WO2011071083A1 - Sonde moléculaire pour l'imagerie d'îlots pancréatiques, et utilisation de celle-ci - Google Patents

Sonde moléculaire pour l'imagerie d'îlots pancréatiques, et utilisation de celle-ci Download PDF

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WO2011071083A1
WO2011071083A1 PCT/JP2010/072041 JP2010072041W WO2011071083A1 WO 2011071083 A1 WO2011071083 A1 WO 2011071083A1 JP 2010072041 W JP2010072041 W JP 2010072041W WO 2011071083 A1 WO2011071083 A1 WO 2011071083A1
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group
imaging
molecular probe
polypeptide
islet
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PCT/JP2010/072041
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Japanese (ja)
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佐治英郎
稲垣暢也
豊田健太郎
木村寛之
平尾佳
永川健児
松田洋和
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国立大学法人京都大学
アークレイ株式会社
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Priority to EP10836003.3A priority Critical patent/EP2510951B1/fr
Priority to CN201080056397.6A priority patent/CN102695527B/zh
Priority to JP2011507740A priority patent/JP5700835B2/ja
Publication of WO2011071083A1 publication Critical patent/WO2011071083A1/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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/13—Labelling of peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons

Definitions

  • the present invention relates to a molecular probe for islet imaging and use thereof.
  • type 2 diabetes in Japan exceeds an estimated 8.8 million people in 2007 statistics, and continues to increase further than in 2002.
  • intervention before the onset of diabetes based on the glucose tolerance test is performed, but sufficient results have not been obtained.
  • the cause of this is that islet damage has already progressed to a high degree at the borderline stage where functional abnormalities are revealed by a glucose tolerance test, and the start of intervention may be late.
  • pancreatic islets has already decreased at the time of onset in both domestic and overseas, and further reduction of pancreatic ⁇ cells after onset is considered to be one of treatment resistance for type 2 diabetes. ing. For this reason, if the amount of pancreatic islets and / or the amount of ⁇ -cells of the pancreas can be detected, there is a possibility that the etiology of type 2 diabetes, ultra-early diagnosis, and the onset can be prevented. For this reason, there is a demand for technical development for detecting the amount of pancreatic islets and / or the amount of pancreatic ⁇ cells.
  • pancreatic islets and / or pancreatic ⁇ -cells for example, a method of noninvasive quantification using an image diagnostic method, that is, development of a noninvasive islet imaging technique is performed. Yes. Therefore, there is a need for a molecular probe that enables non-invasive imaging of pancreatic islets, preferably pancreatic ⁇ cells and measurement of pancreatic ⁇ cell mass.
  • GLP-1R glycopeptide 1 receptor
  • a molecular probe obtained by labeling a derivative of Exendin-4 (9-39) with [ 18 F] fluorine for example, Non-Patent Document 1
  • adding lysine to the C-terminal of Exendin-4 and adding the added lysine
  • Molecular probe (Lys 40 (Ahx-DTPA- 111 In) Exendin-4) labeled with [ 111 In] indium via diethylenetriaminepentaacetic acid (DTPA) bonded to a residue for example, Non-Patent Documents 2 and 3
  • DTPA- 111 In) Exendin-4 (9-39)) for example, Non-Patent Document 3
  • the present invention provides a molecular probe for islet imaging capable of three-dimensional imaging of islets.
  • the present invention is a molecular probe used for imaging of islets, A polypeptide represented by the following formula (1), (2) or (3): A polypeptide in which one to several amino acids have been deleted, added or substituted from the polypeptide of the following formula (1), (2) or (3), which is capable of binding to islets, or
  • the present invention relates to a molecular probe for imaging comprising a polypeptide having 80% or more homology with an amino acid sequence of a polypeptide of the following formula (1), (2) or (3), which comprises a polypeptide capable of binding to an islet.
  • X represents a lysine residue in which the side chain amino group is labeled with a radionuclide
  • Z- represents that the ⁇ -amino group at the N-terminal is non- Indicates that the group is modified or modified by a non-charged modifying group.
  • the present invention is a precursor of an imaging molecular probe for producing the imaging molecular probe of the present invention,
  • a polypeptide in which one to several amino acids are deleted, added or substituted from the polypeptide of the following formula (4), (5) or (6), which can bind to islets after labeling and deprotection Or Imaging comprising a polypeptide having 80% or more homology with an amino acid sequence of a polypeptide of the following formula (4), (5) or (6), which can bind to islets after labeling and deprotection
  • the present invention relates to a molecular probe precursor.
  • the present invention also relates to a method for imaging pancreatic islets including, as yet another aspect, detecting a signal of the molecular probe for imaging from a subject administered with the molecular probe for imaging of the present invention.
  • the present invention detects a signal of the molecular probe for imaging from a subject administered with the molecular probe for imaging of the present invention, and islets from the detected signal of the molecular probe for imaging.
  • the present invention relates to a method for measuring the amount of islets including calculating the amount.
  • three-dimensional imaging of islets preferably non-invasive three-dimensional imaging of islets is possible.
  • FIGS. 1A and 1B are graphs showing an example of changes over time in the body distribution of the molecular probe for imaging of Example 1.
  • FIGS. 2A to 2C are graphs showing an example of a temporal change in the distribution in the body of the molecular probe for imaging in Example 1 (ratio of pancreas to other organs).
  • 3A and 3B are diagrams showing an example of the results of changes over time in the distribution of the molecular probe of Reference Example 1.
  • FIG. 4A and 4B are diagrams showing an example of the results of changes over time in the biodistribution of the molecular probe of Reference Example 2.
  • FIG. FIG. 5 is an image showing an example of the result of three-dimensional imaging (PET imaging) using the imaging molecular probe of Example 2.
  • FIG. 6A and 6B are graphs showing an example of changes over time in the body distribution of the imaging molecular probe of Example 3.
  • FIG. 7A and 7B are graphs showing an example of results of a blocking experiment on the imaging molecular probe of Example 3.
  • FIG. 8 is an image showing an example of the result of imaging analysis of a pancreas section using the imaging molecular probe of Example 3.
  • FIG. 9 is an image showing an example of the result of SPECT imaging using the molecular probe for imaging of Example 4.
  • FIG. 10 is a graph showing an example of changes over time in the distribution of the molecular probe for imaging in Example 5.
  • FIG. 11 is a diagram illustrating an example of a temporal change in the biodistribution of the molecular probe of Reference Example 4.
  • 12 is an image showing an example of the result of imaging analysis of a pancreas section using the imaging molecular probe of Example 5.
  • the diameter of the islets is, for example, about 50 to 500 ⁇ m for humans.
  • a molecular probe that can specifically accumulate on the pancreatic islets and cause contrast with surrounding organs is required. It is believed that. For this reason, research and development of various molecular probes as described above have been conducted, but from the viewpoint of clearer imaging or more accurate quantification, it accumulates specifically in the pancreas, and with the surrounding organs.
  • a new molecular probe capable of obtaining a desired contrast (S / N ratio) has been demanded.
  • the present invention is a molecular probe containing the polypeptide represented by the above formula (1), (2) or (3) or a polypeptide having homology with the polypeptide, for example, the accumulation rate in the pancreas, Specificity to the pancreas is improved, and it may be possible to provide molecular probes suitable for non-invasive islet three-dimensional imaging by positron emission tomography (PET) and single photon radiation computed tomography (SPECT) Based on knowledge.
  • PET positron emission tomography
  • SPECT single photon radiation computed tomography
  • a molecular probe suitable for three-dimensional imaging of islets by PET or SPECT more preferably a molecular probe suitable for three-dimensional imaging of non-islet islets by PET.
  • a molecular probe used for imaging of pancreatic islets comprising a polypeptide represented by the following formula (1), (2) or (3), a polypeptide represented by the following formula (1), (2) or (3): A polypeptide in which one to several amino acids have been deleted, added or substituted from the peptide and can bind to the islet, or the amino acid of the polypeptide of the following formula (1), (2) or (3)
  • a molecular probe for imaging comprising a polypeptide having a sequence homology of 80% or more and a polypeptide capable of binding to an islet; Z-HGEGTFTSDLSXQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2 (1) (SEQ ID NO: 1) Z-HGEGTFTSDLSKQMEEEAVRLFIEWLXNGGPSSGAPPPS-NH 2 (2) (SEQ ID NO: 2) B-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2 (3) (SEQ ID NO: 3)
  • SEQ ID NO: 1 Z-
  • the radionuclide is 11 C, 13 N, 15 O, 18 F, 64 Cu, 67 Ga, 68 Ga, 75 Br, 76 Br, 77 Br, 99m Tc, 111 In, 123 I, 124 I, The molecular probe for imaging according to [1], which is 125 I, 131 I or 186 Re; [3] The molecular probe for imaging according to [1] or [2], wherein an amino group of a side chain of lysine labeled with the radionuclide is bonded to a group represented by the following formula (I):
  • A represents an aromatic hydrocarbon group or an aromatic heterocyclic group
  • R 1 represents a substituent containing a radionuclide
  • R 2 represents 1 or different from a hydrogen atom or R 1 shows a plurality of substituents
  • R 3 represents either a bond, C 1 -C 6 alkylene group and C 1 -C 6 oxyalkylene groups.
  • Molecular probe precursor for imaging comprising a possible polypeptide, * -HGEGTFTSDLSKQMEEEAVRLFIEWLK * NGGPSSGAPPPS-NH 2 (4) (SEQ ID NO: 4) * -HGEGTFTSDLSK * QMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2 (5) (SEQ ID NO: 5) HGEGTFTSDLSK *
  • the molecular probe precursor for imaging is labeled with 11 C, 13 N, 15 O, 18 F, 64 Cu, 67 Ga, 68 Ga, 75 Br, 76 Br, 77 Br, 99m Tc, 111 In , 123 I, 124 I, 125 I, 131 I or 186 Re, a method for producing a molecular probe for imaging according to [5], comprising labeling the molecular probe precursor for imaging with a compound containing a radionuclide.
  • the labeling of the molecular probe precursor for imaging includes labeling the molecular probe precursor for imaging with a compound having a group represented by the following formula (I) [5] or [ 6], a method for producing an imaging molecular probe according to In the formula (I), A represents an aromatic hydrocarbon group or an aromatic heterocyclic group, R 1 represents a substituent containing a radionuclide, and R 2 represents 1 or different from a hydrogen atom or R 1 shows a plurality of substituents, R 3 represents either a bond, C 1 -C 6 alkylene group and C 1 -C 6 oxyalkylene groups.
  • A represents an aromatic hydrocarbon group or an aromatic heterocyclic group
  • R 1 represents a substituent containing a radionuclide
  • R 2 represents 1 or different from a hydrogen atom or R 1 shows a plurality of substituents
  • R 3 represents either a bond, C 1 -C 6 alkylene group and C 1 -C 6 oxyalkylene groups.
