WO2012000746A1 - Peptide marqué 11c pour la détection d'un tissu malade exprimant un récepteur de chimiokine - Google Patents

Peptide marqué 11c pour la détection d'un tissu malade exprimant un récepteur de chimiokine Download PDF

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Publication number
WO2012000746A1
WO2012000746A1 PCT/EP2011/059448 EP2011059448W WO2012000746A1 WO 2012000746 A1 WO2012000746 A1 WO 2012000746A1 EP 2011059448 W EP2011059448 W EP 2011059448W WO 2012000746 A1 WO2012000746 A1 WO 2012000746A1
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WIPO (PCT)
Prior art keywords
peptide
chemokine receptor
diseased tissue
carbon atom
cells
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PCT/EP2011/059448
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German (de)
English (en)
Inventor
Oliver Lade
Ursus KRÜGER
Arno Steckenborn
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Siemens Aktiengesellschaft
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Publication of WO2012000746A1 publication Critical patent/WO2012000746A1/fr

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    • 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

  • C-labeled peptide for detection of a pathological tissue ⁇ bes which expresses a chemokine receptor
  • the invention relates to the use of a peptide for the manufacture ⁇ position of an agent for detecting a diseased tissue expressing a chemokine receptor. It further relates to a radiopharmaceutical which comprises such a peptide, for Loka- neutralization of a diseased tissue expressing a Chemokinrezep ⁇ tor.
  • biochemical analyzes of blood and other bodily fluids as well as imaging methods for example for the detection of tumors.
  • X-ray, ultrasound, and magnetic resonance imaging have been used to localize diseased tissue and ectopic cell aggregates.
  • Newer methods use the increased metabolic activity of tumor cells compared to healthy tissue.
  • the patient is injected with radioactively labeled sugar molecules that accumulate in the tumor cells.
  • the radioactivity of these molecules for example using a gamma ⁇ Ka ra, the so-called scintigraphy was added and the polyvinyl sition of the tumor is observed.
  • Biochemically, cancer diseases, as well as other diseases are detected by specific molecules.
  • Pati ⁇ ducks The presence and amount of these substances in blood or tissue samples of Pati ⁇ ducks is determined.
  • diseased cells In addition to soluble substances that are released into the body fluids, diseased cells also produce molecules that remain anchored to their cell surface. These are, above all, cell receptors, such as chemokine receptors. On the basis of these surface molecules, biochemical detection of pathological cells in vivo are possible by visualizing them using imaging techniques.
  • Chemokines are small, often pro-inflammatory proteins belonging to the cytokine family. They have a high chemotactic activity and are mainly for the In ⁇ munzellmigration and during angiogenesis is important. Chemokines bind to specific G protein-coupled trans ⁇ membrane receptors, called chemokine receptors. Your activated by chemokines vation leads to the so-called chemotaxis, that is a transformation of the cytoskeleton and Induct ⁇ on cell migration along the chemokine gradient. So far, a total of 20 chemokine receptors are known to be Natli ⁇ chamba, expressed mainly by cells of the immune system, beispiels- example of T cells.
  • chemokine receptors CCR1, CCR5 and CXCR4 have been detected in various cancers (Meier R et al., 2007, Erreni M et al., 2009).
  • chemokine receptors in diseased tissue, whether on the surface of immune cells or on the cells of the tissue itself, has been demonstrated using antibodies in vitro.
  • biopsies of a suspected tissue are removed and these cells are examined by conventional immunocytological and / or immunohistological methods. Besides being an invasive intervention is required for this proceedingswei ⁇ se, it does not allow to determine the actual distribution of chemokine receptor-expressing cells in an organism or within a specific tissue / organ.
  • the invention is therefore based on the object, a cost-effective and well-tolerated for the patient agent for Detecting a diseased tissue that expresses a chemokine receptor.
  • This object is achieved by the use of a peptide for the production of an agent for the detection of a diseased tissue that expresses a chemokine receptor.
  • a peptide which binds to the Chemokinre ⁇ Zeptor and having a 11 C carbon atom is used, the agent can be produced inexpensively and in which Or ⁇ organism in which the pathological tissue is detected, well metabolized.
  • peptide refers to an organic compound of at least two amino acids linked via a peptide bond. It includes both oligopeptides of up to about ten amino acids, polypeptides of up to about 50 amino acids and proteins of up to 150 amino acids, regardless of their primary, secondary or tertiary structure. In this case, both naturally occurring and biotechnologically or synthetically produced compounds are included.
  • the peptide used in the invention is chosen so that it binds to the chemokine receptor. Antibodies, their fragments and other polypeptides that bind to the chemokine receptor are suitable for this purpose. By their specific binding to the chemokine receptor, the peptides can be used to detect diseased tissues that form the chemokine receptor.
