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WO2012000843A1 - Peptide marqué au carbone 11 (11c) permettant de détecter un antigène - Google Patents

Peptide marqué au carbone 11 (11c) permettant de détecter un antigène Download PDF

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Publication number
WO2012000843A1
WO2012000843A1 PCT/EP2011/060352 EP2011060352W WO2012000843A1 WO 2012000843 A1 WO2012000843 A1 WO 2012000843A1 EP 2011060352 W EP2011060352 W EP 2011060352W WO 2012000843 A1 WO2012000843 A1 WO 2012000843A1
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WO
WIPO (PCT)
Prior art keywords
peptide
antigen
amino acid
antibody
acid sequence
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.)
Ceased
Application number
PCT/EP2011/060352
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German (de)
English (en)
Inventor
Hartmuth Kolb
Ursus KRÜGER
Oliver Lade
Marilena Manea
Michael Przybylski
Arno Steckenborn
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
Universitaet Konstanz
Siemens Corp
Original Assignee
Siemens AG
Universitaet Konstanz
Siemens Corp
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 Siemens AG, Universitaet Konstanz, Siemens Corp filed Critical Siemens AG
Publication of WO2012000843A1 publication Critical patent/WO2012000843A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/008—Peptides; Proteins

Definitions

  • the invention relates to the use of a peptide for the production of an agent for the detection of an antigen. It also relates to a radiopharmaceutical for the localization of a tumor comprising such a peptide.
  • the immune system serves to ward off foreign molecules, viruses and bacteria and identifies foreign substances with the help of antibodies. These recognize and bind foreign body molecules, so-called antigens, which are then broken down by other components of the immune system and excreted.
  • antibodies do not bind the entire antigen, but only small well-defined regions thereof, which are also referred to as epitopes.
  • Each antibody has two identical antigen-binding parts called paratopes that bind to identical epitopes.
  • the bond itself is based on electrostatic, hydrophobic and / or van der Waals interactions and / or on hydrogen bonds.
  • the specific binding affinities between antibody and antigen are also used for diagnostic and therapeutic purposes.
  • Diseased cells often produce antigens, for example proteins that do not occur in healthy tissue or only in very small quantities. Tumor cells also form specific molecules, so-called tumor antigens.
  • antigens predominantly with biotechnologically produced antibodies, are detected in blood or tissue samples in vitro.
  • the resulting antibody-antigen complexes for example via fluorescence-labeled secondary antibodies detected.
  • antibodies detected in vivo are directly labeled, for example by a radionuclide.
  • a drug containing such directly labeled antibody is WX-G250, Redectanee, from Wilex AG, Kunststoff, Germany (Divgl CR et al., 2007).
  • the antibody is labeled with 124 iodine and can be detected by its radioactive radiation in the living organism.
  • the production of directly labeled antibodies is very complicated, because they must first be produced biotechnologically and then provided with a label. As a result, their production is expensive.
  • antibodies in the organism are only metabolized very slowly, so that their biological half-life is about 200 hours.
  • radioactive element also referred to as radioisotope
  • the antibodies that are not bound to an antigen continue to circulate in the organism and generate a strong background signal. To reduce the background signal, it is therefore necessary to wait until the free radiolabelled antibodies have been degraded.
  • radioisotopes with particularly long half-lives must be used. However, these emit a lower amount of radiation per time interval, so that a correspondingly high radiation dose must be used in order to ensure the necessary radiation intensity during the recording. This increases the radiation exposure for the patient. In addition, there are long examination and monitoring times of the patient.
  • the invention is therefore based on the object to provide a cost-effective to manufacture and tolerated by the patient agent for the detection of an antigen in vivo.
  • This object is achieved by the use of a peptide for the production of an agent for the detection of an antigen.
  • the peptide has an amino acid sequence of a paratope of a Having antibody which is directed against the antigen and specifically binds to an epitope of the antigen, the distribution and position of the antigen can be determined in an organism with this peptide.
  • the detection of the peptide and the antigen bound thereto is made possible by the 11 C carbon atom of the peptide.
  • 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, as well as polypeptides of up to about 30 amino acids, regardless of their primary, secondary or tertiary structure. Both naturally occurring and biotechnologically or synthetically produced compounds are included.
  • antigen refers to any type of inorganic or organic compound, in particular proteins, peptides and polysaccharides whose surface structure is suitable for being recognized and bound by an antibody.
  • antibody denotes natural or synthetic protein complexes from the group of immunoglobulins. They are usually composed of two light and two heavy polypeptide chains, each one light chain and the N-terminal part of a heavy chain together forming a paratope of the antibody. The paratope mediates binding between the antibody and the antigen by interacting with a particular, relatively small, structure of the antigen, the epitope. The specificity of the binding is determined by the individual structure of the paratope and the epitope. For a defined epitope, the specificity of the corresponding paratope results from its amino acid sequence.