  • a kit for imaging pancreatic islets comprising at least one of the imaging molecular probe according to any one of [1] to [3] and the imaging molecular probe precursor according to [4] ; [9] The kit according to [8], which contains the molecular probe for imaging in the form of an injection solution; [10] A reagent for imaging pancreatic islets, comprising a molecular probe for imaging according to any one of [1] to [3]; [11] A method for imaging pancreatic islets comprising detecting a signal of the molecular probe for imaging from a subject administered with the molecular probe for imaging according to any one of [1] to [3] Imaging method; [12] The imaging method according to [11], comprising: reconstructing the detected signal into an image and displaying the image; [13] The imaging method according to [11] or [12], further comprising determining a state of the islet from a result of islet imaging using the molecular probe for imaging; [14] Detecting a signal of
  • pancreatic islet imaging refers to molecular imaging of islets and includes imaging the spatial and / or temporal distribution of islets in vivo.
  • pancreatic islet imaging is preferably performed using pancreatic ⁇ cells as a target molecule, more preferably using GLP-1R of pancreatic ⁇ cells as a target molecule from the viewpoint of prevention / treatment / diagnosis related to diabetes. is there.
  • islet imaging is preferably non-invasive three-dimensional imaging from the viewpoint of quantitative determination of islet volume and application to humans.
  • the imaging method is not particularly limited as long as noninvasive pancreatic islet imaging is possible, and examples thereof include positron emission tomography (PET) and single photon radiation computed tomography (SPECT).
  • PET positron emission tomography
  • SPECT single photon radiation computed tomography
  • the “polypeptide capable of binding to islets” means that the polypeptide can bind to cells constituting the pancreatic islets, preferably capable of binding to pancreatic ⁇ cells, more preferably pancreatic ⁇ cells. And more preferably, can specifically bind to GLP-1R of pancreatic ⁇ cells.
  • “specifically bindable” means a degree of contrast that can be sufficiently distinguished from other organs and surrounding organs such as organs in non-invasive imaging using the molecular probe for imaging of the present invention. It is preferable to be specific to such an extent that a signal can be detected, and it is more preferable to be specific to such an extent that a desired contrast (S / N ratio) with surrounding organs can be obtained.
  • the molecular probe for imaging of the present invention is a molecular probe used for imaging of islets, and is a polypeptide represented by the above formula (1), (2) or (3), the above formula (1), (2) Or a polypeptide in which one to several amino acids have been deleted, added or substituted from the polypeptide of (3) and can bind to islets, or the above formula (1), (2) or (3)
  • a molecular probe for islet imaging comprising a polypeptide having a homology of 80% or more with the amino acid sequence of said polypeptide and capable of binding to the islet, preferably the above formula (1), (2) or ( 3) A polypeptide having 1 to several amino acids deleted, added or substituted from the polypeptide of the above formula (1), (2) or (3), which can bind to the islet Polypeptide or poly of the above formula (1), (2) or (3)
  • a polypeptide having an amino acid sequence 80% or more homology of peptide is pancreatic islets molecular probe for imaging consisting of a polypeptide capable
  • the molecular probe for imaging of the present invention can be used for, for example, three-dimensional imaging of islets, preferably non-invasive three-dimensional imaging of islets, and more preferably quantification of the amount of islets.
  • the amino acid sequence of the polypeptide of the above formula (1) is the amino acid sequence set forth in SEQ ID NO: 1 in the sequence listing, and the amino group of the 12th lysine side chain of the polypeptide of the above formula (1) is radioactive. Labeled with nuclides.
  • the amino acid sequence of the polypeptide of the above formula (2) is the amino acid sequence shown in SEQ ID NO: 2 in the sequence listing, and the amino group of the side chain of the 27th lysine of the polypeptide of the above formula (2) is Labeled with a radionuclide.
  • the ⁇ -amino group at the N-terminus of the polypeptides of the above formulas (1) and (2) is unmodified or modified with a modifying group having no charge.
  • the C-terminal carboxyl group of the polypeptides of the above formulas (1) and (2) is amidated with an amino group from the viewpoint of improving binding to pancreatic ⁇ cells and / or stability in vivo. .
  • the amino acid sequence of the polypeptide of the above formula (3) is the amino acid sequence described in SEQ ID NO: 3 in the sequence listing, and the N-terminal ⁇ -amino group of the polypeptide of the above formula (3) is labeled with a radionuclide. ing.
  • the C-terminal carboxyl group of the polypeptide of the above formula (3) is amidated with an amino group from the viewpoint of improving the binding property to pancreatic ⁇ cells and / or the stability in vivo.
  • the amino acid sequence of the above formula (1) (SEQ ID NO: 1 in the sequence listing) and formula (2) (SEQ ID NO: 2 in the sequence listing) is the amino acid sequence of exendin-4 except for the lysine residue labeled with a radionuclide. Matches.
  • the 1st to 39th amino acid sequences in the above formula (3) (SEQ ID NO: 3 in the sequence listing) are such that the N-terminal ⁇ -amino group is labeled with a radionuclide and the C-terminal carboxyl group. Except that is amidated, it matches the amino acid sequence of exendin-4.
  • Exendin-4 is a GLP-1 analog and is known to act as an agonist by binding to GLP-1R expressed in pancreatic ⁇ cells. Therefore, the molecular probe for imaging of the present invention can also bind to pancreatic islets, preferably bind to pancreatic ⁇ cells, and more preferably bind to GLP-1R of pancreatic ⁇ cells.
  • the molecular probe for imaging of the present invention is a polypeptide used for imaging, wherein one to several amino acids are deleted from the polypeptide of the above formula (1), (2) or (3).
  • An added or substituted polypeptide which may include a polypeptide capable of binding to an islet.
  • the one to several pieces are 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, and one piece. Can be included.
  • the polypeptide when the polypeptide has one to several amino acids deleted, added or substituted from the polypeptide of the above formula (1) or (2), It preferably contains one lysine to be labeled and contains amidation of the C-terminal carboxyl group, and the ⁇ -amino group at the N-terminus may be unmodified or charged. It may be modified with no modifying group.
  • the polypeptide of the formula (3) is a polypeptide in which one to several amino acids have been deleted, added or substituted
  • the N-terminal ⁇ -amino It is preferred that the group is labeled with a radionuclide and includes amidation of the C-terminal carboxyl group.
  • a polypeptide in which one to several amino acids are deleted, added or substituted from the polypeptide of the above formula (1), (2) or (3) is a polypeptide of the above formula (1), (2) or (3). It is preferable to have the same effect as the peptide, and more preferably to have the same effect as the polypeptide of the above formula (1).
  • the molecular probe for imaging of the present invention is a polypeptide used for imaging as another embodiment, which is 80% or more of the amino acid sequence of the polypeptide of the above formula (1), (2) or (3).
  • a polypeptide capable of binding to islets may be calculated by an algorithm usually used by those skilled in the art, for example, BLAST or FASTA.
  • the number of identical amino acid residues of two polypeptides to be compared is determined as one polypeptide. It may be based on the number obtained by dividing by the total length.
  • the homology may include 85% or more, 90% or more, or 95% or more.
  • the polypeptide when the polypeptide has 80% or more homology with the polypeptide of the above formula (1) or (2), lysine labeled with a radionuclide And the amidation of the C-terminal carboxyl group is preferred, and the ⁇ -amino group at the N-terminus may be unmodified or modified with a non-charged modifying group May be.
  • the N-terminal ⁇ -amino group when the polypeptide has the homology of 80% or more with the polypeptide of the above formula (3), the N-terminal ⁇ -amino group is a radionuclide. It is preferable to include amidation of a C-terminal carboxyl group.
  • polypeptide having 80% or more homology with the amino acid sequence of the polypeptide of the above formula (1), (2) or (3) is the same as the polypeptide of the above formula (1), (2) or (3) It is preferable to have the same effect as the polypeptide of the above formula (1).
  • amino group labeled with radionuclide The amino group of the side chain of the lysine residue represented by X in the amino acid sequences of the polypeptides of the above formulas (1) and (2), that is, the side chain of the twelfth lysine of the polypeptide of the above formula (1) And the amino group of the side chain of the 27th lysine of the polypeptide of the above formula (2) are labeled with a radionuclide.
  • the N-terminal ⁇ -amino group of the polypeptide of the above formula (3) is labeled with a radionuclide.
  • radionuclide examples include 11 C, 13 N, 15 O, 18 F, 64 Cu, 67 Ga, 68 Ga, 75 Br, 76 Br, 77 Br, 82 Rb, 99m Tc, 111 In, 123 I, and 124. I, 125 I, 131 I, and 186 Re.
  • the radionuclide is preferably a positron emitting nuclide such as 11 C, 13 N, 15 O, 18 F, 62 Cu, 64 Cu, 68 Ga, 75 Br, 76 Br, 82 Rb, and 124 I. .
  • the radionuclide is preferably a ⁇ -ray emitting nuclide such as 67 Ga, 99m Tc, 77 Br, 111 In, 123 I, and 125 I.
  • radioactive halogen nuclides such as 18 F, 75 Br, 76 Br, 77 Br, 123 I, and 124 I are more preferable, and 18 F, 123 I, and 124 I are particularly preferable.
  • the side chain amino group of lysine labeled with a radionuclide and the N-terminal ⁇ -amino group labeled with a radionuclide are preferably bonded to a group represented by the following formula (I).
  • a radionuclide to lysine using a group represented by the following formula (I)
  • the molecular probe for imaging of the present invention can be more specifically accumulated on the pancreatic islet, and preferably for imaging of the present invention.
  • Molecular probes can be more specifically accumulated in GLP-1R of pancreatic ⁇ cells.
  • A represents an aromatic hydrocarbon group or an aromatic heterocyclic group.
  • the aromatic hydrocarbon group is preferably an aromatic hydrocarbon group having 6 to 18 carbon atoms, such as a phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2,4-xylyl group, p- Cumenyl group, mesityl group, 1-naphthyl group, 2-naphthyl group, 1-anthryl group, 2-anthryl group, 9-anthryl group, 1-phenanthryl group, 9-phenanthryl group, 1-acenaphthyl group, 2-azurenyl group 1-pyrenyl group, 2-triphenylenyl group, o-biphenylyl group, m-biphenylyl group, p-biphenylyl group, terphenyl group and the like.
  • the aromatic heterocyclic group has 1 or 2 nitrogen atoms, oxygen atoms or sulfur atoms, and is preferably a 5- to 10-membered heterocyclic group.
  • R 1 represents a substituent containing a radionuclide.
  • the “substituent containing a radionuclide” means, for example, the above radionuclide, a C 1 -C 3 alkyl group substituted by the radionuclide, a C 1 -C 3 alkoxy group substituted by the radionuclide.
  • the “C 1 -C 3 alkyl group” means an alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, and a propyl group.
  • the “C 1 -C 3 alkyl group substituted by a radionuclide” refers to an alkyl group having 1 to 3 carbon atoms and a hydrogen atom substituted by the above radionuclide.
  • the “C 1 -C 3 alkoxy group” means an alkoxy group having 1 to 3 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, and a propoxy group.
  • the “C 1 -C 3 alkoxy group substituted by a radionuclide” means an alkoxy group having 1 to 3 carbon atoms and a hydrogen atom substituted by the above radionuclide.