  • the peptide is chosen so that the Bin ⁇ connection between the peptide and the chemokine receptor, so called a linear coefficient.
  • KD value comprising of ⁇ 100 nM, preferably ⁇ 10 nM, more preferably of 7.5 nM.
  • the peptide itself is composed of amino acids, that is, of the body's own or body-like molecules, so that it is very well tolerated by the patient. It is non-toxic and can be naturally metabolized, broken down and excreted ⁇ to.
  • the term "diseased tissue” refers to cells, parts of organs or whole organs that do not or not fully fulfill their physiological function.
  • chemokines express diseased cells, they attract immune cells that detect the chemokines with their chemokine receptors.
  • large amounts of chemokine receptor positive cells accumulate in the diseased tissue.
  • CCR5-expressing T cells have been found in the affected kidney tissue (Segerer S et al., 1999).
  • Such accumulations of Chemokinre ⁇ Zeptor positive cells can be detected by means of the inventively used peptide.
  • tumor cells often express themselves chemokine receptors that sit on the cell surface and can be bound by the erfindungsge ⁇ Gurss peptide used there. So far, chemokine receptors have been found mainly on breast cancer and colon cancer ⁇ cells.
  • chemokine receptors have been found mainly on breast cancer and colon cancer ⁇ cells.
  • metastases of such tumors can be detected, provided that they also form the chemokine receptor.
  • the detection of the peptide and of the chemokine receptor bound thereto takes place via an integrated 11 C carbon atom.
  • positrons also referred to as ⁇ + radiation
  • ⁇ + radiation Upon decay of the 11 C carbon isotope, positrons, also referred to as ⁇ + radiation, are formed. Push the positron on an electron, they form two photons away at an angle of 180 °, which is exactly opposite in ge ⁇ modifying the direction of each other.
  • the photons can detected and from the position of the positron emission, or the 11 C carbon, are calculated.
  • the Integra ⁇ tion of a C-11 carbon atom in the peptide used in the invention makes it possible to avoid the use of chemical, physi- per advertder substances.
  • Another advantage of the peptide directly labeled with X1 C lies in the favorable signal / background ratio during detection.
  • the peptide binds specifically to the chemokine receptor and forms a stable complex with it. Free, unbound peptides, on the other hand, are rapidly metabolized and excreted from the organism because they can be rapidly degraded by endogenous enzymes. This results in a strong and specific signal at the position of the chemokine receptor, and the background signal is minimized.
  • the peptide has at least one D-amino acid.
  • D-amino acid With the exception of glycine, amino acids have their alpha-C-carbon atom is a chiral center and can therefore be present as configuration isomers, namely as D- or L-amino acid.
  • Endogenous peptides and proteins are largely made up of amino acids in ⁇ L-configuration.
  • most natural proteases and peptidases work stereoselectively and mainly metabolize L-amino acids. Therefore, the degradation of D-amino acids by endogenous enzymes takes longer than that of L-amino acids.
  • the non-natural amino acids are metabolized more slowly because the stressesei ⁇ -related proteolytic enzymes are specially adapted to the exploitation of natural amino acids.
  • the non-natural amino acids should be chosen so that the binding affinity of the peptide is not altered.
  • other chemical Mo ⁇ dtechniken individual amino acids of the peptide are possible to influence the half-life of the peptide specifically.
  • the terminal amino group of the peptide may be replaced by an isonitrile group.
  • Such modes ⁇ fication reduces, mediated by the amino group, in ⁇ ter syndrome with proteolytic enzymes without altering the bond between the peptide used in the invention and the chemo- kinrezeptor.
  • the peptide is an antagonist of the chemokine receptor.
  • Chemokine receptors are usually activated by the binding of chemokines and mediate changes in the cytoskeleton and directed migration of the cell.
  • the peptide binds to the chemokine receptor without activating it.
  • Particularly suitable for this purpose are peptides that lust as antagonists of the chemokine receptor fun ⁇ . They show specific binding affinity to the receptor, but do not result in the activation of subsequent cellular signaling pathways.
  • the agent is a radiopharmaceutical.
  • radiopharmaceuticals refers to medicines containing radionuclides whose radiation is used for diagnosis and therapy. The main applications are in oncology, Kar ⁇ ogy and neurology, as well as pharmaceutical research.
  • radionuclides are gamma or beta radiation emitting nuclides, for example Xenon 133, "technetium, gallium 68, fluorine 18 and used. They are usually bound via com- formers such as DOTA, DTPA or EDTA mono- or polysaccharides.
  • the nuclides are detected by scintigraphy, single photon emission com- puted tomography (SPECT) or positron emission tomography (PET), depending on the nature of their radiation, but conventional radiopharma- ceuticals can be used because of their non-physiological components