  • a peptide which binds specifically to an epitope of an antigen in order to detect this antigen.
  • the peptide sos is chosen such that its amino acid sequence corresponds to the amino acid sequence of the paratope. speaks, which binds the epitope of the antigen.
  • an antibody is selected which is directed against the antigen to be detected, the paratope thus interacts with an epitope of the antigen. Subsequently, the amino acid sequence of the paratope of this antibody is determined. For this it is necessary to investigate which amino acids of the polypeptide chains of the antibody are involved in the formation of the paratope.
  • the number and type of amino acids of the paratope distinguishes antibodies from each other and determines their specificity for an epitope.
  • the sequence of the amino acids that actually constitute the paratope can be determined, for example, by a point mutation analysis of the antibody (Colbi DW et al., 2004). For this purpose, the binding affinity of different variants of the antibody carrying different point mutations is examined.
  • the paratope may also be analyzed by the use of alanine scanning and surface plasmon resonance techniques as described in Heap CJ et al., 2005.
  • the peptide is synthesized according to the amino acid sequence of the paratope so that it has a particularly high specificity for the epitope of the antigen and does not bind to other molecules.
  • the peptide is chosen such that the bond between the peptide and the antigen has a linear coefficient, so-called kD value, of £ 100 nM, preferably of ⁇ 10 nM, most preferably of 7.5 nM.
  • kD value so-called kD value
  • the detection takes place via the radioactive labeling of the peptide with an 11 C-Kohlenstoffatora.
  • positrons also known as ß * -
  • Radiation be formed formed.
  • the positrons hit an electron, they form two photons, which move away from each other at an angle of 180 °, ie exactly in the opposite direction.
  • the photons can be detected and used to calculate the position of the positron emission, or of the 11 C carbon atom.
  • the integration of an 11 C carbon atom into the peptide used according to the invention allows both the presence and the position of the peptide to be detected and displayed.
  • the processes described in patent applications DE 10 2009 035 648.7 and DE 10 2009 035 645.2 are particularly suitable.
  • the amount of peptides located at a particular site can also be quantified.
  • An advantage of using an 11 C-labeled peptide is its structure of endogenous amino acids, making it compatible with the organism.
  • the peptide and its individual amino acids are non-toxic, they can of course be metabolized, degraded and excreted.
  • a radioactive impurity such as fluorine l8, 133 Xenon, or "Gallium has to be introduced into the organism.
  • Another advantage of using a peptide labeled directly with 11 C lies in the favorable signal / background
  • the peptide binds to the epitope of the antigen, with which it forms a stable complex, which is difficult to access for enzymatic degradation. Free, unbound peptides, however, become fast
  • the agent is a radiopharmaceutical.
  • radiopharmaceuticals refers to medicines containing radionuclides whose radiation is used for diagnosis and therapy. The most important fields of application are oncology, cardiology and neurology as well as drug research. As radionuclides, gamma or beta rays are emitted.
  • de nuclides for example, l33 xenon, "" technetium, “gallium, and 18 fluorine, are commonly used via complexing agents, such as diethylenetriaminepentaacetate (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10, Tetraacetic acid (DOTA) or ethylenediaminetetraacetate (EDTA) bound to mono- or polysaccharides
  • DTPA diethylenetriaminepentaacetate
  • DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10
  • DOTA Tetraacetic acid
  • EDTA ethylenediaminetetraacetate
  • the nuclides are detected by scintigraphy, single photon emission computed tomography (SPECT) or positron emission tomography (PET), depending on the nature of their radiation.
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • radiopharmaceuticals can cause side effects, such as anaphylactic or allergic reactions, in a patient's body.
  • side effects such as anaphylactic or allergic reactions
  • the antigen is formed by a tumor.
  • tumor refers to a local increase in the volume of a tissue, such as by an inflammatory swelling or a spontaneous, unrestrained new formation of cells.
  • Tumor cells often express certain antigens that are recognized and bound by the body's own or biotechnologically produced antibodies. The detection of such an antigen is medically particularly relevant because it allows the detection of a tumor in vivo.
  • the antigen is a tumor antigen. Tumor antigens are specifically expressed by tumor cells, but do not occur or only in very small amounts in healthy tissue.
  • the amino acid sequence of the peptide is the amino acid sequence of a variable region of a polypeptide chain of the antibody.
  • the formation of the paratope involves the N-terminal ends of a light and a heavy polypeptide chain of the antibody.
  • antibodies are most different from each other because the gene coding for the polypeptide chains always changes in that region.
  • the N-terminal ends of the polypeptide chains are therefore referred to as "variable regions". Since they determine the binding specificity of the antibody, it is advantageous to use a peptide whose amino acid sequence corresponds to the amino acid sequence of one of these regions.
