcinoma which is known to have somatostatin receptors.
- CC531 Colon Carcinoma which is known to have somatostatin receptors.
- the subcutaneous tumour implants had reached a size of ⁇ 1.5cm diameter, one group was injected with Technetium Somatostatin complex by intravenous injection and a second group was injected in a similar manner with Indium-Ill Octreotide complex for comparison.
- the animals were anaesthetised by means of nembutal and serial scintigrams were made.
- the Technetium Somatostatin was clearly visible in the tumour within 4-5 minutes post injection.
- the animals were sacrificed by cervical dislocation and tissue samples were taken and counted.
- Approximately 11% of the injected dose was found in the total tumour tissue with a tumour to soft tissue uptake ratio of 4.2/1.
- the blood concentration was relatively high tumour to blood ratios being 0.23.
- the bulk of the activity was recovered in the stomach, liver, spleen and kidneys.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5500596A JPH06508357A (en) | 1991-06-03 | 1992-06-02 | Labeled polypeptide, its production method and use |
AU20174/92A AU657770B2 (en) | 1991-06-03 | 1992-06-02 | Radiolabelled somatostatin derivatives, their preparation and use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL9100954 | 1991-06-03 | ||
NL9100954 | 1991-06-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992021383A1 true WO1992021383A1 (en) | 1992-12-10 |
Family
ID=19859317
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1992/004559 WO1992021383A1 (en) | 1991-06-03 | 1992-06-02 | Radiolabelled somatostatin derivatives, their preparation and use |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0588905A1 (en) |
JP (1) | JPH06508357A (en) |
AU (1) | AU657770B2 (en) |
CA (1) | CA2102633A1 (en) |
WO (1) | WO1992021383A1 (en) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993015770A1 (en) * | 1992-02-05 | 1993-08-19 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
US5382654A (en) * | 1992-02-05 | 1995-01-17 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
US5405597A (en) * | 1991-09-10 | 1995-04-11 | Diatech, Inc. | Technetium-99m labeled somatostatin-derived peptides for imaging |
US5574140A (en) * | 1993-09-03 | 1996-11-12 | Resolution Pharmaceutical Inc. | Hydrazino-type N2 S2 chelators |
WO1997005167A1 (en) * | 1995-07-28 | 1997-02-13 | Romano Deghenghi | Somatostatin-analogous cyclic peptides with inhibitory activity on growth hormone |
US5659041A (en) * | 1993-07-19 | 1997-08-19 | Resolution Pharmaceuticals, Inc. | Hydrazino-type radionuclide chelators having an N3 S configuration |
EP0831936A1 (en) * | 1995-06-07 | 1998-04-01 | Immunomedics, Inc. | Thiolation of peptides for radionuclide-based radiodetection and radiotherapy |
WO1998028336A1 (en) * | 1996-12-20 | 1998-07-02 | Map Medical Technologies Oy | Polysaccharide-peptide derivatives |
US5843401A (en) * | 1992-06-23 | 1998-12-01 | Diatide, Inc. | Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses |
US5849261A (en) * | 1991-02-08 | 1998-12-15 | Diatide, Inc. | Radiolabeled vasoactive intestinal peptides for diagnosis and therapy |
US5858327A (en) * | 1993-09-03 | 1999-01-12 | Resolutions Pharmaceuticals, Inc. | Hydrazino-type N2 S2 radionuclide chelating compounds |
US5866097A (en) * | 1991-11-27 | 1999-02-02 | Diatide, Inc. | Technetium-99m labeled peptides for imaging |
US5871711A (en) * | 1992-06-23 | 1999-02-16 | Diatide, Inc. | Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses |
US5981477A (en) * | 1991-11-27 | 1999-11-09 | Diatide, Inc. | Peptide-metal chelate conjugates |
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 |
US7060679B2 (en) | 1998-06-19 | 2006-06-13 | Develogen Israel Ltd. | Conformationally constrained backbone cyclized somatostatin analogs |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2021121A (en) * | 1978-05-19 | 1979-11-28 | Meyers Ca Coy D H | Somatostatin analogues having a substituted tryptophyl residue in position eight |
WO1989012068A2 (en) * | 1988-06-03 | 1989-12-14 | Societe D'etudes De Produits Chimiques | Peptides useful for inhibiting blood vessel blockage |
WO1990006949A2 (en) * | 1988-12-05 | 1990-06-28 | Sandoz Ag | Peptide derivatives |
WO1991001754A1 (en) * | 1989-08-09 | 1991-02-21 | Rhodes Buck A | Direct radiolabeling of antibodies and other proteins with technetium or rhenium |
-
1992