  • the diseased tissue expresses increased amounts of the chemokine receptor.
  • the cells in different diseased tissues carry particularly high levels of chemokine receptors on their surface. In some diseases, such as many kidney diseases, large amounts of T cells carrying chemokine receptors migrate into the diseased tissue.
  • chemokine receptors can express even increased amounts of chemokine receptors, as has been observed, for example, in breast and colon cancer cells. In both cases, local accumulations of chemokine receptors arise, which can be detected by the peptide used according to the invention.
  • the C-carbon atom is the carbonyl carbon atom of an amino acid.
  • the carbonyl groups are part of the peptide bonds between the amino acids and are located inside the peptide. This ensures that the ⁇ C carbon atom is not cleaved off the peptide, as would be possible with a side chain of one of the amino acids.
  • the C-carbon atom is the carbonyl carbon atom of the N-terminal amino acid of the peptide.
  • This embodiment is particularly preferred because the peptide immediately after the on ⁇ bring the 11 C-labeled amino acid can be used.
  • ⁇ C-carbon has a half-life of only about 20 Minu ⁇ th, so that the radiation dose to be selected the higher, the more time between the synthesis of the peptide and sides ner use is. If the 11 C-labeling with the N-terminal amino acid and thus in the last step of the synthesis is applied, the peptide can be used immediately after its synthesis.
  • the time between the processing of the 11 C carbon and the use of the peptide is reduced, so that the radiation loss during the preparation of the peptide is minimized. Therefore, the radiation dose that must be used in the processing of the 11 C carbon to ensure a certain radiation intensity of the product, be correspondingly lower.
  • Another object of the invention is a radiopharmaceutical comprising a peptide having an 11 C carbon atom for the localization of a diseased tissue expressing a chemokine receptor.
  • the radiopharmaceutical invention provides a host ⁇ economically and medically beneficial agent to the posi- tion of a diseased tissue that expresses a chemokine receptor to determine in vivo.
  • the peptides contained therein are distributed into the body and bind specifically to chemokine receptors.
  • they accumulate on the cells of the diseased tissue, where they are detected by the radioactive signal of the 11 C carbon atom.
  • the diseased tissue expresses increased amounts of the chemokine receptor.
  • the cells in different diseased tissues carry particularly high levels of chemokine receptors on their surface.
  • the 11 C carbon atom is a carbonyl carbon atom of an amino acid, preferably the carbonyl carbon atom of the N-terminal amino acid of the peptide.
  • the radiopharmaceutical is a PET biomarker.
  • PET is an established method for detecting the radiation of radioactive elements and determining their position (Massoud TF, Gambhir SS, 2003). With the aid of detector devices arranged annularly around the patient, sectional images are created on which the decay events are represented in their spatial distribution in the interior of the body. In contrast to the usual scintigraphic chromatography method, is by the annular configuration of the PET detectors a more precise spatial localization of the positron ⁇ nenemission and thus a substantially more accurate and detailed ⁇ profiled imaging the diseased tissue is possible. PET also makes it possible to quantify the amount of labeled molecules in a tissue.
  • a method for localization of a diseased tissue in an organism which expresses a chemokine receptor comprising the steps of a) Treatmenttel- len a peptide b) administering the peptide to the Orga ⁇ mechanism and c) detecting the peptide in the Organism with ⁇ positron emission tomography (PET).
  • PET ⁇ positron emission tomography
  • the peptide binds to the chemokine receptor and has an 11 C carbon atom.
  • the peptide used in the invention is a chemokine receptor in the interior of an organism is detected and lenti ⁇ Siert, so that the distribution of the chemokine receptor can be observed in the body of a patient.
  • the size or extent of a pathological tissue are determined at ⁇ game as an infection or a tumor expressing the chemo- kinrezeptor.
  • the peptide used according to the invention is therefore outstandingly suitable for observing the course and success of a treatment, so-called therapy monitoring.
  • Figure 1 shows schematically the binding between a peptide 1 and a chemokine receptor 4.
  • the peptide 1 comprises 8 amino acids 2, of which the N-terminal amino acid 3 is radioactively labeled with an 11 C carbon atom.
  • the radioactive label is represented by an asterisk (*).
  • a part of the peptide 1 is attached to the Che ⁇ mokinrezeptor 4, which is located on the surface of a diseased tissue 18th
  • the ⁇ C-labeled peptide 1 binds specifically to the chemokine ⁇ receptor 4, but not to other molecules.
  • the peptide 1 can therefore be used for the detection of the chemokine receptor 4.
  • the Po ⁇ sitronen delivered at the decay of the 11 C carbon are detected by positron emission tomography (PET).
  • PET positron emission tomography
  • the location of the positron emission corresponds to the location of the peptide 1 and attached thereto Chemokinrezep ⁇ tors 4.