  • R 1 is preferably a substituent containing a radioactive halogen, for example, a substituent containing 18 F, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I or 131 I is preferable.
  • R 1 is preferably a substituent containing a radionuclide that emits positron, for example, a substituent containing 18 F, 75 Br, 76 Br, or 124 I.
  • R 1 is preferably a substituent containing a radionuclide that emits gamma rays, for example, a substituent containing 77 Br, 99m Tc, 111 In, 123 I, or 125 I.
  • R 1 is preferably in the ortho position, the meta position, or the para position, and more preferably in the meta position or the para position.
  • R 2 represents a hydrogen atom or one or more substituents different from R 1 .
  • R 2 may be a hydrogen atom or a substituent, but is preferably a hydrogen atom. That is, in the above formula (I), A is preferably not substituted with a substituent other than R 1 .
  • R 2 is a plurality of substituents, they may be the same or different. Examples of the substituent include a hydroxyl group, an electron withdrawing group, an electron donating group, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, and the like.
  • Examples of the electron withdrawing group include a cyano group, a nitro group, a halogen atom, a carbonyl group, a sulfonyl group, an acetyl group, and a phenyl group.
  • Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “C 1 -C 6 alkyl group” means an alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl.
  • C 2 -C 6 alkenyl group refers to an alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group. 1-butenyl group, 2-butenyl group and 3-butenyl group.
  • C 2 -C 6 alkynyl group refers to an alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, and a 1-butynyl group.
  • the substituent is preferably a hydroxyl group or an electron withdrawing group.
  • R 3 is preferably a bond, a C 1 -C 6 alkylene group or a C 1 -C 6 oxyalkylene group.
  • C 1 -C 6 alkylene group means an alkylene group having 1 to 6 carbon atoms, such as methylene group, ethylene group, propylene group, butylene group, pentyl group, hexyl group. And a linear or branched alkylene group such as a group.
  • the “C 1 -C 6 oxyalkylene group” means an oxyalkylene group having 1 to 6 carbon atoms, such as oxymethylene group, oxyethylene group, oxypropylene group, oxybutylene.
  • R 3 is a bond from the viewpoint of the affinity between the molecular probe and the pancreatic islet, preferably the affinity between the molecular probe and the pancreatic ⁇ cell, more preferably the affinity between the molecular probe and the GLP-1R of the pancreatic ⁇ cell.
  • a methylene group and an ethylene group are preferable, and a bond is more preferable.
  • the affinity between the molecular probe for imaging of the present invention and pancreatic islets preferably the affinity between the molecular probe and pancreatic ⁇ cells, more preferably the GLP of the molecular probe and pancreatic ⁇ cells
  • A is a phenyl group
  • R 2 is a hydrogen atom
  • R 3 is a bond
  • A is a phenyl group
  • R 1 is [ 18 F] fluorine atom or [ 123/124/125/131 I] iodine atom
  • R 2 is a hydrogen atom
  • R 3 is a bond.
  • the group represented by the above formula (I) is preferably a group represented by the following formula (Ia), more preferably a group represented by the following formula (Ib) ([ 18 F] fluorobenzoyl group), A group represented by the formula (Ic) ([ 123 I] 3-iodobenzoyl group), a group represented by the following formula (Id) ([ 124 I] 3-iodobenzoyl group), and the following formula (Ie) A group ([ 125 I] 3-iodobenzoyl group) and a group represented by the following formula (If) ([ 131 I] 3-iodobenzoyl group).
  • R 1 is as described above.
  • the amino group of the side chain of lysine labeled with a radionuclide may be labeled with a metal nuclide via a chelate site capable of chelating a metal radioisotope (metal nuclide).
  • metal nuclide examples include 64 Cu, 67 Ga, 68 Ga, 82 Rb, 99m Tc, 111 In, and 186 Re.
  • Examples of the compound capable of forming a chelate site include diethylenetriaminepentaacetic acid (DTPA), 6-hydrazinopyridine-3-carboxylic acid (HYNIC), tetraazacyclododecanetetraacetic acid (DOTA), dithisosemicarbazone (DTS), diaminedithiol ( DADT), mercaptoacetylglycylglycylglycine (MAG3), monoamidemonoaminedithiol (MAMA), diamidedithiol (DADS), propylene diamine dioxime (PnAO) and the like.
  • DTPA diethylenetriaminepentaacetic acid
  • HYNIC 6-hydrazinopyridine-3-carboxylic acid
  • DTS dithisosemicarbazone
  • DADT diaminedithiol
  • MAG3 monoamidemonoaminedithiol
  • MAMA monoamidemonoaminedithiol
  • DADS diamided
  • the ⁇ -amino group at the N-terminus in the polypeptide of the above formula (1) or (2) cancels the positive charge of the ⁇ -amino group at the N-terminus
  • it may be modified with a modifying group having no charge.
  • the modifying group having no charge include 9-fluorenylmethyloxycarbonyl group (Fmoc), tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), 2,2,2-trichloroethoxy.
  • the modifying group is acetyl group, benzyl group, benzyloxymethyl group, o-bromobenzyloxycarbonyl group, t-butyl group, t-butyldimethylsilyl group, 2-chlorobenzyl group, 2,6-dichlorobenzyl group.
  • a cyclohexyl group, a cyclopentyl group, an isopropyl group, a pivalyl group, a tetrahydropyran-2-yl group, a tosyl group, a trimethylsilyl group and a trityl group are preferable, and an acetyl group is more preferable.
  • the molecular probe for imaging according to the present invention has, as another form, an N-terminal in the polypeptide represented by the above formula (1) (SEQ ID NO: 1) or the polypeptide represented by the above formula (2) (SEQ ID NO: 2).
  • a polypeptide having 1, 2, 3, 4, 5, 6 or 7 amino acids deleted from the side and capable of binding to an islet or a polypeptide having homology with the polypeptide A molecular probe for islet imaging comprising a polypeptide capable of binding, preferably consisting of the above polypeptide.
  • the amino group of the side chain of lysine corresponding to the 12th lysine of the polypeptide of the above formula (1) is labeled with a radionuclide.
  • the amino group of the side chain of lysine corresponding to the 27th lysine of the polypeptide of the above formula (2) is labeled with a radionuclide. ing.
  • the N-terminal ⁇ -amino group of the polypeptide may be unmodified or modified with a non-charged modifying group, and the C-terminal carboxyl group may be amidated. preferable.
  • the polypeptide having homology with the polypeptide includes the polypeptide represented by the above formula (1) (SEQ ID NO: 1) or the polypeptide represented by the above formula (2) (SEQ ID NO: 2) on the N-terminal side.
  • SEQ ID NO: 1 polypeptide represented by the above formula (1)
  • SEQ ID NO: 2 polypeptide represented by the above formula (2) (SEQ ID NO: 2) on the N-terminal side.
  • the molecular probe for imaging of the present invention 1, 2, 3, 4, 5, 6 or 7 from the N-terminal side in the polypeptide represented by the above formula (3) (SEQ ID NO: 3)
  • This is a molecular probe for islet imaging.
  • the ⁇ -amino group at the N-terminal of the polypeptide is labeled with a radionuclide.
  • the C-terminal carboxyl group is preferably amidated.
  • a polypeptide having homology with a polypeptide represented by the above formula (3) (SEQ ID NO: 3) from which 1, 2, 3, 4, 5, 6 or 7 amino acids have been deleted from the N-terminal side In the polypeptide represented by the above formula (3) (SEQ ID NO: 3), 1 to 2 from the polypeptide in which 1, 2, 3, 4, 5, 6 or 7 amino acids are deleted from the N-terminal side.
  • Polypeptides in which several amino acids have been deleted, added or substituted, and polypeptides having 80% or more homology with the amino acid sequences of the polypeptides are included.
  • the molecular probe for imaging according to the present invention is still another form of the polypeptide of the formula (1), (2) or (3) from 1 to 9, 1 to 8, 1 to 7, 1 to 6 from the C-terminal side.
  • a polypeptide having 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 amino acid deleted and capable of binding to an islet, or a polypeptide having homology with the polypeptide A molecular probe for islet imaging comprising a polypeptide that is capable of binding to an islet and is preferably composed of the above polypeptide.
  • the imaging molecular probe of this embodiment it is preferable to include amidation of the C-terminal carboxyl group, and the N-terminal ⁇ -amino group may be unmodified, or may be modified by an uncharged modifying group. It may be modified.
  • the molecular probe for imaging of the present invention can be used, for example, for islet imaging, preferably for pancreatic ⁇ -cell imaging, and more preferably for GLP-1R imaging of pancreatic ⁇ -cells.
  • the molecular probe for imaging of the present invention is preferably used for non-invasive islet imaging from the viewpoint of human examination / diagnosis, and from the same viewpoint, it may be used for islet imaging for quantifying the amount of islets. preferable.
  • the molecular probe for imaging of the present invention can be used for imaging for prevention, treatment or diagnosis of diabetes, for example.
  • the molecular probe for imaging of the present invention can be used, for example, as a composition, imaging reagent, contrast agent, diagnostic imaging agent, etc.
  • compositions, diagnostic imaging agents, etc. include, for example, solutions, powders, etc. In consideration of the half-life of radionuclides and decay of radioactivity, injection solutions are preferred.
  • Another aspect of the present invention is a precursor of an imaging molecular probe (hereinafter, also referred to as “molecular probe precursor”) for producing the imaging molecular probe of the present invention, which has the following formula (4), A polypeptide in which one to several amino acids are deleted, added or substituted from the polypeptide represented by (5) or (6), the polypeptide of the following formula (4), (5) or (6): A polypeptide capable of binding to an islet after labeling and deprotection, or a polypeptide having 80% or more homology with the amino acid sequence of the polypeptide of the following formula (4), (5) or (6)
  • the present invention relates to a molecular probe precursor for imaging comprising a polypeptide capable of binding to an islet after conversion and deprotection.
  • the molecular probe precursor of the present invention is 1 to several from the polypeptide represented by the above formula (4), (5) or (6), or the polypeptide of the above formula (4), (5) or (6).
  • a polypeptide in which the amino acid is deleted, added or substituted, and which can bind to the islet after labeling and deprotection, or the amino acid sequence of the polypeptide of the above formula (4), (5) or (6) It is preferably a molecular probe precursor for imaging consisting of a polypeptide having a homology of 80% or more and a polypeptide that can bind to islets after labeling and deprotection.
  • the amino acid sequence of the polypeptide of the above formula (4) is the amino acid sequence shown in SEQ ID NO: 4 in the sequence listing, and the amino group of the side chain of the 27th lysine of the polypeptide of the above formula (4) has amino A protecting group for protecting the group is bonded, and a protecting group for protecting the amino group or a modifying group for modifying the amino group is bonded to the N-terminal ⁇ -amino group.
  • the amino acid sequence of the polypeptide of the above formula (5) is the amino acid sequence shown in SEQ ID NO: 5 in the sequence listing, and the amino group of the side chain of the twelfth lysine of the polypeptide of the above formula (5) has amino A protecting group for protecting the group is bonded, and a protecting group for protecting the amino group or a modifying group for modifying the amino group is bonded to the N-terminal ⁇ -amino group.
