WO2012000784A1 - Peptide marqué 11c pour la détection de neurones exprimant un récepteur de l'acétylcholine - Google Patents

Peptide marqué 11c pour la détection de neurones exprimant un récepteur de l'acétylcholine Download PDF

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Publication number
WO2012000784A1
WO2012000784A1 PCT/EP2011/059875 EP2011059875W WO2012000784A1 WO 2012000784 A1 WO2012000784 A1 WO 2012000784A1 EP 2011059875 W EP2011059875 W EP 2011059875W WO 2012000784 A1 WO2012000784 A1 WO 2012000784A1
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WIPO (PCT)
Prior art keywords
peptide
acetylcholine receptor
neurons
carbon atom
amino acids
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Ceased
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PCT/EP2011/059875
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German (de)
English (en)
Inventor
Ursus KRÜGER
Oliver Lade
Arno Steckenborn
Sylvie Von Werder
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.)
Siemens AG
Siemens Corp
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Siemens AG
Siemens Corp
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Publication of WO2012000784A1 publication Critical patent/WO2012000784A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

  • the invention relates to the use of a peptide for the manufacture ⁇ position of an agent for the detection of neurons expressing an acetylcholine receptor. It further relates to a radiolabel comprising such a peptide for the detection of neurons expressing an acetylcholine receptor.
  • a challenge of modern medicine is the correct diagnosis of increasingly common neurological diseases.
  • CNS central nervous system
  • PNS peripheral-nervous system
  • Some of these diseases can be difficult against other be distinguished because on the one hand their symptoms are similar and on the other hand, atypical symptoms often occur, especially in the early stages.
  • the socially very significant neurological diseases Alzheimer dementia and Parkinson's disease are both based on the loss of neurons of the CNS and are initially characterized by unspecific, not clearly classifiable symptoms. This complicates an accurate diagnosis, increasing the risk of a false treatmen ⁇ development of the patient.
  • CT computer tomography
  • MRT Kernspintomogra ⁇ tomography
  • the invention is therefore based on the object, a cost-effective and well-tolerated for the patient agent for the detection of neurons that carry an acetylcholine receptor provide.
  • This object is achieved by the use of a peptide for the production of an agent for the detection of neurons expressing an acetylcholine receptor.
  • the agent according to the invention it is possible to specifically differentiate diseases attributable to the loss of acetylcholine receptor-positive neurons from other neurological diseases.
  • the agent may be prepared kos ⁇ -effectively and can not be easily metabolized in the organism in which the New ⁇ rone be detected.
  • 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 up to about 50 Amino Text ⁇ ren and proteins of up to 150 amino acids, regardless of their primary, secondary or tertiary structure. Here are both naturally occurring as well as biotechnological or comprises synthetically produced compounds.
  • the peptide used in the invention is chosen so that it binds to the acetylcholine receptor. Antibodies, their fragments and other polypeptides which bind to the acetylcholine receptor are suitable for this purpose. By their specific binding, the peptides can be used to detect neurons that carry the acetylcholine receptor.
  • the peptide is selected since at such ⁇ that the bond between the peptide and the acetylcholine receptor, so called a linear coefficient.
  • KD value comprises 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 not toxic and can of course be metabolized, broken down and excreted.
  • nerve refers to a nerve cell of the PNS or CNS. Nerve cells are classified according to their function, morphology, localization or gene expression. Together with macroglia (astrocytes) and oligodendroglia (oligodendrocytes), they form cellular systems that fulfill specific functions in the nervous system. These systems may be limited to certain Re ⁇ regions of the nervous system, or may extend over several regions of the brain of time, such as nerve fiber bundles from the ventral tegmental area of the Sehhü ⁇ gel (thalamus) and the midbrain (mesencephalon) innervie ⁇ ren.
  • astrocytes oligodendroglia
  • oligodendrocytes oligodendrocytes
  • Such neural systems often characterized by spe ⁇ -specific properties, for example in that Ner ⁇ venimpulse mediated rotransmitter between these cells by a specific new.
  • Bil ⁇ the use projection neurons of the ventral tegmental area and out of the basal forebrain (Stria- growth), as well as a subset of neurons of the striatum Inter the three essential cholinergic system of the central nervous system, acetylcholine as a neurotransmitter.
  • the presynaptic cholinergic neuron releases acetylcholine in response to a nerve impulse. This binds to the acetylcholine receptor of the postsynaptic neuron and triggers a depolarization of this neuron.
  • the cells of the cholinergic system are thus characterized by the formation of Acetylcho ⁇ lin and acetylcholine receptors, and can be detected by means of the inventively used peptide, which binds to the acetone tylcholinrezeptor.
  • the detection of the peptide and of the acetylcholine receptor bound thereto takes place via an integrated 11 C carbon atom.
  • the decay of the C-11 carbon isotope positron ⁇ nen are also referred to as SS + radiation is formed. Push the positron on an electron, they form two photon clays ent remove at an angle of 180 °, which is exactly in ⁇ opposite direction, from each other.
  • the photons can be detected and the position of the positrons ⁇ nemission, or the C 11 carbon atom calculated therefrom.