  • the peptide 1 can therefore be used to determine the position a diseased tissue 18 can be used which forms the chemo ⁇ kinrezeptor 4.
  • a patient is administered a radiopharmaceutical containing the 11 C-labeled peptide 1.
  • the peptide 1 binds specifically to the chemokine receptor 4 and thus accumulates on the diseased tissue 18 with the cells that form the chemokine receptor 4. This accumulation is represented by PET and determines the distribution of the chemokine receptor 4 or the localization of the diseased tissue 18 in the body of the patient.
  • the medication of a therapeutic agent for example active ingredient and amount of administration ⁇ plan be adjusted according to the position, size and distribution of the diseased tissue 18th
  • FIG. 2 shows a representation of a peptide having the sequence SEQ ID NO: 1 by means of a chemical formula.
  • the peptide of SEQ ID NO: 1 comprises 8 amino acids 2 of the following sequence: D-alanine-serine-threonine-threonine-threonine-asparagine-tyrosine-threonine Am i c i.
  • the N-terminal amino acids 2 D-alanine and serine are represented by the structural formula, the following amino acids 2 by their respective three-letter code.
  • the amino acid threonine Am i d is designated Thr A and has a C-termial amide.
  • the sequence of the peptide is also given in SEQ ID NO: 1.
  • the carbonyl carbon atom of the N-terminal D-alanine is an 11 C carbon atom represented by the number 11 above the carbonyl carbon atom.
  • Peptide 1 is prepared by conventional protein synthesis methods and the 11 C-labeled N-terminal amino acid 3 im added last step, because the half-life of the C-carbon isotope is only about 20 minutes. By completing the peptide synthesis with the 11 C-labeled amino acid 3, the peptide 1 can be used immediately after the radioactive labeling.
  • the peptide of SEQ ID No .: 1 specifically binds to the chemo- kinrezeptor-5 (CCR5) 4.
  • CCR5 4 This receptor is located in the gro ⁇ SEN amounts at the surface of T cells, which migrate into the interstitial tium diseased kidneys (Segerer S et al., 1999). It is also ectopically expectorated by tumor cells, such as breast or intestinal cells.
  • the natural ligands of CCR5 4 include the cytokines RANTES, MIP-la (macrophage inflammatory protein la) and MIP-lß.
  • peptide 1 also referred to as DAPTA, binds to CCR5 4 without activating it (Polianova MT et al., 2005). It is Antago ⁇ nist of the used inter alia as CCR5 4 to inhibit the binding of the human immune ⁇ weakness virus (HIV) to T cells.
  • HAV human immune ⁇ weakness virus
  • the peptide of SEQ ID NO: 1 binds to CCR5 4 but without inducing cellular signaling (Polianova MT et al., 2005). It is therefore particularly suitable for the detection of a CCR5 4-expressing tissue.
  • the peptide of SEQ ID NO: 1 with only eight amino acids 2 is particularly small and therefore fast and easy to metabolize for the patient. Labeling by means of 11 C carbon is particularly suitable because it does not affect the physiological structure of peptide 1 and does not adversely affect the distribution in the tissue or the compatibility of peptide 1.
  • FIG. 3 shows a schematic representation (greatly simplified according to Faller A, Schünke M, The human body, Thieme, 2008) of a circulatory system 10 of an organism and the distribution of a peptide 1 therein.
  • the circulation system 10 includes various organs schematically represented, such as the lungs 12, heart 13, liver 14, 15 intestine and kidney 16 and the main wires 11 which these organs ver ⁇ bind.
  • the peptide 1 is represented by triangles along the wires 11.
  • the degradation products 17 of the peptide 1 are represented by individual lines within the outline of the kidney 16. Left of center of the circulatory system 10, a diseased tissue is additionally shown ⁇ 18 with chemokine receptors 4, are attached to the increased peptides. 1
  • the distribution of peptide 1 in the circulatory system 10 comprises four phases, which are listed along the top-down view.
  • Phase I Peptide 1 is injected into the circulatory system 10 of the organism.
  • Phase II is via the blood circulatory system 10 Peptide 1 in the organs 12, 13, 14, 15, and 16 of the body transported ⁇ advantage.
  • Phase III The circulating peptide 1 binds specifically to the chemokine receptor 4 and accumulates on the diseased tissue 18 because it produces the chemokine receptor 4.
  • Phase IV Unbound peptide 1 is rapidly metabolised and enzymatically degraded.
  • the organism not failed ⁇ det between own peptides and the peptide 1, because it is composed of amino acids 2, 3, which correspond to the body's own molecules.
  • the degradation products 17 of the peptide 1 and the amino acids 2, 3 accumulate predominantly in the kidney 16 from where they are ejected via the bladder and the ureter.
  • Massoud TF, Gambhir SS Molecular imaging in living subjects: seeing fundamental biological processes in a new light; Genes Dev. 2003 Mar 1; 17 (5): 545-80. Meier R, Mühlethaler Mottet A, Flahaut M, Coulon A, Fusco C, Louache F, Auderset K, Bourloud KB, Daudigeos E, Ruegg C, Vassal G, Gross N, Joseph JM; The chemokine receptor CXCR4 strongly promotes neuroblastoma primary tumor and metastatic growth, but not invasion; PLoS One, 2007 Oct 10; 2 (10): elOl 6.