  • the molecular probe precursor of the present invention containing the polypeptide of the above formula (4) or the polypeptide of the above formula (5) is labeled with a labeling system for labeling the amino group described later, lysine that is not protected by a protecting group
  • the side chain amino groups can be labeled.
  • the side chain amino group of the 12th lysine is labeled
  • the side chain amino group of the 27th lysine is Can be labeled.
  • the ⁇ -amino group at the N-terminus of the polypeptides of the above formulas (4) and (5) is bonded to a protecting group to protect the amino group, or is a modified group having no charge. It is qualified.
  • the amino acid sequence of the polypeptide of the above formula (6) is the amino acid sequence shown in SEQ ID NO: 6 in the sequence listing, and the amino group of the side chain of the 12th lysine of the polypeptide of the above formula (6) and the 27th A protecting group for protecting the amino group is bonded to the amino group of the side chain of the second lysine.
  • the molecular probe precursor of the present invention containing the polypeptide of the above formula (6) is labeled with a labeling system for labeling the amino group described below, the N-terminal ⁇ -amino group not protected by the protecting group is labeled. Can be done.
  • the C-terminal carboxyl group of the polypeptides of the above formulas (4), (5) and (6) may be converted to an amide by an amino group from the viewpoint of improving binding to pancreatic ⁇ cells and / or stability in vivo. It has become.
  • the C-terminal amidated carboxyl group of the polypeptides of the above formulas (4), (5) and (6) has a protective group or a further modifying group bonded thereto. Alternatively, they may not be bonded, and preferably they are not bonded. However, the present invention does not exclude a form in which protection by a protecting group or a further modifying group is added.
  • amino acid sequences of the above formula (4) (SEQ ID NO: 4 in the sequence listing) and the above formula (5) (SEQ ID NO: 5 in the sequence listing) except for the protecting group bonded to the amino group of the side chain of lysine.
  • amino acid sequence of exendin-4 Consistent with the amino acid sequence of exendin-4.
  • amino acid sequence of the above formula (6) (SEQ ID NO: 6 in the sequence listing) is identical to the amino acid sequence of exendin-4, except for the protecting group bonded to the amino group of the side chain of lysine.
  • the protecting group protects other amino groups of the molecular probe precursor while labeling the side chain amino group of the desired lysine or the ⁇ -amino group at the N-terminus, and performs such a function. Any known protecting group can be used.
  • the protecting group is not particularly limited, and for example, 9-fluorenylmethyloxycarbonyl group (Fmoc), tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), 2,2,2-trichloroethoxy Carbonyl group (Troc), allyloxycarbonyl group (Alloc), 4-methoxytrityl group (Mmt), amino group, alkyl group of 3 to 20 carbons, 9-fluoreneacetyl group, 1-fluorenecarboxylic acid group, 9 -Fluorenecarboxylic acid group, 9-fluorenone-1-carboxylic acid group, benzyloxycarbonyl group, xanthyl group (Xan), trityl group (Trt), 4-methyltrityl group (Mtt), 4-methoxy2,3,6 -Trimethyl-benzenesulfonyl group (Mtr), mesitylene-2-sulf
  • a protecting group is bonded to the polypeptide of the above formula (4) or the polypeptide of the above formula (5).
  • a chelate moiety capable of chelating a metal radioisotope (metal nuclide) may be bound to the amino group of the side chain of lysine.
  • a chelate site capable of chelating a metal radioisotope (metal nuclide) may be bound to the N-terminal ⁇ -amino group.
  • the compound capable of forming the metal nuclide and the chelate moiety is as described above.
  • the molecular probe precursor of the present invention has an N-terminal in the polypeptide represented by the above formula (4) (SEQ ID NO: 4) or the polypeptide represented by the above formula (5) (SEQ ID NO: 5).
  • a polypeptide having 1, 2, 3, 4, 5, 6 or 7 amino acids deleted from the side and capable of binding to an islet after labeling and deprotection or a polypeptide having homology with the polypeptide It includes a polypeptide that can bind to islets after labeling and deprotection, and preferably consists of the above polypeptide.
  • the 27th of the polypeptide of the above formula (4) A protecting group for protecting the amino group is bonded to the amino group of the side chain of lysine corresponding to lysine, and a protecting group or amino group for protecting the amino group is attached to the ⁇ -amino group at the N-terminus.
  • a modifying group for modifying is bonded.
  • the twelfth polypeptide of the above formula (5) in which the 1, 2, 3, 4, 5, 6 or 7 amino acids are deleted from the N-terminal side, the twelfth polypeptide of the above formula (5) A protecting group for protecting the amino group is bonded to the amino group of the side chain of lysine corresponding to lysine, and a protecting group or amino group for protecting the amino group is attached to the ⁇ -amino group at the N-terminus.
  • a modifying group for modifying is bonded.
  • the polypeptide having homology with the polypeptide includes the polypeptide represented by the above formula (4) (SEQ ID NO: 4) or the polypeptide represented by the above formula (5) (SEQ ID NO: 5) on the N-terminal side.
  • the molecular probe precursor of the present invention is 1, 2, 3, 4, 5, 6 or 7 from the N-terminal side in the polypeptide represented by the above formula (6) (SEQ ID NO: 6).
  • a polypeptide that lacks the amino acid and can bind to islets after labeling and deprotection, or a polypeptide that is homologous to the polypeptide and that can bind to islets after labeling and deprotection Preferably comprising the above polypeptide.
  • the twelfth polypeptide of the above formula (6) A protecting group for protecting the amino group is bonded to the amino group of the side chain of lysine corresponding to lysine and the amino group of the side chain of lysine corresponding to the 27th lysine.
  • a polypeptide having homology with a polypeptide represented by the above formula (6) (SEQ ID NO: 6) from which 1, 2, 3, 4, 5, 6 or 7 amino acids have been deleted from the N-terminal side In the polypeptide represented by the above formula (6) (SEQ ID NO: 6), 1 to 2 from the polypeptide in which 1, 2, 3, 4, 5, 6 or 7 amino acids are deleted from the N-terminal side.
  • Polypeptides in which several amino acids have been deleted, added or substituted, and polypeptides having 80% or more homology with the amino acid sequences of the polypeptides are included.
  • the present invention relates to a method for producing a molecular probe for imaging, which includes labeling and deprotecting the molecular probe precursor of the present invention. According to the production method of the present invention, the molecular probe for imaging of the present invention can be produced.
  • the molecular probe precursor of the present invention can be produced by peptide synthesis according to a conventional method such as the Fmoc method, and the peptide synthesis method is not particularly limited.
  • the labeling can be performed on the molecular probe precursor of the present invention by an imaging method and / or a known method corresponding to the radionuclide.
  • the labeling may be performed, for example, by binding a radionuclide to a compound capable of binding to the amino group of the side chain of lysine, and using this to bind the radionuclide to the molecular probe precursor of the present invention.
  • only the nuclide may be bound to the molecular probe precursor of the present invention.
  • Deprotection can be performed by a known method according to the type of the protecting group.
  • the labeling of the molecular probe precursor is performed using 11 C, 13 N, 15 O, 18 F, 64 Cu, 67 Ga, 68 Ga, 75 Br, 76 Br, 77 Br, 99m Tc, 111 In, 123 I, 124 I.
  • the method comprises labeling the imaging molecular probe precursor of the present invention with a compound containing a radionuclide of 125 I, 131 I or 186 Re.
  • the labeling of the molecular probe precursor preferably includes labeling the molecular probe precursor of the present invention using a compound having a group represented by the following formula (I).
  • A, R 1 , R 2 and R 3 are as described above.
  • the compound having a group represented by the above formula (I) is a succinimidyl ester compound in which the group represented by the above formula (I) is bonded to succinimide via an ester bond from the viewpoint of labeling efficiency.
  • it is a succinimidyl ester compound represented by the following formula (II).
  • the affinity with pancreatic islets preferably with pancreatic ⁇ cells, more preferably with pancreatic ⁇ cells with GLP-1R
  • A is a phenyl group
  • R 2 is a hydrogen atom
  • R 3 is a bond
  • A is a phenyl group
  • R 1 is a [ 18 F] fluorine atom
  • R 2 is a hydrogen atom
  • R 3 is a bond.
  • the compound having a group represented by the above formula (I) is preferably a succinimidyl ester compound represented by the following formula (II), more preferably a succinimidyl ester represented by the following formula (IIa).
  • A, R 1 , R 2 and R 3 are the same as in the above formula (I), and in the following formula (IIa), R 1 is the same as in the above formula (I).
  • the labeling compound used for labeling is, for example, in the above formula (IIa) where R 1 is [ 123/124/125/131 I]
  • a compound which is an iodine atom is preferable, and more preferably, R 1 is [ 123/124/125/131 I] an iodine atom which is bonded to the 3 position (meta position), specifically, [ 123 I] N-succinimidyl 3-iodobenzoate , [124 I] N-succinimidyl3-iodobenzoate, [125 I] N-succinimidyl3-iodobenzoate, or [131 I] N-succinimidyl3- iodobenzoate and the like are preferable.
  • the method for producing a molecular probe for imaging of the present invention further comprises a step of synthesizing a compound having a group represented by the above formula (I), preferably a compound having a group represented by the above formula (II). May be.
  • the compound used for labeling can be synthesized, for example, using an automatic synthesizer.
  • the method for producing a molecular probe for imaging of the present invention may further comprise a step of producing the molecular probe precursor of the present invention, and further, synthesis of a compound having a group represented by the above formula (I),
  • labeling and deprotection of the molecular probe precursor using the labeling compound may be performed by one automatic synthesizer.
  • a protected amino acid in which an N-terminal ⁇ -amino group and / or a side chain functional group is protected by a protecting group is represented by the following formula (20): Synthesizing a polypeptide having the amino acid sequence shown, deprotecting the side chain amino group of lysine that is not radiolabeled in the synthesized polypeptide (deprotection 1), and before deprotecting the deprotected amino group Reprotecting with a protecting group different from the protecting group of lysine, deprotecting the side chain amino group of lysine or the N-terminal ⁇ -amino group for radiolabeling in the deprotected and reprotected polypeptide (Deprotection 2), a method for producing a molecular probe for imaging, comprising radiolabeling a deprotected amino group, and deprotecting a radiolabeled polypeptide To.
  • lysine that is not radiolabeled in deprotection 1 is deprotected
  • lysine or N-terminal ⁇ -amino group that is radiolabeled in deprotection 2 is deprotected.
  • Examples of combinations of lysine or N-terminal ⁇ -amino groups to be deprotected in deprotection 1 and deprotection 2 are as follows.
  • a target amino group an amino group at the side chain of lysine or an ⁇ -amino group at the N-terminus
  • the labeling efficiency can be improved, and the yield of the desired radiolabeled peptide can be improved.
  • Peptide synthesis can be performed using, for example, a known organic chemical peptide synthesis method.