  • the integration of a C-11 carbon atom in the inventiveness used according to the peptide makes it possible to avoid the use of chemical ⁇ shear, foreign substances.
  • 11 C-carbon isotope in the peptide is the ra ⁇ diozine marking without complexing agents such as diethylenetriamine minpentaacetat (DTPA), 1, 4, 7, 10-tetraazacyclododecane- 1, 4, 7, 10-tetraacetic acid ( DOTA) or ethylenediamine tetraacetate (EDTA). You can also avoid that
  • radioactive foreign substance such as fluorine, xenon, or 68 gallium
  • the processes described in patent applications DE 10 2009 035 648.7 and DE 10 2009 035 645.2 are particularly suitable.
  • both the presence, and the position of the acetylcholine receptor can be detected by the inventive Ver ⁇ application of the peptide and tobil- be.
  • Another advantage of the directly labeled with 11 C peptide lies in the favorable signal / background ratio during detection. The peptide binds specifically to the acetylcholine receptor and forms a stable complex with it.
  • the peptide has at least one D-amino acid.
  • amino acids have a chiral center at their alpha carbon atom and can therefore exist as configurational isomers, namely as the D or L amino acid. Endogenous peptides and proteins are largely made up of amino acids in ⁇ L-configuration.
  • a wide ⁇ re possibility that pharmacological clearance of the peptide to to affect, is to replace some of the amino acids of the peptide by non-natural amino acids with similar chemical properties.
  • the non-natural amino acids are metabolized more slowly because the body's proteolytic enzymes are specially adapted to the breakdown 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 modifications of individual amino acids of the peptide are possible in order to specifically influence the half-life of the peptide.
  • the terminal amino group of the peptide may be replaced by an isonitrile group.
  • Such modes ⁇ fication reduces, mediated by the amino group of an interaction with proteolytic enzymes without altering the bond between the peptide used in the invention and the acetyl cholinrezeptor.
  • the peptide is an antagonist of the acetylcholine receptor.
  • acetylcholine receptors are activated by the binding of acetylcholine or its agonists, so that there is a depolarization or hyperpolarization of the cell membrane.
  • the peptide binds to the acetyl ⁇ cholinrezeptor without activating it.
  • Particularly suitable for this purpose are peptides which act as antagonists of the acetylcholine receptor. They show a specific
  • the peptide is chosen so that it traverses the blood-brain barrier independently.
  • the blood-brain barrier represents a barrier between the brain and the rest of the organism, which can not be overcome by all molecules, without further ado. Small, especially lipophilic molecules can diffuse through the blood-brain barrier ⁇ formed of astrocytes of the brain and Epithelzel ⁇ len of the blood vessels. Other molecules, such as ions, amino acids, and sugar molecules, are transported across the blood-brain barrier by channels or active transporter proteins.
  • the blood brain barrier independently, preferably by free diffusion, is particularly advantageous because the agent can be injected into the bloodstream and (not directly into the cerebrospinal fluid CSF ce ⁇ rebrospinalis ) must be applied.
  • the acetylcholine receptor is a nicotinic acetylcholine receptor.
  • the loss of the dopamine transporter goes well with a reduction of nicotiner- gen acetylcholine receptors in the neurons of the nucleus caudatus and putamen of the forebrain accompanied (Quik M et al., 2001).
  • a strong decrease of nicotinergic acetylcholine receptors of the striatal interneurons has also been observed (Dani JA and Bertrand D, 2007).
  • 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 Kom ⁇ formers such as DOTA, DTPA or EDTA mono- or polysaccharides. Depending on the nature of their radiation, the nuclides are detected by means of scintigraphy, single photon emission com- puted tomography (SPECT) or positron emission tomography (PET)
  • SPECT single photon emission com- puted tomography
  • PET positron emission tomography
  • 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 from the peptide, as it would be possible at about a 39ket ⁇ th one of the amino acids.
  • the C-carbon atom is the carbonyl carbon atom of 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.
  • 11 C-carbon has ten a half-life of only about 20 for minutes, so that the radiation dose to be selected the higher, the more time between the synthesis of the peptide and be ⁇ ner is situated. 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.
  • Another object of the invention is a radiopharmaceutical comprising a peptide having an 11 C carbon atom for the detection of neurons expressing an acetylcholine receptor.
  • the radiopharmaceutical according to the invention therefore offers an economically and medically advantageous agent for determining in vivo the amount and distribution of neurons expressing an acetylcholine receptor.
  • the peptides contained therein are distributed into the body and bind specifically Acetylcholine receptors. As a result, they accumulate at the acetylcholine receptor-positive neurons, where they are detected by the radioactive signal of the 11 C carbon atom. In this way, the neurons are detected in the nervous system of the patient.
  • 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.
  • Also disclosed is a method of detecting neurons in an organism expressing an acetylcholine receptor comprising the steps of a) providing a peptide, b) administering the peptide to the organism, and c) detecting the peptide in the organism by positron emission Tomography (PET).
  • PET positron emission Tomography
  • the peptide binds to the acetylcholine receptor and has an 11 C carbon atom.
