EP1196200A2 - Analogue peptidique de tachykinine mammalienne radiomarque - Google Patents

Analogue peptidique de tachykinine mammalienne radiomarque

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Publication number
EP1196200A2
EP1196200A2 EP00954837A EP00954837A EP1196200A2 EP 1196200 A2 EP1196200 A2 EP 1196200A2 EP 00954837 A EP00954837 A EP 00954837A EP 00954837 A EP00954837 A EP 00954837A EP 1196200 A2 EP1196200 A2 EP 1196200A2
Authority
EP
European Patent Office
Prior art keywords
tachykinin
peptide
analogue
receptor
neurokinin
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Withdrawn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
EP00954837A
Other languages
German (de)
English (en)
Inventor
Pedro Ortiz Aruma
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Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP1196200A2 publication Critical patent/EP1196200A2/fr
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Classifications

    • 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

Definitions

  • the present invention relates to a radiolabeled mammalian tachykinin peptide analogue; use of the analogue for mammalian in vivo tachykinin peptide receptor imaging; and a diagnostic kit comprising the analogue.
  • Tachykinins are a family of peptides that share a common C-terminal amino acid sequence, -Phe-X-Gly-Leu-Met-NH2, where X represents either Phe, He, or Val.
  • the mammalian tachykinins include substance P (SP), neurokinins A and B and two N-terminally extended forms of neurokinin A, i.e. neuropeptide K and neuropeptide Y.
  • SP substance P
  • neurokinins A and B and two N-terminally extended forms of neurokinin A, i.e. neuropeptide K and neuropeptide Y.
  • tachykinin receptor nomenclature defines three homologous receptor types: (a) the neurokinin 1 receptor, preferring substance P, (b) the neurokinin 2 receptor, preferring neurokinin A, and (c) the neurokinin 3 receptor, preferring neurokinin B.
  • the tachykinin receptors have a wide tissue distribution, and interaction with their lig- ands is associated with diverse responses, such as immunological responses, histamine release, inflammation, nerve regeneration and wound healing (P.M. van Hagen, "Somatostatin and Sub- stance P analogues: Applications on autuimmune and haematological diseases", Thesis Erasmus, University of Rotterdam (1995), Chapter 8.1; Breeman et al. J. of Nuclear Medicine 37:108-117 (1996)).
  • a further advantage is that it does forms less aggregates as compared to prior art known radiolabeled tachykinin analogues.
  • the present invention relates in a second aspect to use of a radiolabeled tachykinin analogue as described herein for mammalian in vivo tachykinin peptide receptor imaging.
  • the present invention relates to a diagnostic kit comprising a radiolabeled tachykinin analogue as described herein and which is suitable to be used in any of the uses of the radiolabeled tachykinin analogue as described herein.
  • a diagnostic kit comprising a radiolabeled tachykinin analogue as described herein and which is suitable to be used in any of the uses of the radiolabeled tachykinin analogue as described herein.
  • the preparation of such a diagnostic kit having special suitable extra ingredients is within the skilled persons general knowledge. Definitions:
  • tachykinin peptide are a common known term in the art for a family of peptides. See above and e.g. Breeman et al. (J. of Nuclear Medicine 37: 108-1 17 (1996)). These peptides are well defined also at amino acid levels (see below) and characterized by their specific binding to important mammalian receptors (see above).
  • tachykinin peptide denotes herein these well known peptides in their natural form, i.e. with their natural amino acid sequences. However, it is well known in the art that a polypeptide sequence may be modified in the sense of a change in the amino acid sequence without a significant change in its essential characteristics.
  • tachykinin peptide As described herein is its binding affinity to the receptor which has the specific tachykinin peptide as preferred sub- strate/ligand.
  • the neurokinin 1 receptor has substance P as preferred substrate
  • the neurokinin 2 receptor has neurokinin A as preferred substrate
  • the neuro- kinin 3 receptor has neurokinin B as preferred substrate. Accordingly, beside denoting these well known tachykinin peptides in their natural form, the scope of the term "tachykinin peptide" also includes an amino acid changed variant of these peptides which has maintained essentially the same binding affinity for the receptor.
  • the tachykinin peptide substance P is the preferred substrate for the receptor neurokinin 1.
  • 99m Tc denotes the 99m Technetium isotope (Molinski V. J. Int. J. Appl. Radial Isot. 33:811-819 (1982)). The nomenclature “ 99m Tc” and “Tc-99m” may be used herein interchangeably.
  • the measurement of the term "half-life" is determined according to standard assays in a human.
  • the assay determines a time course of total ( 99m Tc- + 99m Tc-tachykinin peptide) and peptide bound ( 99m Tc-tachykinin peptide) radioactivity in human blood plasma at selected time periods up to 50 hours. Based on this the half-life is calculated. It is within the skilled persons general knowledge to identify a suitable strategy for separating the non peptide bound radioisotope " 99m ⁇ c .” nd the peptide bound radioisotope " 99m Tc-tachykinin peptide" in the blood plasma. An example of a suitable strategy is described below.