  • a known organic chemical peptide synthesis method For example, “Biochemistry Experiment Course” edited by the Japanese Biochemical Society, Volume 1, “Protein IV”, 207- 495 (published by Tokyo Kagaku Dojin in 1977), edited by The Japan Biochemical Society, “New Chemistry Laboratory”, Volume 1, “Protein VI”, pages 3-74 (1992, published by Tokyo Kagaku Doujin) This can be done based on the description.
  • Examples of the organic chemical peptide synthesis method include a peptide solid phase synthesis method and a peptide liquid phase synthesis method, and a peptide solid phase synthesis method is preferable.
  • the “peptide solid-phase synthesis method” refers to a method in which the C-terminal of an amino acid or peptide is fixed to a solid-phase carrier via a linker, and the amino acids are sequentially extended to the N-terminal side.
  • Examples of the peptide solid phase synthesis method include the Fmoc method and the Boc method, and the Fmoc method is preferred.
  • the “Fmoc method” is a method of synthesizing a peptide by using amino acids in which the N-terminal ⁇ -amino group is protected by Fmoc (9-fluorenylmethyloxycarbonyl group) and condensing them. I mean.
  • an amino acid corresponding to the C-terminus of each peptide to be synthesized or a peptide containing an amino acid corresponding to the C-terminus is bound to a solid phase carrier such as a resin, which is a protective group for the ⁇ -amino group at the N-terminus
  • a solid phase carrier such as a resin
  • the peptide of interest can be synthesized by repeatedly deprotecting and washing the Fmoc group and condensing and washing the protected amino acid to elongate the peptide chain and finally carry out a final deprotection reaction.
  • Peptide synthesis may be performed using, for example, an automatic peptide synthesizer. Examples of the peptide automatic synthesizer include A443A type (Applied Biosystems), PSSM8 (Shimadzu Corporation), and the like.
  • Fmoc-amino acid derivatives used in ordinary Fmoc-peptide synthesis methods can be used as protected amino acids used in peptide synthesis.
  • the functional groups are protected by protective groups depending on the type of functional group.
  • amino acids whose N-terminal ⁇ -amino group is protected by Fmoc can be used, and for other amino acids, amino acids whose N-terminal ⁇ -amino group is protected by Fmoc can be used.
  • a lysine to be deprotected by deprotection 1 (lysine not radioactively labeled)
  • an amino group on the side chain of lysine that serves as a radioactive labeling site or a protecting group for the ⁇ -amino group at the N-terminus It is preferable to use lysine in which the amino group of the side chain is protected by a different protecting group.
  • a lysine protected by a carbamate-based protecting group other than Fmoc is used as a lysine to be a radiolabeled site
  • a lysine in which the amino group of the side chain is protected by a trityl-type protecting group as a lysine to be deprotected by deprotection 1 May be used.
  • carbamate-based protecting groups other than Fmoc include Boc, Cbz, Alloc, Troc, etc. Among them, Boc is preferable.
  • the trityl-type protecting group include Mmt, Trt, Mtt, Mtr and the like. From the viewpoint of more selective deprotection, Mmt and Mtt are preferable.
  • Deprotection 1 is preferably performed without deprotecting the amino group of the side chain of lysine that is deprotected by deprotection 2, for example.
  • the lysine to be deprotected by deprotection 1 is Lys27, selectively deprotect only the amino group of the lysine side chain of Lys27 without deprotecting functional groups other than the amino group of the side chain of Lys27. Is preferred.
  • the protecting group of the amino group on the side chain of lysine to be deprotected is a trityl-type protecting group, for example, the trityl-type protecting group can be selectively removed by subjecting the objective group to mildly acidic conditions.
  • the amino group on the side chain of lysine can be deprotected.
  • the reagent under weakly acidic conditions include a reagent containing trifluoroacetic acid.
  • the re-protection includes, for example, protecting the amino group of the deprotected lysine side chain with a protecting group different from the removed protecting group, and preferably the N-terminal ⁇ -amino group used for peptide synthesis.
  • Protecting with a protecting group more preferably protecting with Fmoc.
  • Fmoc can be introduced, for example, by reacting the Fmoc reagent with the deprotected lysine side chain amino group in the presence of an amine.
  • the Fmoc reagent include N- (9-fluorenylmethoxycarbonyloxy) succinimide (Fmoc-OSu), 9-fluorenylcarbinyl chloride (Fmoc-Cl), and the like.
  • the N-terminal ⁇ -amino group of the polypeptide may be deprotected and reprotected as necessary.
  • deprotection 2 is performed, whereby a probe precursor for performing radiolabeling can be obtained.
  • Deprotection 2 only needs to deprotect at least the amino group serving as the radiolabeling site.
  • the side chain of lysine deprotected with deprotection 1 is preferably used. It is preferable to deprotect an amino group and, if necessary, a functional group other than the N-terminal ⁇ -amino group.
  • the polypeptide (probe precursor) represented by the formulas (4) to (6) can be obtained.
  • Deprotection can be performed according to a known method depending on the type of protecting group to be deprotected.
  • the deprotection is performed together with the excision of the peptide from the solid phase carrier.
  • the protecting group may be deprotected under the conditions for excision from the solid phase carrier.
  • the polypeptide to be radiolabeled (probe precursor) has a target amino group (an amino group on the side chain of lysine or N) because the amino group to be radiolabeled is deprotected and other amino groups are protected. Only the terminal ⁇ -amino group) can be selectively radiolabeled.
  • Radiolabeling can be performed according to a known method depending on the polypeptide to be radiolabeled. Although it does not restrict
  • the chelate compound etc. which can chelate the labeled compound which has group represented by the formula (I) mentioned above, and a metal radioisotope (metal nuclide), etc. are mentioned.
  • the metal nuclide include 64 Cu, 67 Ga, 68 Ga, 82 Rb, 99m Tc, 111 In, and 186 Re.
  • the chelate compound include DTPA, HYNIC, DOTA, DTS, DADT, MAG3, MAMA, DADS, PnAO, and the like.
  • the labeled compound is preferably a labeled compound having a group represented by the above formula (I), more preferably a succin represented by the above formula (II). It is an imidyl ester compound, more preferably a succinimidyl ester compound represented by the above formula (IIa).
  • the remaining protecting groups of the polypeptide after radiolabeling are removed.
  • the polypeptide by which the 1st target amino group was radiolabeled can be manufactured.
  • Deprotection can be carried out according to a known method depending on the kind of the protecting group.
  • the protecting group is Fmoc
  • the deprotection can be performed, for example, under piperidine conditions.
  • the method for producing a molecular probe for imaging according to the present invention may further include a purification step and the like from the viewpoint of producing a radiolabeled high-purity peptide.
  • the purification step can be performed, for example, between deprotection 2 and the radiolabel, between the radiolabel and subsequent deprotection (final deprotection), and after the final deprotection.
  • the method for producing a molecular probe for imaging of the present invention includes, for example, a step of modifying the ⁇ -amino group at the N-terminus of a radiolabeled polypeptide with a non-charged modifying group, A step of amidation may be included.
  • the present invention relates to a method for imaging pancreatic islets including imaging pancreatic islets using the molecular probe for imaging of the present invention. Furthermore, the present invention, as yet another aspect, relates to a method for imaging pancreatic islets including detecting a signal of the molecular probe for imaging from a subject administered with the molecular probe for imaging of the present invention. According to the imaging method of the present invention, pancreatic islets, preferably pancreatic ⁇ cells, can be imaged because the molecular probe for imaging of the present invention is used.
  • the imaging method of the present invention is performed by detecting a signal of the imaging molecular probe from a subject administered with the imaging molecular probe of the present invention after a lapse of a certain time from the administration of the molecular probe for imaging of the present invention.
  • a signal of the imaging molecular probe from a subject administered with the imaging molecular probe of the present invention after a lapse of a certain time from the administration of the molecular probe for imaging of the present invention.
  • Can do. Examples of the subject include humans and / or mammals other than humans.
  • the detection of the signal of the molecular probe for imaging includes, for example, detecting the signal of the radionuclide used for labeling the molecular probe for imaging.
  • the imaging method of the present invention may include reconstructing the detected signal and converting it to an image, and may further include displaying the converted image.
  • signal detection can be appropriately determined according to the type of radionuclide of the molecular probe to be used, and can be performed by, for example, measurement using PET, measurement using SPECT, or the like.
  • the measurement using SPECT includes, for example, measuring ⁇ rays emitted from a subject administered with the molecular probe for imaging of the present invention with a gamma camera.
  • the measurement by the gamma camera includes, for example, measuring the radiation ( ⁇ rays) emitted from the radionuclide used for labeling the molecular probe for imaging of the present invention in a certain time unit, and preferably the radiation is emitted. Including measuring the direction and quantity of radiation in fixed time units.
  • the imaging method of the present invention may further include representing the distribution of the molecular probe for imaging of the present invention obtained by measurement of radiation as a cross-sectional image and reconstructing the obtained cross-sectional image. .
  • the measurement using PET includes, for example, simultaneously counting gamma rays generated by pair annihilation of positron and electrons from a subject administered with the molecular probe for imaging of the present invention with a PET detector. It may include describing a three-dimensional distribution of the position of the radionuclide that emits the positron based on the measured result.
  • measurement by X-ray CT or MRI may be performed together with SPECT measurement or PET measurement.
  • SPECT or an image obtained by PET functional image
  • CT or an image obtained by MRI morphological image
  • the imaging method of the present invention may further include determining the islet state from the result of imaging using the molecular probe for imaging of the present invention.
  • Determining the state of islets from the results of islet imaging using a molecular probe includes, for example, determining the presence or absence of islets by analyzing an image of islet imaging, determining increase or decrease in the amount of islets.
  • the imaging method of the present invention may include administering the imaging molecular probe of the present invention to a subject.
  • administration of the molecular probe for imaging of the present invention to a subject it is preferable to administer an amount sufficient to obtain a desired contrast for imaging.
  • Administration to a subject may be local or systemic.
  • the administration route can be appropriately determined according to the condition of the subject, and examples thereof include intravenous, arterial, intradermal, intraperitoneal injection or infusion.
  • the molecular probe for imaging of the present invention is preferably administered together with a pharmaceutical additive such as a carrier.
  • a pharmaceutical additive refers to a compound that has been approved as a pharmaceutical additive in the Japanese Pharmacopoeia, the American Pharmacopoeia, the European Pharmacopoeia, and the like.
  • the carrier for example, an aqueous solvent and a non-aqueous solvent can be used.
  • the aqueous solvent include potassium phosphate buffer, physiological saline, Ringer's solution, distilled water and the like.
  • the non-aqueous solvent include polyethylene glycol, vegetable oil, ethanol, glycerin, dimethyl sulfoxide, propylene glycol and the like.
  • the dose of the molecular probe for imaging of the present invention for islet imaging or islet amount measurement can be, for example, 1 ⁇ g or less.
  • the time from administration to measurement can be appropriately determined according to, for example, the binding time of the molecular probe to the islet, the type of the molecular probe, the decomposition time of the molecular probe, and the like.
