EP0588905A1 - Derives de somatostatine radiomarques, leur preparation et utilisation - Google Patents

Derives de somatostatine radiomarques, leur preparation et utilisation

Info

Publication number
EP0588905A1
EP0588905A1 EP92912727A EP92912727A EP0588905A1 EP 0588905 A1 EP0588905 A1 EP 0588905A1 EP 92912727 A EP92912727 A EP 92912727A EP 92912727 A EP92912727 A EP 92912727A EP 0588905 A1 EP0588905 A1 EP 0588905A1
Authority
EP
European Patent Office
Prior art keywords
amino acid
group
trp
lys
phe
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP92912727A
Other languages
German (de)
English (en)
Inventor
Peter Henry Cox
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mallinckrodt Inc
Original Assignee
Mallinckrodt Medical Inc
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
Application filed by Mallinckrodt Medical Inc filed Critical Mallinckrodt Medical Inc
Publication of EP0588905A1 publication Critical patent/EP0588905A1/fr
Withdrawn legal-status Critical Current

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.

Landscapes

  • 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

L'invention concerne des dérivés de somatostatine marqués au technetium radioactif et marqués au rhénium radioactif utilisés dans la détection/localisation sélective ou dans le traitement thérapeutique sélectif de tumeurs à l'aide de récepteurs de somatostatine. Les polypeptides sont caractérisés par la formule générale R1-S1-A1-A2-(D)Trp-A3-A4-A5-Thr-S2-R2, dans laquelle R1 représente un atome d'hydrogène ou un groupe alkylcarbonyle C1-C4, R2 représente un groupe amino, un groupe hydroxy ou un groupe alcoxy C1-C4, A1 et A5 représentent chacun indépendamment Phe, MePhe, EtPhe, Tyr, Trp, Nal (naphtylalanyle), ou Cys, A2 représente Phe, MePhe, EtPhe, Tyr, Trp ou Nal, A3 représente Lys, MeLys ou (epsilon-Me)Lys, A4 représente Thr ou Val, S1 représente une séquence d'acides aminés comprenant 1 à 6 acides aminés, choisis dans le groupe constitué par Ala, Cys, Asn, Phe, MePhe, EtPhe, Tyr, Trp, Nal, Gly, Lys, MeLys, (epsilon-Me)Lys, Thr, Val, Asn et Ser, et S2 représente une séquence d'acides aminés comprenant 0 à 3 acides aminés choisis dans le groupe appelé sous-S1, à condition que le polypeptide comprenne deux radicaux d'acides aminés de cystéine, le radionuclide de métal étant choisi entre un isotope Tc et Re radioactif, lequel en tant que cation, est lié de manière covalente aux groupes mercapto des radicaux d'acides aminés de cystéine.
EP92912727A 1991-06-03 1992-06-02 Derives de somatostatine radiomarques, leur preparation et utilisation Withdrawn EP0588905A1 (fr)

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
EP0588905A1 true EP0588905A1 (fr) 1994-03-30

Family

ID=19859317

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92912727A Withdrawn EP0588905A1 (fr) 1991-06-03 1992-06-02 Derives de somatostatine radiomarques, leur preparation et utilisation

Country Status (5)