  • the radioactivity in plasma which is eluted with ethanol from the SEP-PAK C ⁇ 8 columns, is termed peptide bound radioactivity.
  • Total amount of radioactivity is the sum of peptide bound radioactivity and free m Tc related radioactivity.
  • Blood samples are collected directly 2, 5, 10, 20, and 40 min, 1, 4, 10, 20, and 50 hours after infusion.
  • Embodiment(s) of the present invention is described below, by way of example(s) only.
  • a radiolabeled tachykinin analogue relates to a tachykinin peptide analogue, wherein the tachykinin peptide is selected from the group consisting of: a neurokinin A peptide; a neurokinin B peptide; a neuropeptide K (a N terminally extended form of neurokinin A); a neuropeptide Y (a N terminally extended form of neurokinin A); and preferably a substance P (SP) peptide.
  • Example 2 herein shows that a 99m Tc-SP peptide analogue is capable of performing a specific binding in the salivary glands of a mice of 0.62% injected dose per gram organ (%ID/g).
  • an embodiment relates to a tachykinin peptide analogue, as described herein, wherein the analogue is capable of performing a specific binding in the salivary glands of a mice of at least 0.35% injected dose per gram organ (%ID/g), preferably wherein the analogue is capable of performing a specific binding in the salivary glands of a mice of at least 0.45% injected dose per gram organ (%ID/g); more preferably wherein the analogue is capable of performing a specific binding in the salivary glands of a mice of at least 0.55% injected dose per gram organ (%ID/g), expressed as the difference in tissue uptake (90 minutes uptake) between untreated mice and mice treated with 90 nmol of a non-radioactive tachykinin peptide.
  • the tachykinin peptide is pref- 5 erably a substance P (SP) peptide.
  • SP substance P
  • an embodiment of the invention relates to a tachykinin peptide analogue as described herein, wherein the tachykinin peptide comprises the C-terminal amino acid se- i o quence, -Phe-X-Gly-Leu-Met-NH2, where X represents either Phe, He, or Val (SEQ ID NO 1 ).
  • linking molecules are a 1 -imino-4-mercaptobutyl molecule; a DTPA molecule; or a 3-(p-Hydroxypheny)propinyl molecule. 5 The use DTPA and 3-(p-Hydroxypheny)propinyl as a linking molecule is described by
  • a radiolabeled tachykinin analogue as described herein may be made by use of one of these molecules as linking molecules and using the strategy of the "Materials and Method" section of Breeman et al., combined with the skilled persons knowledge, wherein the radioisotope ⁇ n In of Breeman et al. is changed to the 0 radioisotope 99m Tc.
  • Working example 1 herein describes a method for making a 99m Tc-SP peptide analogue using a l-imino-4-mercaptobutyl molecule as linking molecule. Accordingly, an aspect of the invention relates to a method for making a radiolabeled 99m Tc-SP peptide comprising:
  • a radiolabeled tachykinin analogue as described herein may be used for mammalian in vivo tachykinin peptide receptor imaging.
  • the tachykinin receptor is a neurokinin 1 receptor expressed by arterioles and/or venules located in the submucosa, muscularis mucosa, external longtitudinal muscle, and/or serosa, and in relation to this it is preferred that the tachykinin peptide is a substance P (SP) peptide since SP is the preferred substrate for the neurokinin 1 receptor.
  • SP substance P
  • tachykinin receptor is a neurokinin 2 receptor and wherein the tachykinin peptide is a neurokinin A peptide; or wherein the tachykinin receptor is a neurokinin 3 receptor and wherein the tachykinin peptide
  • An embodiment of the invention relates to the use as described herein, wherein the in vivo tachykinin receptor imaging is done in vivo in a human.
  • tachykinin receptor is a neurokinin 1 receptor and the tachykinin peptide is a substance P (SP) peptide.
  • SP substance P
  • the purpose of the tachykinin receptor imaging is a diagnostic purpose, and in particular wherein the diagnostic purpose is a diagnostic relating to inflammation or a diagnostic relating to a tumor.
  • the diagnostic purpose is a diagnostic relating to inflammation or a diagnostic relating to a tumor.
  • Tc-99m-SP was prepared using a 1 -imino-4-mercaptobutyl group linked between reduced Tc-99m and SP.
  • a formulation of 30 nmol SP, 1 ⁇ mol of 2- iminothiolane (2-1T) and 22 ⁇ mol of SnCl 2 resulted with a Tc-99m-SP labeling efficiency of >90% and stable over 6 hours.
  • the excess unreacted linker molecule was removed from modified SP by gel chromatography and the reaction vials were 0 stored at -20°C.
  • Tc-99m was dissociated from labeled molecule following 1 hour incubation of Tc-99m labeled SP with 500:1 molar excess of cysteine.
  • This 2-1T derivatization method is a simple, efficient and amenable to a formulation for the preparation of Tc-99m labeled SP analogues.
  • Example 2 Specific binding/uptake in the salivary glands of a mice of Tc-99m-SP: Mice: a commercial available laboratory mice