  • the present invention further comprises detecting the signal of the molecular probe for imaging from a subject administered with the molecular probe for imaging of the present invention, and determining the amount of islets from the signal of the detected molecular probe for imaging.
  • the present invention relates to a method for measuring an islet amount including calculating.
  • this invention relates to the measuring method of an islet amount including imaging an islet amount using the molecular probe for imaging of this invention as another aspect, and calculating an islet amount from an imaging result.
  • the amount of islet can be calculated, for example, by analyzing the amount of the detected signal, the imaging image obtained by reconstructing the signal, and the like. Further, it is possible for a person skilled in the art to quantify the object to be imaged from the result of imaging, for example, using a calibration curve or an appropriate program.
  • the imaging object is, for example, an islet, preferably a pancreatic ⁇ cell, more preferably a GLP-1R of pancreatic ⁇ cell.
  • the method for measuring the amount of pancreatic islets according to the present invention is preferably a method for measuring the amount of pancreatic ⁇ cells from the viewpoint of use for examination and diagnosis.
  • the method for measuring the amount of islet according to the present invention may further include presenting the calculated amount of islet.
  • Presenting the calculated amount of islets includes, for example, storing or outputting the calculated amount of islets to the outside.
  • Outputting to the outside includes, for example, displaying on a monitor and printing.
  • the present invention relates to a method for preventing or treating or diagnosing diabetes.
  • the amount of islets (especially the amount of ⁇ -cells in the pancreas) decreases prior to abnormal glucose tolerance in the onset of diabetes, but diabetes has already been treated after reaching the stage where functional abnormalities are detected and recognized. Is at a difficult stage.
  • a decrease in the amount of pancreatic islets and / or pancreatic ⁇ cells can be detected at an early stage. Diabetes prevention / treatment / diagnosis can be established. Examples of the subject for prevention / treatment / diagnosis of diabetes include humans and / or mammals other than humans.
  • the method for diagnosing diabetes according to the present invention includes imaging an islet using the molecular probe for imaging according to the present invention, and determining the state of the islet based on the obtained islet image and / or islet amount. Furthermore, it may include performing a diagnosis of diabetes based on the determination result.
  • the determination of the islet state is performed by, for example, comparing the obtained islet image with the reference islet image, comparing the obtained islet amount with the reference islet amount, and the like. Including determining an increase or decrease or change.
  • the state of the islets may be determined using an information processing apparatus. When it is determined that the amount of islets is decreasing, the information is presented and it is determined that the amount of islets is increased or maintained. Sometimes it is preferable to present that information.
  • Diagnosis of diabetes based on the determination result includes, for example, determining the risk of developing diabetes, determining that it is diabetes, determining the degree of progression of diabetes, and the like.
  • the method for treating diabetes according to the present invention comprises imaging pancreatic islets using the molecular probe for imaging according to the present invention, and determining the state of the islets based on the obtained islet image and / or islet amount. Performing a diagnosis and treating diabetes based on the diagnosis. The determination of the islet state and the diagnosis of diabetes can be performed in the same manner as in the method for diagnosing diabetes of the present invention.
  • the method for treating diabetes according to the present invention can include evaluating a therapeutic effect including medication and diet therapy performed on a subject by paying attention to a change in islet amount.
  • the method for preventing diabetes according to the present invention comprises performing imaging of islets using the molecular probe for imaging according to the present invention, and determining the state of the islets based on the obtained islet image and / or amount of islets and developing diabetes. Including determining the risk.
  • the method for preventing diabetes according to the present invention can include, for example, periodically measuring the amount of islets and checking for a tendency to decrease the amount of islets.
  • the present invention relates to a method for ultra-early diagnosis of diabetes as another preferred embodiment.
  • the ultra-early diagnosis method for diabetes according to the present invention includes, for example, a human dock, imaging of islets and / or measurement of islet amount by the method of the present invention in a health check, and an image of the obtained islet and / or islet amount. Determining the state of the islets based on.
  • the method for treating diabetes according to the present invention comprises performing islet imaging and / or measurement of islet amount by the method of the present invention, and restoring the function of the islet based on the obtained islet image and / or islet amount. It can include evaluating.
  • the present invention relates to a kit including the molecular probe for imaging of the present invention.
  • the kit of the present embodiment include a kit for performing the imaging method of the present invention, a kit for performing the method for measuring an islet amount of the present invention, a kit for preventing or treating or diagnosing diabetes of the present invention, and the like. It is done.
  • the molecular probe for imaging of the present invention is preferably included in the form of an injection solution. Therefore, the kit of the present invention preferably includes an injection solution containing the molecular probe for imaging of the present invention.
  • the injection solution contains the molecular probe for imaging of the present invention as an active ingredient, and may further contain a pharmaceutical additive such as a carrier.
  • Pharmaceutical additives and carriers are as described above.
  • the kit of the present invention may further include a container for containing the molecular probe for imaging of the present invention, and the injection liquid containing the molecular probe for imaging of the present invention and / or the molecular probe for imaging of the present invention is a container. It may be filled. Examples of the container include a syringe and a vial.
  • the kit of the present invention can further include, for example, components for preparing a molecular probe such as a buffer and an osmotic pressure regulator, and instruments used for administration of the molecular probe such as a syringe.
  • components for preparing a molecular probe such as a buffer and an osmotic pressure regulator
  • instruments used for administration of the molecular probe such as a syringe.
  • the present invention relates to an imaging reagent including the molecular probe for imaging of the present invention.
  • the imaging reagent of the present invention contains the molecular probe for imaging of the present invention as an active ingredient, and may further contain, for example, a pharmaceutical additive such as a carrier.
  • the carrier is as described above.
  • the present invention relates to a kit containing the molecular probe precursor.
  • kits containing the molecular probe precursor of the present invention include a kit for preparing the molecular probe for imaging of the present invention, a kit for performing the imaging method of the present invention, and a method for measuring the amount of islets of the present invention.
  • a kit for the prevention, treatment or diagnosis of diabetes of the present invention preferably includes an instruction manual according to each form.
  • the form of the molecular probe precursor of the present invention contained in the kit is not particularly limited, and examples thereof include solutions and powders. From the viewpoint of handling, powders are preferable, and lyophilized powders (lyophilized) Formulation).
  • the kit containing the molecular probe precursor of the present invention is, for example, a compound used for labeling a molecular probe precursor for imaging, and may contain a compound having a group represented by the above formula (I).
  • the compound having a group represented by the above formula (I) is preferably a succinimidyl ester compound in which the group represented by the above formula (I) is bonded to succinimide via an ester bond, and more preferably A succinimidyl ester compound represented by the formula (II), more preferably a succinimidyl ester compound represented by the formula (IIa).
  • the kit of the embodiment preferably contains [ 18 F] N-succinimidyl 4-fluorobenzoate or a starting material of [ 18 F] N-succinimidyl 4-fluorobenzoate as a labeling compound.
  • the starting material include ethyl 4- (trimethylammonium triflate) benzoate, ethyl 4- (tosyloxy) benzoate, ethyl 4- (methylsulfonyloxy) benzoate, and the like.
  • the kit of this embodiment may further include, for example, an instruction manual describing a method for labeling the molecular probe precursor of the present invention using the above compound.
  • the kit containing the molecular probe precursor of the present invention comprises [ 123 I] N-succinimidyl 3-iodobenzoate, [ 124 I] N-succinimidyl 3-iodobenzoate, [ 125 I] N-succinimidyl 3-iodobenzoate, and / or [ 131 I]. It preferably contains a labeled compound such as N-succinimidyl3-iodobenzoate and a starting material for the labeled compound.
  • starting materials include 2,5-dioxopyrrolidin-1-yl 3- (tributylstannyl) benzoate, 2,5-dioxopyrrolidin-1-yl 3-bromobenzoate, 2,5-dioxopyrrolidin-1-yl 3-chlorobenzoate, and 2,5-dioxopyrrolidin-1-yl 3-iodobenzoate and the like.
  • the kit containing the molecular probe precursor of the present invention may further contain, for example, a reagent used for deprotection of the molecular probe for imaging and / or a reagent used for labeling.
  • the kit containing the molecular probe precursor of the present invention further includes, for example, an automatic synthesis apparatus for a labeled compound and a compound having a group represented by the above formula (I) using the automatic synthesis apparatus for the labeled compound. Instructions describing the method may be included.
  • the automatic synthesizer may be an automatic synthesizer capable of labeling and deprotecting a molecular probe precursor using the synthesized labeled compound in addition to the synthesis of the labeled compound.
  • the kit may further contain a reagent containing a radionuclide used for the synthesis of the labeled compound.
  • reagent containing a radionuclide examples include 11 C, 13 N, 15 O, 18 F, 64 Cu, 67 Ga, 68 Ga, 75 Br, 76 Br, 77 Br, 99m Tc, 111 In, 123 I, and 124.
  • reagent containing a radioisotope such as I, 125 I, 131 I or 186 Re.
  • the present invention provides an automatic peptide synthesizer for synthesizing the molecular probe precursor of the present invention, and an automatic synthesis of a compound having a group represented by the above formula (I) and / or a labeled compound. It relates to a kit comprising the device.
  • the automatic synthesizer may be an automatic synthesizer capable of labeling and deprotecting a molecular probe precursor using the synthesized labeled compound in addition to the synthesis of the labeled compound.
  • the kit may include an instruction manual describing a method for synthesizing the molecular probe precursor of the present invention.
  • the instruction manual may further describe, for example, a method for synthesizing a compound having a group represented by the above formula (I), a labeling method using the compound, a deprotection method, and the like.
  • the kit may further contain a reagent containing a radionuclide used for the synthesis of the labeled compound.
  • the synthesis of the molecular probe precursor of the present invention relates to a kit including an instruction manual describing a method for producing a molecular probe for imaging of the present invention using an automatic synthesizer.
  • the instruction manual preferably describes, for example, a method for synthesizing the molecular probe precursor, a method for synthesizing the labeled compound, a method for labeling and deprotecting the molecular probe precursor using the labeled compound, and the like.
  • the kit may further contain a reagent containing a radionuclide used for the synthesis of the labeled compound.
  • the amino acid sequence of the above formula (1) (SEQ ID NO: 1 in the sequence listing) and formula (2) (SEQ ID NO: 2 in the sequence listing) is the amino acid sequence of exendin-4 except for the lysine residue labeled with a radionuclide. Matches.
  • the amino acid sequence of the above formula (3) (SEQ ID NO: 3 in the sequence listing) is identical to the amino acid sequence of exendin-4 except that the C-terminal carboxyl group is amidated.
  • Exendin-4 is a GLP-1 analog and is known to bind to GLP-1R expressed on pancreatic ⁇ cells.