  • an acetyl ⁇ cholinrezeptor is detected inside an organism and lo ⁇ kalillon, so that the distribution of the acetylcholine receptor can be observed in the body of a patient. In this way, the amount and distribution of acetylcholine receptor positive neurons can be determined.
  • the present invention ver ⁇ turned peptide therefore also for observing the progression of a disease and its treatment, so-called. Therapy monitoring, are suitable.
  • FIG. 1 shows schematically the bond between a peptide 1 and a nicotinergic acetylcholine receptor 4.
  • Peptide 1 comprises 16 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 (*).
  • the amino acids 2 at positions two and eight, and three and sixteen are each connected by disulfide bridges 5, which are represented by lines. This covalent bond between the sulfur atoms of two cysteine side chains contributes to the stability of the three-dimensional structure of the molecule.
  • Part of peptide 1 is attached to the nicotinic acetylcholine receptor 4, which is located on the surface of a neuron 18.
  • the C-labeled peptide 1 ⁇ specifically binds to the nicoti ⁇ nergen acetylcholine receptor 4, but not to other molecules.
  • the peptide 1 can therefore be used to detect the nicotinergic acetylcholine receptor 4.
  • the positrons released upon the decay of the 11 C carbon are
  • Positron emission tomography detected.
  • the location of the positron emission corresponds to the location of the peptide 1 and the nicotinic acetylcholine receptor 4 bound thereto.
  • the peptide 1 can therefore be used to determine the position of a Neurons 18, which forms the nicotinergic acetylcholine receptor 4.
  • a patient is a radiopharmaceutical containing the 11 C-labeled peptide 1, administered to detect neurons 18 that express a nicotinergic acetylcholine receptor 4.
  • Peptide 1 binds specifically to the nicotinic acetylcholine receptor 4 and thus accumulates on the neurons 18 which carry the nicotinic acetylcholine receptor 4. This accumulation is represented by PET and the distribution of the nicotinergic acetylcholine receptor 4 or the amount and distribution of the neurons 18, especially in the caudate nucleus and in the putamen of the patient.
  • the medication of a therapeutic agent for example, amount of active ingredient and administration schedule can be adjusted accordingly entspre ⁇ the result of such an investigation can.
  • FIG. 2 shows a representation of a peptide 1 having the sequence SEQ ID NO: 1 by means of a chemical formula sold under the trade name -Conotoxin MII by Tocris Bioscience (16144 Westwoods Business Park, Ellisville, Missouri 63021, USA).
  • the peptide of SEQ ID NO: 1 comprises 16 amino acids 2 of the following sequence: glycine-cysteine-cysteine-serine-asparagine-proline-valine-cysteine-histidine-leucine-glutamic acid-histidine-serine-asparagine-leucine-cysteine Am i d .
  • the N-terminal amino acids 2 glycine and cysteine are represented by structural formula, the following amino acids 2 by their respective three-letter code.
  • the amino acid 2 cysteine Am i d is designated Cys A and possesses a C-termial amide.
  • the cysteines at position two and eight resp. three and sixteen are connected by disulfide bridges, represented by lines.
  • the sequence of the peptide is also given in SEQ ID NO: 1.
  • the carbonyl carbon atom of the N-terminal glycine 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 is added in the last step because the half-life of the 11 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 binds specifically to a nicotinic acetylcholine receptor 4. These receptors belong to the family of ligand-gated ion channels and consist of a total of five identical or different subunits. They are activated by the binding of acetylcholine or an agonist, resulting in a conformational change of the
  • Nicotinergic acetylcholine receptors 4 are cation channels through which, in particular, sodium and calcium ions enter the cell. This leads to the depolarization of the cell membrane and the transmission of the nerve impulse.
  • the peptide of SEQ ID NO: 1 binds to the nicotinergic acetylcholine receptor 4, but without activating it. It is therefore particularly suitable for the detection of neurons 18 which express nicotinergic acetylcholine receptors 4. Labeling by means of X1 carbon carbon is particularly advantageous because it does not affect the physiological structure of the peptide 1 and does not adversely affect the distribution in the tissue or the compatibility of the peptide 1.
  • Alzheimer dementia or Parkinson's disease can be excluded with great certainty. If, on the other hand, a loss becomes visible, it is possible to treat the affected patients early enough. This is particularly important because a Regenera ⁇ tion already dead neurons is not possible and the preservation of intact cells must be promoted. Therefore, the therapies available with early use show significantly better treatment results.
  • Figure 3 shows a schematic representation (greatly simplified by 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 circulatory system 10 includes various schematically illustrated organs such as lung 12, heart 13, liver 14, intestine 15, kidney 16, and brain 19, as well as neurons 18 therein.
  • the main veins 11 which represented these organs ver ⁇ bind are.
  • the peptide 1 is represented by triangles along the wires 11.
  • the degradation products 17 of the peptide 1 are represented by individual dashes within the outline of the kidney 16.
  • 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 Via the blood circulation system 10, the peptide 1 is trans ⁇ ported into the organs 12, 13, 14, 15, 16 and 19 of the organism.
  • Phase III The circulating peptide 1 binds specifically to the acetylcholine receptor 4 and accumulates on the neurons 18 because they produce the acetylcholine 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 of amino acids 1 and 2, 3 collect predominantly they are over the bladder and the ureter excreted ⁇ in the kidney 16 from where. references