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un analogue peptidique de tachykinine mammalienne radiomarqué, l'utilisation de l'analogue pour l'imagerie du récepteur peptidique de tachykinine mammalienne in vivo, et une trousse de diagnostic comprenant cet analogue.
EP00954837A 1999-07-05 2000-07-05 Analogue peptidique de tachykinine mammalienne radiomarque Withdrawn EP1196200A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ES9901489 1999-07-05
ES9901489 1999-07-05
PCT/IB2000/001260 WO2001002021A2 (fr) 1999-07-05 2000-07-05 Analogue peptidique de tachykinine mammalienne radiomarque

Publications (1)

Publication Number Publication Date
EP1196200A2 true EP1196200A2 (fr) 2002-04-17

Family

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EP00954837A Withdrawn EP1196200A2 (fr) 1999-07-05 2000-07-05 Analogue peptidique de tachykinine mammalienne radiomarque

Country Status (4)

Country Link
EP (1) EP1196200A2 (fr)
AU (1) AU6718900A (fr)
WO (1) WO2001002021A2 (fr)
ZA (1) ZA200200096B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1208852B1 (fr) * 2000-11-24 2007-08-01 Jean-Claude Reubi Composés fixantes de récepteur de Neuropeptide Y1 dans le traitement et le diagnostic du cancer
ES2312983T3 (es) * 2003-03-19 2009-03-01 Universitatsspital Basel Conjugados radiomarcados basados en sustancia p y sus usos.
US20070154448A1 (en) 2005-11-22 2007-07-05 Ted Reid Methods and compositions using Substance P to promote wound healing

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0892053A3 (fr) * 1997-07-14 1999-12-29 Smithkline Beecham Plc Production de polypeptide HPMBQ91 recombinant et ses utilisations
AU3282300A (en) * 1999-02-24 2000-09-14 Mallinckrodt, Inc. Molecules for the treatment and diagnosis of tumors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0102021A3 *

Also Published As

Publication number Publication date
WO2001002021A2 (fr) 2001-01-11
ZA200200096B (en) 2003-06-25
AU6718900A (en) 2001-01-22
WO2001002021A3 (fr) 2002-02-07

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