  • the molecular probe containing the polypeptide represented by the above formulas (1) to (3) and a polypeptide having homology with the polypeptide can bind to GLP-1R, and preferably binds to GLP-1R. Since it can bind specifically, it can be used, for example, for imaging and quantification of GLP-1R positive cells, diagnosis and treatment of diseases involving GLP-1R expression, and the like. Therefore, the “islet” described above in this specification can be read as a GLP-1R-positive cell, and the imaging and quantification of GLP-1R-positive cells, GLP-1R, Diagnosis and treatment of diseases involving the expression of can be performed. Examples of diseases involving GLP-1R expression include neuroendocrine tumors (NET). Examples of neuroendocrine tumors include insulinoma, small cell bronchial cancer, pancreatic cancer and the like.
  • NET neuroendocrine tumors
  • neuroendocrine tumors include insulinoma, small cell bronchial cancer, pancreatic cancer and the like.
  • Example 1 [Preparation of molecular probe] The molecular probe of the following formula (7), wherein the amino group of the side chain of the 12th lysine residue of SEQ ID NO: 1 is labeled with [ 18 F] fluorobenzoyl group and the C-terminal carboxyl group is amidated (SEQ ID NO: 7) was prepared.
  • the synthesis of the polypeptide was performed according to the attached software using an automated peptide synthesizer (433A type) manufactured by Applied Biosystems.
  • the amino acids having functional groups in the side chains are His (Trt), Asp (OBu), Ser (OBu), Lys (Boc), Gln (Trt), Glu (OBu), Arg (Pbf), Asn (Trt), respectively. ), Trp (Boc) was used.
  • Lys (Mmt) was used as the 27th lysine.
  • Rink Amide MBHA (0.125 mmol, 0.34 mmol / g) as a starting resin, amino acids were sequentially extended according to the sequence to obtain a polypeptide having the sequence of the following formula (8).
  • the side chain protecting group of the 27th lysine residue was obtained from the polypeptide of the above formula (8) by a conventional treatment using 1.5% TFA-5% TIS-93.55% CH 2 Cl 2. (Mmt group) was removed, and the amino group in the side chain of the released 27th lysine residue was converted to Fmoc.
  • the obtained molecular probe precursor (560 ⁇ g) of the above formula (9) is dissolved in Borate Buffer (pH 7.8), and [ 18 F] N-succinimidyl 4-fluorobenzoate ([ 18 F] SFB) is added to the reaction.
  • the solution was adjusted to pH 8.5 to 9.0 for labeling. Thereafter, DMF and Piperidine were added to perform a deprotection reaction, and the molecular probe of the above formula (7) (a molecular probe labeled with the 12th lysine residue of SEQ ID NO: 1) was obtained. .
  • the N-terminal ⁇ -amino group is unmodified.
  • accumulation of the molecular probe of the formula (7) in the pancreas was 15.4% dose / g 5 minutes after administration, and 16.1% dose / g 15 minutes after administration. It was 20.2% dose / g 30 minutes after administration, and 20.4% dose / g 60 minutes after administration.
  • the molecular probe of the above formula (7) accumulates most in the pancreas except for the lungs and kidneys in the time zone of 15 to 30 minutes after administration, and excludes the lungs in the time zone after 60 minutes after administration. For example, it accumulated most in the pancreas. In addition, accumulation in the pancreas was maintained at a level exceeding 20% dose / g during the period of 30 to 60 minutes after administration.
  • the molecular probe of the above formula (7) has an accumulation ratio in the pancreas with respect to accumulation in the blood (pancreas / blood ratio ((% dose / g) / (% dose / g))). The accumulation ratio exceeded 15 at 30 minutes after administration, and the accumulation ratio exceeded 30 at 60 minutes after administration. As shown in FIG. 2C, the molecular probe of the above formula (7) has an accumulation ratio (pancreas / kidney ratio ((% dose / g) / (% dose / g))) with respect to accumulation in the kidney over time. The accumulation ratio reached around 1 at 30 minutes after administration, and reached around 2 at 60 minutes after administration.
  • the molecular probe of the above formula (7) can provide a desired contrast for imaging by PET, for example.
  • the molecular probe of the above formula (7) has a low radioactivity accumulation in the bone and does not undergo defluorination metabolism in vivo.
  • the molecular probe of Example 1 represented by the above formula (7) is considered suitable for imaging of pancreatic ⁇ cells.
  • Reference Example 1 As Reference Example 1, a molecular probe precursor of the following formula (10) in which a protecting group (Fmoc) is bonded to the N-terminal ⁇ -amino group and the 19th lysine residue and the C-terminal carboxyl group is amidated A molecular probe was prepared from the body (SEQ ID NO: 10), and the distribution in the mouse was measured using the molecular probe. That is, the amino acid sequence of SEQ ID NO: 10 is represented by the following formula (11) in which [ 18 F] FB is bonded to the amino group of the side chain of the fourth lysine and the C-terminal carboxyl group is amidated. The molecular distribution of the mouse was measured using a molecular probe (SEQ ID NO: 11).
  • the molecular probe of Example 1 represented by the above formula (7) is the molecule of Reference Example 1 represented by the above formula (11).
  • the accumulation amount in the pancreas was large, and the accumulation amount in the liver which is an adjacent organ of the pancreas was small.
  • the molecular probe of this Example 1 represented by the above formula (7) has an accumulation amount in the pancreas of the molecular probe of Reference Example 1 and the molecule of Reference Example 2 above. It was more than 5 times compared to the probe. From this, it can be said that the molecular probe of formula (7) prepared in Example 1 specifically accumulated in the pancreas.
  • the molecular probe of Reference Example 1 represented by the above formula (11) By administering the molecular probe of Reference Example 1 represented by the above formula (11) to a mouse, a three-dimensional imaging image of the mouse islet is obtained. In addition, by administering the molecular probe of Reference Example 2 represented by the above formula (13) to a mouse, a noninvasive three-dimensional imaging image of the mouse islet is obtained.
  • the molecular probe of Example 1 represented by the above formula (7) labeled with the side chain of the C-terminal lysine is more likely to enter the pancreas than the molecular probe of Reference Example 1 and the molecular probe of Reference Example 2. Since the accumulation amount in the liver, which is an adjacent organ of the pancreas, is small, the molecular probe of Example 1 can perform noninvasive three-dimensional imaging of islets. It was suggested.
  • the molecular probe for imaging according to the present invention enables non-invasive three-dimensional imaging of the pancreas, particularly non-invasive pancreatic ⁇ cells.
  • pancreas / liver ratio (the amount of pancreas accumulated / the amount of liver accumulated)
  • pancreas / kidney ratio the amount of pancreas accumulated / The amount of kidney accumulation
  • pancreas / blood ratio the amount of pancreas accumulation / the amount of kidney accumulation
  • the molecular probe of Example 1 represented by the above formula (7) has a pancreas / liver ratio that increases with time, and the molecular probe of Reference Example 1 and The pancreas / liver ratio exceeding 10 times the pancreas / liver ratio of the molecular probe of Reference Example 2 was shown.
  • the pancreas / kidney ratio of the molecular probe of the above formula (7) was higher than that of the molecular probe of Reference Example 1 and the molecular probe of Reference Example 2.
  • the pancreas / blood ratio of the molecular probe of formula (7) was significantly higher than that of Reference Example 1 and Reference Example 2, and after administration, It was 4 or more at an early stage, and showed very good blood clearance.
  • the molecular probe of the above formula (7) which has a high accumulation in the pancreas, a small accumulation in the peripheral organs of the pancreas, and an excellent blood clearance, a clear pancreas image can be obtained upon imaging. It was suggested that
  • Example 2 Three-dimensional imaging with PET using the molecular probe prepared in Example 1 (the molecular probe of the above formula (7)) was performed.
  • CT contrast agent for experimental animals Fenestra LC (trade name, manufactured by GE) was administered by intravenous injection. Together with the PET image, the mouse CT image was imaged using the following CT apparatus and conditions.
  • the obtained PET image and CT image were fused using PMOD (product name, PMOD, manufactured by Technologies).
  • PMOD product name, PMOD, manufactured by Technologies
  • An example of the obtained results is shown in FIG.
  • the image is taken 30 minutes after administration of the molecular probe (integration time: 15 minutes).
  • FIG. 5 (a) is a transverse image (transverse ⁇ view), (b) is a coronal image (coronal view), and (c) is a sagittal image (sagittal view).
  • a white circle indicates the position of the pancreas
  • a white circle with a broken line indicates the position of the kidney in (a)
  • a white circle with a dashed line indicates the position of the liver in (b) and (c).
  • the contrasts (a) to (c) are the same.
  • the position of the pancreas could be clearly determined non-invasively by using the molecular probe of the above formula (7). That is, it was confirmed that non-invasive three-dimensional imaging of pancreatic islets is possible with the molecular probe of the present invention.
  • Example 3 In the amino acid sequence of SEQ ID NO: 1, the amino group in the side chain of the 12th lysine residue is labeled with a [ 125 I] 3-iodobenzoyl group (hereinafter also referred to as “[ 125 I] IB label”), and the C-terminal Using the molecular probe (SEQ ID NO: 14) of the following formula (14) in which the carboxyl group of a is amidated and the N-terminal ⁇ -amino group is unmodified, measurement of biodistribution in mice, blocking experiments and two-dimensional imaging Analysis was performed.
  • a [ 125 I] 3-iodobenzoyl group hereinafter also referred to as “[ 125 I] IB label
  • FIG. 6A is a graph showing the change over time of the accumulation of molecular probes in each organ
  • FIG. 6B is an enlarged graph of FIG. 6A.
  • the molecular probe of the above formula (14) does not undergo significant changes in accumulation in the thyroid, suggesting that it has not undergone deiodination metabolism in vivo. Thereby, it is considered that the molecular probe of the above formula (14) is suitable for pancreatic ⁇ cell imaging, in particular, noninvasive imaging of pancreatic ⁇ cells.
  • the molecular probe of Example 3 represented by the above formula (14) has a higher accumulation amount in the pancreas than the molecular probe of Reference Example 3 represented by the above formula (16). There were many. In particular, the accumulation of the molecular probe of the formula (14) in the pancreas was maintained at a high level exceeding 30% dose / g in the time zone of 15 to 60 minutes after administration. In addition, the molecular probe of the above formula (14) was significantly less accumulated in the liver, which is an adjacent organ of the pancreas, than the molecular probe of Reference Example 3. Therefore, it can be said that the molecular probe of the above formula (14) is excellent in organ specificity to the pancreas.
  • pancreas / liver ratio, pancreas / kidney ratio, and pancreas / blood ratio are shown in Tables 9 to 11 below.
  • the molecular probe of Example 3 represented by the above formula (14) has a pancreas / liver ratio that increases with time, and in any time zone, the molecular probe of Reference Example 3 Compared, it showed a high pancreas / liver ratio.
  • the molecular probe of the above formula (14) was at the same level as the molecular probe of Reference Example 3 for the pancreas / kidney ratio (see Table 10), the molecular probe of Reference Example 3 for the pancreas / blood ratio. (See Table 11), 4 or more at the early stage of administration, indicating good blood clearance.
  • FIGS. 7A and 7B are graphs showing an example of accumulation amount (% dose / g) with pre-administration and control (% dose / g) of control (no pre-administration), and FIG. 7B is an enlarged view of FIG. 7A. It is a graph. As shown in FIGS. 7A and B, it was observed that the pre-administration of the cold probe to inhibit the binding to the receptor inhibited the uptake of the molecular probe of the formula (14) by about 95%.