  • the 11 C carbon atom is a 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 11 C carbon atom is not cleaved off the peptide, as would be possible with a side chain of one of the amino acids.
  • the 11 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 can be used directly after attachment of the 11 C-labeled amino acid.
  • 11 C-carbon has a half-life of only about 20 minutes, so the higher the radiation dose, the more time is left between the synthesis of the peptide and its use. 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 be used. In this way, the time between the processing of the 1- carbon and the use of the peptide is reduced, so that the radiation loss during the production 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. As a result, the production is made more cost-effective and the radiation exposure for the technical staff producing the peptide is reduced.
  • the peptide has at least one D-amino acid.
  • D-amino acid the peptide has at least one D-amino acid.
  • all amino acids have a chiral center at their alpha carbon atom and can therefore be considered as
  • Another object of the invention is a radiopharmaceutical for the localization of a tumor comprising a peptide having a U C carbon atom.
  • the radiopharmaceutical of the present invention provides a cost effective and well tolerated means for determining the position of a tumor in vivo.
  • the radiopharmaceutical is administered to the patient and the peptides contained therein are rapidly and efficiently distributed in the body because of their size. They bind the epitope of the disease-specific antigen and accumulate on the tissue that produces the antigen. This tissue may be, for example, an inflammatory focus or a tumor.
  • the accumulation of radioactively labeled peptides is detected by PET, thus determining the exact location of the inflammation or tumor in the body of the patient.
  • the amino acid sequence of the peptide is the amino acid sequence of a variable region of a polypeptide chain of the antibody.
  • 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 curvature. PET also makes it possible to quantify the amount of labeled molecules in a tissue.
  • Also disclosed is a method of localizing an antigen in an organism 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 has an amino acid sequence of a paratope of an antibody directed against the antigen, binds specifically to an epitope of the antigen, and has an 11 C carbon atom.
  • FIG. 1A shows schematically the binding between an antibody 6 and an antigen 4.
  • the antibody 6 consists of two heavy polypeptide chains 9 and two light polypeptide chains 8, each represented by long and short, mutually parallel lines.
  • One of the two identical, opposing, paratopes 7 of the antibody 6 binds to an epitope 5 of the antigen 4.
  • the antigen 4 is located on the surface of a diseased tissue 18, which in the case shown is a tumor.
  • FIG. 1B schematically shows peptide 1 bound to epitope 5 of antigen 4.
  • Peptide 1 comprises nine 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 specific binding affinity between the antigen 4 and the antibody 6 is due to chemical interactions between the epitope 5 of the antigen 4 and the paratope 7 of the antibody 6. These interactions are determined by the amino acid sequences of epitope 5 and paratope 7.
  • the amino acid sequence of the 11 C-labeled peptide 1 corresponds to the amino acid sequence of the paratope 7 of the antibody 6, so that the peptide 1 has the binding affinity of the paratope 7 and specifically binds to the epitope 5 of the antigen 4. Due to this binding specificity, the 11 C-labeled peptide 1 can be used to detect antigen 4.
  • the positrons emitted upon the decay of the 11 C carbon atom 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 the antigen 4 bound thereto.
  • Tumor cells often form substances that are absent in healthy tissue and against which natural or biotechnological antibodies 6 can be produced.
  • the amino acid sequence of the paratopes 7 of these antibodies 6 is determined by means of point mutation analyzes (Colby DW et al., 2004). Then, an 11 C-labeled peptide 1 corresponding to the amino acid sequence of the paratope 7 of the antibody 6 is prepared. It specifically binds to the epitope 5 of the tumor antigen 4. In order to determine the position of the tumor 18 in the body of a patient, the 11 C-labeled peptide 1 is administered to the patient. The peptide 1 binds to the epitope 5 of the tumor antigen 4 and accumulates on the cells of the tumor 18. This accumulation is visible in a positron emission tomography (PET), so that the distribution of the tumor antigen 4 or the position of the tumor 18 be determined.
  • PET positron emission tomography
  • FIG. 2 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 represented organs such as lung 12, heart 13, liver 14, intestine 15 and kidney 16, and the main arteries 11 connecting these organs.
  • the peptide 1 is represented by triangles along the wires 11.
  • the degradation products 17 of peptide 1 are represented by individual dashes within the outline of the kidney 16.
  • a pathological tissue 18, for example a tumor or an inflammation is shown, to which peptides 1 are increasingly attached.
  • 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 transported into the organs 12, 13, 14, 15, and 16 of the organism.
  • Phase III The circulating peptide 1 binds specifically to the epitope 5 of the antigen 4 and accumulates on the diseased tissue 18 because this forms the antigen 4.
  • Phase IV Unbound peptide 1 is rapidly metabolised and enzymatically degraded. The organism does not distinguish between its own peptides and the peptide 1, because it is made up 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 excreted 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.