- 1992-06-02 CA CA002102633A patent/CA2102633A1/en not_active Abandoned
- 1992-06-02 EP EP92912727A patent/EP0588905A1/en not_active Withdrawn
- 1992-06-02 WO PCT/US1992/004559 patent/WO1992021383A1/en not_active Application Discontinuation
- 1992-06-02 JP JP5500596A patent/JPH06508357A/en active Pending
- 1992-06-02 AU AU20174/92A patent/AU657770B2/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2021121A (en) * | 1978-05-19 | 1979-11-28 | Meyers Ca Coy D H | Somatostatin analogues having a substituted tryptophyl residue in position eight |
WO1989012068A2 (en) * | 1988-06-03 | 1989-12-14 | Societe D'etudes De Produits Chimiques | Peptides useful for inhibiting blood vessel blockage |
WO1990006949A2 (en) * | 1988-12-05 | 1990-06-28 | Sandoz Ag | Peptide derivatives |
WO1991001754A1 (en) * | 1989-08-09 | 1991-02-21 | Rhodes Buck A | Direct radiolabeling of antibodies and other proteins with technetium or rhenium |
Non-Patent Citations (3)
Title |
---|
CHEMICAL ABSTRACTS, vol. 112, no. 16, 16 April 1990, Columbus, Ohio, US; abstract no. 150685, C.KREMER ET AL: 'Solid-phase reduction of 99mTcO4 with zinc: a method for the preparation of difficult Tc-99m complexes' page 797 ;column 2 ; * |
EUROPEAN JOURNAL OF NUCLEAR MEDICINE vol. 18, no. 8, August 1991, page 558; P.H.COX: 'TECHNETIUM LABELLED SOMATOSTATINE FOR IN VIVO TUMOUR LOCALISATION' * |
THE LANCET vol. 1, no. 8632, 4 February 1989, LONDON pages 242 - 244; E.P.KRENNING ET AL: 'Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin' * |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5849261A (en) * | 1991-02-08 | 1998-12-15 | Diatide, Inc. | Radiolabeled vasoactive intestinal peptides for diagnosis and therapy |
US5405597A (en) * | 1991-09-10 | 1995-04-11 | Diatech, Inc. | Technetium-99m labeled somatostatin-derived peptides for imaging |
US5985241A (en) * | 1991-11-27 | 1999-11-16 | Diatide, Inc. | Peptide-metal chelate conjugate complexes |
US5866097A (en) * | 1991-11-27 | 1999-02-02 | Diatide, Inc. | Technetium-99m labeled peptides for imaging |
US5981477A (en) * | 1991-11-27 | 1999-11-09 | Diatide, Inc. | Peptide-metal chelate conjugates |
WO1993015770A1 (en) * | 1992-02-05 | 1993-08-19 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
US5753205A (en) * | 1992-02-05 | 1998-05-19 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
US5382654A (en) * | 1992-02-05 | 1995-01-17 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
US5843401A (en) * | 1992-06-23 | 1998-12-01 | Diatide, Inc. | Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses |
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 |
US5659041A (en) * | 1993-07-19 | 1997-08-19 | Resolution Pharmaceuticals, Inc. | Hydrazino-type radionuclide chelators having an N3 S configuration |
US5574140A (en) * | 1993-09-03 | 1996-11-12 | Resolution Pharmaceutical Inc. | Hydrazino-type N2 S2 chelators |
US5858327A (en) * | 1993-09-03 | 1999-01-12 | Resolutions Pharmaceuticals, Inc. | Hydrazino-type N2 S2 radionuclide chelating compounds |
US6051206A (en) * | 1994-06-03 | 2000-04-18 | Diatide, Inc | Radiolabeled somatostatin-derived peptides for imaging and therapeutic uses |
EP0831936A4 (en) * | 1995-06-07 | 2001-05-16 | Immunomedics Inc | Thiolation of peptides for radionuclide-based radiodetection and radiotherapy |
EP0831936A1 (en) * | 1995-06-07 | 1998-04-01 | Immunomedics, Inc. | Thiolation of peptides for radionuclide-based radiodetection and radiotherapy |
WO1997005167A1 (en) * | 1995-07-28 | 1997-02-13 | Romano Deghenghi | Somatostatin-analogous cyclic peptides with inhibitory activity on growth hormone |
KR100321448B1 (en) * | 1995-07-28 | 2002-07-31 | 데겐기로마노 | Somatostatin-Alike Cytotype Peptides with Growth Hormone Inhibitory Activity |
WO1998028336A1 (en) * | 1996-12-20 | 1998-07-02 | Map Medical Technologies Oy | Polysaccharide-peptide derivatives |
US6455025B1 (en) | 1996-12-20 | 2002-09-24 | Map Medical Technologies Oy | Polysaccharide-peptide derivatives |
US7060679B2 (en) | 1998-06-19 | 2006-06-13 | Develogen Israel Ltd. | Conformationally constrained backbone cyclized somatostatin analogs |
Also Published As
Publication number | Publication date |
---|---|
EP0588905A1 (en) | 1994-03-30 |
AU657770B2 (en) | 1995-03-23 |
JPH06508357A (en) | 1994-09-22 |
AU2017492A (en) | 1993-01-08 |
CA2102633A1 (en) | 1992-12-04 |
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