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  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne l'utilisation d'un peptide (1) pour la production d'un agent destiné à la détection d'un tissu malade (18) qui exprime un récepteur de chimiokine (4). Le peptide se lie au récepteur de chimiokine (4) et il comprend un atome de carbone 11C. L'invention porte également sur un radiopharmaceutique destiné à la localisation d'un tissu malade (18) qui exprime un récepteur de chimiokine (4). Ce radiopharmaceutique comporte un peptide (1) qui se lie au récepteur de chimiokine (4) et comporte un atome de carbone 11C.
PCT/EP2011/059448 2010-06-30 2011-06-08 Peptide marqué 11c pour la détection d'un tissu malade exprimant un récepteur de chimiokine WO2012000746A1 (fr)

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DE102010026059.2 2010-06-30
DE201010026059 DE102010026059A1 (de) 2010-06-30 2010-06-30 11C-markiertes Peptid zur Detektion eines krankhaften Gewebes, das einen Chemokinrezeptor exprimiert

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Citations (3)

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WO2009027706A2 (fr) * 2007-08-30 2009-03-05 Technische Universität München Imagerie et traitement d'un cancer
WO2011012414A1 (fr) * 2009-07-29 2011-02-03 Siemens Aktiengesellschaft Procédé de fabrication d'un peptide radiomarqué
DE102009035648B3 (de) 2009-07-29 2011-03-17 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markierten Carboxylats sowie die Verwendung einer Mikroelektrode zur elektrochemischen Synthese eines radioaktiv markierten Carboxylats

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WO2009045579A2 (fr) * 2007-06-14 2009-04-09 The Regents Of The University Of California Sondes d'imagerie multimodes pour imagerie et thérapie in vivo ciblées et non ciblées
CA2748691A1 (fr) * 2008-12-12 2010-06-17 Lutz Lehmann Composes de triaryl-sulphonium, kit et procede pour etiqueter des isotopes emettant des positrons

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WO2009027706A2 (fr) * 2007-08-30 2009-03-05 Technische Universität München Imagerie et traitement d'un cancer
WO2011012414A1 (fr) * 2009-07-29 2011-02-03 Siemens Aktiengesellschaft Procédé de fabrication d'un peptide radiomarqué
DE102009035645A1 (de) 2009-07-29 2011-02-03 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markiertren Peptids
DE102009035648B3 (de) 2009-07-29 2011-03-17 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markierten Carboxylats sowie die Verwendung einer Mikroelektrode zur elektrochemischen Synthese eines radioaktiv markierten Carboxylats

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