Country Link
EP (1) EP0588905A1 (fr)
JP (1) JPH06508357A (fr)
AU (1) AU657770B2 (fr)
CA (1) CA2102633A1 (fr)
WO (1) WO1992021383A1 (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5382654A (en) * 1992-02-05 1995-01-17 Mallinckrodt Medical, Inc. Radiolabelled peptide compounds
US5443815A (en) * 1991-11-27 1995-08-22 Diatech, Inc. Technetium-99m labeled peptides for imaging
US5849261A (en) * 1991-02-08 1998-12-15 Diatide, Inc. Radiolabeled vasoactive intestinal peptides for diagnosis and therapy
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
CA2129033A1 (fr) * 1992-02-05 1993-08-19 Leon Lyle Composes peptidiques marques par des radio-isotopes
US6017512A (en) * 1992-06-23 2000-01-25 Diatide, Inc. Radiolabeled peptides
US5871711A (en) * 1992-06-23 1999-02-16 Diatide, Inc. Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses
US5716596A (en) * 1992-06-23 1998-02-10 Diatide, Inc. Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses
AU7261994A (en) * 1993-07-19 1995-02-20 Resolution Pharmaceuticals Inc. Hydrazino-type radionuclide chelators having an n3s configuration
US5858327A (en) * 1993-09-03 1999-01-12 Resolutions Pharmaceuticals, Inc. Hydrazino-type N2 S2 radionuclide chelating compounds
US5574140A (en) * 1993-09-03 1996-11-12 Resolution Pharmaceutical Inc. Hydrazino-type N2 S2 chelators
US6051206A (en) * 1994-06-03 2000-04-18 Diatide, Inc Radiolabeled somatostatin-derived peptides for imaging and therapeutic uses
ATE246009T1 (de) * 1995-06-07 2003-08-15 Immunomedics Inc Thiolierung von peptiden zur strahlendiagnostik und strahlentherapie auf radionuklidbasis
IT1277391B1 (it) * 1995-07-28 1997-11-10 Romano Deghenghi Peptidi ciclici analoghi della somatostatina ad attivita' inibitrice dell'ormone della crescita
US6355613B1 (en) 1996-07-31 2002-03-12 Peptor Limited Conformationally constrained backbone cyclized somatostatin analogs
FI965181A (fi) * 1996-12-20 1998-06-21 Map Medical Technologies Oy Polyalkoholi-peptidijohdannaiset

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1107273A (fr) * 1978-05-19 1981-08-18 Chester A. Meyers Analogues de la somatostatine ayant un residu tryptophyl substitue en position 8
JPH0725691B2 (ja) * 1988-06-03 1995-03-22 ソシエテ ドゥ コンセイユ ドゥ ルシエルシエ エ ダプリカシオン サイエンティフィック 血管閉塞抑制剤
MY106120A (en) * 1988-12-05 1995-03-31 Novartis Ag Peptide derivatives.
EP0486622B1 (fr) * 1989-08-09 1998-11-04 Rhomed, Incorporated Radiomarquage direct d'anticorps et d'autres proteines a l'aide de technetium ou de rhenium

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9221383A1 *

Also Published As

Publication number Publication date
JPH06508357A (ja) 1994-09-22
CA2102633A1 (fr) 1992-12-04
AU2017492A (en) 1993-01-08
WO1992021383A1 (fr) 1992-12-10
AU657770B2 (en) 1995-03-23

Similar Documents

Publication Publication Date Title
JP3647881B2 (ja) 放射性金属元素結合ペプチドの類似化合物
JP3036602B2 (ja) 撮像用テクネチウム−９９ｍ標識ペプチド
JP3918157B2 (ja) ソマトスタチン結合性ペプチド−金属キレートコンジュゲート
EP0588905A1 (fr) Derives de somatostatine radiomarques, leur preparation et utilisation
EP0831938B1 (fr) Compositions de peptides radiomarques pour le ciblage specifique d'un site
JPH09501419A (ja) ソマトスタチン誘導体およびそれらの放射標識物
JPH04500823A (ja) ポリペプチド誘導体
JPH10501531A (ja) モノアミン、ジアミド、チオール含有金属キレート剤
EP0719790B1 (fr) Peptides chélatants des ions métalliques et leurs utilisation
EP0584256B1 (fr) Composes et compositions pour la detection et la loclisation de tissus comprenant des recepteurs de neurokinine 1
AU3967593A (en) Method of intraoperatively detecting and locating tumoral tissues
WO2001000637A1 (fr) Complexes de metaux de transition du groupe vii a ligands multicoordinants aminopolycarboxylate et trousse de production correspondante
EP0700930A1 (fr) Peptides à affinité pour des tumeurs et composés radioactifs diagnostiques et thérapeutiques les contenant
JP3866317B2 (ja) 金属キレート形成性ペプチド、その用途及びその製造方法
JPH0853494A (ja) 腫瘍親和性ペプチド、該ペプチドを含有してなる放射性診断剤および放射性治療剤

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19931129

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 19950821