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

Abstract

La présente invention concerne l'utilisation d'un peptide (1) pour produire un agent permettant de détecter un antigène (4), lequel peptide a) comprend une séquence d'acides aminés d'un paratope (7) d'un anticorps (6) dirigé contre l'antigène (4), b) se lie de manière spécifique à un épitope (5) de l'antigène (4) et c) présente un atome de carbone 11 (11C). L'invention concerne également un produit radiopharmaceutique permettant de localiser une tumeur et comprenant un peptide (1) qui présente un atome de carbone 11 (11C). Ledit peptide (1) présente une séquence d'acides aminés d'un paratope (7) d'un anticorps (6) dirigé contre la tumeur (18).
PCT/EP2011/060352 2010-06-30 2011-06-21 Peptide marqué au carbone 11 (11c) permettant de détecter un antigène Ceased WO2012000843A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE201010026054 DE102010026054A1 (de) 2010-06-30 2010-06-30 11C-markiertes Peptid zur Detektion eines Antigens
DE102010026054.1 2010-06-30

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WO2012000843A1 true WO2012000843A1 (fr) 2012-01-05

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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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120003148A1 (en) * 2006-12-19 2012-01-05 Ekaterina Dadachova Radioimmunotherapy and imaging of tumor cells that express viral antigens

Patent Citations (3)

* 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
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

Non-Patent Citations (10)

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Title
BERND NEUMAIER ET AL: "Short Communication: 18 F-Immuno-PET: Determination of Anti-CD66 Biodistribution in a Patient with High-Risk Leukemia", CANCER BIOTHERAPY & RADIOPHARMACEUTICALS, vol. 23, no. 6, 1 December 2008 (2008-12-01), pages 819 - 824, XP055012816, ISSN: 1084-9785, DOI: 10.1089/cbr.2008.0512 *
COLBY DW, GARG P, HOLDEN T, CHAO G, WEBSTER JM, MESSER A, INGRAM VM, WITTRUP KD: "Development of a human light chain variable domain (V(L)) intracellular antibody specific for the amino terminus of huntingtin via yeast surface display", J MOL BIOL., vol. 342, no. 3, 17 September 2004 (2004-09-17), pages 901 - 12, XP004536915, DOI: doi:10.1016/j.jmb.2004.07.054
DIVGI CR, PANDIT-TASKAR N, JUNGBLUTH AA, REUTER VE, GÖNEN M, RUAN S, PIERRE C, NAGEL A, PRYMA DA, HUMM J: "reoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial", LANCET ONCOL., vol. 8, no. 4, April 2007 (2007-04-01), pages 304 - 10
FALLER A, SCHÜNKE M: "Der Körper des Menschen", 2008, THIEME-VERLAG
HEAP CJ, WANG Y, PINHEIRO TJ, READING SA, JENNINGS KR, DIMMOCK NJ: "Analysis of a 17-amino acid residue, virusneutralizing microantibody", J GEN VIROL., vol. 86, June 2005 (2005-06-01), pages 1791 - 800, XP002506464, DOI: doi:10.1099/VIR.080812-0
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 *
J. V. LEYTON ET AL: "Engineered humanized diabodies for microPET imaging of prostate stem cell antigen-expressing tumors", PROTEIN ENGINEERING DESIGN AND SELECTION, vol. 22, no. 3, 1 January 2008 (2008-01-01), pages 209 - 216, XP055012799, ISSN: 1741-0126, DOI: 10.1093/protein/gzn055 *
MASSOUD TF, GAMBHIR SS: "Molecular imaging in living subjects: seeing fundamental biological processes in a new light", GENES DEV., vol. 17, no. 5, 1 March 2003 (2003-03-01), pages 545 - 80, XP007905304, DOI: doi:10.1101/gad.1047403
NEUNDORF I, RENNERT R, FRANKE J, KÖZLE I, BERGMANN R: "Detailed analysis concerning the biodistribution and metabolism of human calcitonin-derived cell-penetrating peptides", BIOCONJUG CHEM., vol. 19, no. 8, August 2008 (2008-08-01), pages 1596 - 603, XP002575961, DOI: doi:10.1021/bc800149f
SANDELL J ET AL: "Labelling of a cholecystokinin (CCK) peptide with 11C, and examination of its brain uptake in a cynomolgus monkey with PET", JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, JOHN WILEY, CHICHESTER, GB, vol. 40, 1 December 1997 (1997-12-01), pages 771 - 773, XP002663002, ISSN: 0362-4803 *

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