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  • 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)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne l'utilisation d'un peptide (1) pour la production d'un agent destiné à la détection de neurones (18) qui expriment un récepteur de l'acétylcholine (4). Le peptide se lie au récepteur de l'acétylcholine (4) et il comprend un atome de carbone 11C. L'invention porte également sur un radiopharmaceutique destiné à la localisation de neurones (18) qui expriment un récepteur de l'acétylcholine (4). Ce radiopharmaceutique comporte un peptide (1) qui se lie au récepteur de l'acétylcholine (4) et comporte un atome de carbone 11C.
PCT/EP2011/059875 2010-06-30 2011-06-15 Peptide marqué 11c pour la détection de neurones exprimant un récepteur de l'acétylcholine Ceased WO2012000784A1 (fr)

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DE102010026053.3 2010-06-30
DE102010026053A DE102010026053A1 (de) 2010-06-30 2010-06-30 11C-markiertes Peptid zur Detektion von Neuronen, die einen Acetylcholinrezeptor exprimieren

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DE102011118030A1 (de) * 2011-06-08 2012-12-13 Siemens Aktiengesellschaft Herstellung und Verwendung eines Peptids mit einer N-terminalen 11C-markierten Acetylgruppe

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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AU2001257449A1 (en) * 2000-05-01 2001-11-12 Targacept, Inc. Imaging of nicotinic acetylcholine receptor subtypes

Patent Citations (3)

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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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FALLER A, SCHÜNKE M: "Der Körper des Menschen", 2008, THIEME-VERLAG
HARTVIG P ET AL: "Kinetics of four <11>C-labelled enkephalin peptides in the brain, pituitary and plasma of Rhesus monkeys", REGULATORY PEPTIDES, ELSEVIER SCIENCE BV, NL, vol. 16, no. 1, 1 December 1986 (1986-12-01), pages 1 - 13, XP023462538, ISSN: 0167-0115, [retrieved on 19861201], DOI: 10.1016/0167-0115(86)90190-4 *
HENRIKSEN G ET AL: "Proof of principle for the use of 11C-labelled peptides in tumour diagnosis with PET", EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, SPRINGER VERLAG, HEIDELBERG, DE, vol. 31, no. 12, 10 August 2004 (2004-08-10), pages 1653 - 1657, XP002383248, ISSN: 1619-7070, DOI: 10.1007/S00259-004-1582-1 *
HORTI A G ET AL: "Development of radioligands with optimized imaging properties for quantification of nicotinic acetylcholine receptors by positron emission tomography", LIFE SCIENCES, PERGAMON PRESS, OXFORD, GB, vol. 86, no. 15-16, 10 April 2010 (2010-04-10), pages 575 - 584, XP026987549, ISSN: 0024-3205, [retrieved on 20090318] *
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