  • FIG. 8 is an example of the result of image analysis of a pancreatic section of a MIP-GFP mouse administered with the molecular probe of the above formula (14), and fluorescence for a section 30 minutes after the administration of the molecular probe of the above formula (14). Images showing signal (a) and radioactive signal (b) are shown.
  • a fluorescent GFP signal and a radioactive signal were detected by the image analyzer in the pancreas section of the MIP-GFP mouse, respectively. Further, the localization of the radioactive signal detected from the molecular probe of the formula (14) was consistent with the GFP signal. From this, it was confirmed that the molecular probe of the above formula (14) was specifically accumulated in pancreatic ⁇ cells.
  • 125 I, 123 I and 131 I are all ⁇ -ray emitting nuclides. Furthermore, 125 I and 123 I have the same nuclear spin number. Therefore, even when the radioactive iodine atom ( 125 I) used for labeling the molecular probe of the above formula (14) is 123 I or 131 I, the molecular probe of the above formula (14) It is estimated that the behavior is almost the same. Even if it is 124 I, it is estimated that the behavior is almost the same as that of the molecular probe of the above formula (14).
  • 125 I of the molecular probe of the above formula (14) is 123 I, 124 I or 131 I, for example, non-invasive three-dimensional pancreatic ⁇ cells in SPECT, PET, etc. It was suggested that imaging, preferably pancreatic ⁇ -cell quantification, is possible.
  • Example 4 In the amino acid sequence of SEQ ID NO: 1, the side chain amino group of the 12th lysine residue is labeled with [ 123 I] 3-iodobenzoyl group, the C-terminal carboxyl group is amidated, and the N-terminal ⁇ -amino group is labeled.
  • [Three-dimensional imaging] SPECT imaging of mice was performed using the molecular probe of the above formula (17).
  • the molecular probe of the above formula (17) (172 ⁇ Ci (6.36 MBq) / 120 ⁇ l) was administered intravenously to 6-week-old ddY mice (male, body weight about 30 g), and influrane inhalation anesthesia was started 20 minutes after the administration of the molecular probe. did.
  • SPECT imaging was performed 30 minutes after administration of the molecular probe.
  • the SPECT imaging was performed using a gamma camera (product name: SPECT2000H-40, manufactured by Hitachi Medical Corporation) under the following imaging conditions. The obtained image was reconstructed under the following reconstruction conditions.
  • FIG. 9 An example of the result is shown in FIG.
  • the image shown in FIG. 9 is 30 minutes after administration of the molecular probe, and shows a transverse view, a coronal view, and a sagittal view in order from the left.
  • the position of the pancreas is indicated by a white arrow.
  • pancreas size was smaller than humans and the position of the pancreas was confirmed non-invasively in a mouse with dense organs, the pancreas was larger than the mouse and the organ was It was suggested that a non-congested human can, for example, more clearly determine the position of the pancreas and the size of the pancreas, and further measure the amount of molecular probe that binds to pancreatic ⁇ cells.
  • the molecular probe for imaging of the present invention enables non-invasive three-dimensional imaging of pancreatic islets in humans, especially non-three-dimensional imaging of pancreatic ⁇ cells and GLP-1R of pancreatic ⁇ cells. It was suggested that three-dimensional imaging can be performed invasively.
  • the molecular probe of formula (18) is a polypeptide represented by the first to 30th amino acids of the amino acid sequence of SEQ ID NO: 1, wherein the amino group on the side chain of the twelfth lysine residue is [ 125 I] IB-labeled, the C-terminal carboxyl group is amidated, and the N-terminal ⁇ -amino group is unmodified.
  • the molecular probe of formula (18) was prepared in the same manner as in Example 3 except that the polypeptide to be synthesized was a polypeptide represented by the first to 30th amino acids of the amino acid sequence of SEQ ID NO: 1. did.
  • FIG. 11 is a graph showing an example of a change with time of accumulation of the molecular probe of the formula (19) in each organ.
  • the molecular probe of formula (19) is a polypeptide represented by the 9th to 30th amino acids of the amino acid sequence of SEQ ID NO: 1, and is an amino group on the side chain of the 4th lysine residue. Are labeled with [ 125 I] IB, the C-terminal carboxyl group is amidated, and the N-terminal ⁇ -amino group is unmodified.
  • pancreas / liver ratio pancreas / kidney ratio
  • pancreas / blood ratios are shown in Tables 14, 15 and 16 below, respectively.
  • the pancreas / liver ratio, pancreas / kidney ratio, and pancreas / blood ratio increase with time, and the pancreas / liver ratio and pancreas / blood ratio.
  • the ratio showed a value exceeding 2 in the time zone of 15 minutes after administration.
  • the molecular probe represented by the formula (18) that has little accumulation in the peripheral organs of the pancreas and has excellent blood clearance, a clear image can be obtained when imaging pancreatic ⁇ cells. It was suggested.
  • FIG. 12 is an example of the result of imaging analysis of a pancreatic section of a MIP-GFP mouse administered with the molecular probe represented by formula (18), and shows an image showing a fluorescence signal (upper diagram) and formula (18). The image (lower figure) which shows the radioactive signal of the represented molecular probe is shown.
  • FIG. 12 when Cold is “+”, it is the result of administering the cold probe before administration of the molecular probe represented by formula (18). When Cold is “ ⁇ ”, the cold probe is not administered. It is the result of administering the molecular probe represented by Formula (18).
  • a fluorescent GFP signal and a radioactive signal were detected in the pancreas section of the MIP-GFP mouse by the image analyzer.
  • the localization of the radioactive signal of the molecular probe represented by the formula (18) almost coincided with the GFP signal. From these results, it was confirmed that the molecular probe represented by the formula (18) was specifically accumulated in pancreatic ⁇ cells. Further, when the receptor was blocked by pre-administering a cold probe, the radioactive signal signal of the molecular probe represented by the formula (18) was hardly detected. Therefore, it was suggested that the molecular probe represented by the formula (18) was specifically accumulated in GLP-1R of pancreatic ⁇ cells.
  • the molecular probe represented by the formula (18) has [ 125 I] iodine atom [ 123/124/131 I as in the molecular probe represented by the formula (14) (molecular probe of Example 3).
  • a molecular probe with iodine atoms for example, non-invasive three-dimensional imaging of GLP-1R of pancreatic ⁇ cells using SPECT, PET, etc., preferably GLP-1R of pancreatic ⁇ cells can be quantified It has been suggested.
  • the present invention is useful in, for example, the medical field, the field of molecular imaging, and the field related to diabetes.
  • SEQ ID NO: 1 Amino acid sequence of the molecular probe for imaging of the present invention
  • SEQ ID NO: 2 Amino acid sequence of the molecular probe for imaging of the present invention
  • SEQ ID NO: 3 Amino acid sequence of the molecular probe for imaging of the present invention
  • SEQ ID NO: 4 Imaging of the present invention
  • Amino acid sequence of molecular probe precursor for imaging SEQ ID NO: 5: amino acid sequence of molecular probe precursor for imaging of the present invention
  • SEQ ID NO: 6 amino acid sequence of molecular probe precursor for imaging of the present invention
  • SEQ ID NO: 7 for imaging of Example 1
  • SEQ ID NO: 8 Amino acid sequence of polypeptide used for production of molecular probe for imaging of Example 1
  • SEQ ID NO: 9 Amino acid sequence of molecular probe precursor used for production of molecular probe for imaging of Example 1 No.
  • SEQ ID NO: 11 amino acid sequence of the molecular probe of Reference Example 1
  • SEQ ID NO: 12 amino acid sequence of the molecular probe precursor of Reference Example 2
  • SEQ ID NO: 13 amino acid sequence of the molecular probe of Reference Example 2
  • SEQ ID NO: 14 Example Amino acid sequence of molecular probe for imaging
  • SEQ ID NO: 15 Amino acid sequence of Exendin- (9-39)
  • SEQ ID NO: 16 Amino acid sequence of molecular probe of Reference Example 3
  • SEQ ID NO: 17 Amino acid of molecular probe for imaging of Example 4
  • SEQ ID NO: 18 Amino acid sequence of the molecular probe for imaging of Example 5
  • SEQ ID NO: 19 Amino acid sequence of the molecular probe of Reference Example 4
  • SEQ ID NO: 20 Amino acid sequence of the polypeptide used in the method for producing the molecular probe for imaging of the present invention

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  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne une sonde moléculaire pour l'imagerie d'îlots pancréatiques. La présente invention concerne spécifiquement une sonde moléculaire qui comprend un polypeptide représenté par la formule (1), (2) ou (3) ou un polypeptide ayant une homologie avec le polypeptide : Z-HGEGTFTSDLSXQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (1) (SEQ ID NO: 1) ; Z-HGEGTFTSDLSKQMEEEAVRLFIEWLXNGGPSSGAPPPS-NH2 (2) (SEQ ID NO: 2) ; et B-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (3) (SEQ ID NO: 3). Dans les formules (1) et (2), « X » représente un résidu lysine dans lequel un groupe amino dans la chaîne latérale est marqué avec un nucléide radioactif ; et « Z- » signifie qu'un groupe α-amino situé à l'extrémité N-terminale est non modifié ou modifié avec un groupe de modification n'ayant aucune charge. Dans la formule (3), « B- » signifie qu'un groupe α-amino situé à l'extrémité N-terminale est marqué avec un nucléide radioactif. Dans les formules (1), (2) et (3), « -NH2 » signifie qu'un groupe carboxyle situé à l'extrémité C-terminale est amidé.
PCT/JP2010/072041 2009-12-10 2010-12-08 Sonde moléculaire pour l'imagerie d'îlots pancréatiques, et utilisation de celle-ci WO2011071083A1 (fr)

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EP10836003.3A EP2510951B1 (fr) 2009-12-10 2010-12-08 Sonde moléculaire pour l'imagerie d'îlots pancréatiques, et utilisation de celle-ci
CN201080056397.6A CN102695527B (zh) 2009-12-10 2010-12-08 胰岛成像用分子探针及其使用
JP2011507740A JP5700835B2 (ja) 2009-12-10 2010-12-08 膵島イメージング用分子プローブ及びその使用

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US28529309P 2009-12-10 2009-12-10
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US61/285293 2009-12-10
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JP2010-125983 2010-06-01
US35073210P 2010-06-02 2010-06-02
US61/350,732 2010-06-02
US38894810P 2010-10-01 2010-10-01
US61/388,948 2010-10-01

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WO2012108476A1 (fr) * 2011-02-09 2012-08-16 国立大学法人京都大学 Procédé de production d'un polypeptide marqué radioactivement
WO2014084372A1 (fr) * 2012-11-30 2014-06-05 国立大学法人京都大学 Polypeptide et procédé d'imagerie
JP2016166151A (ja) * 2015-03-10 2016-09-15 国立大学法人群馬大学 ペプチド化合物及びペプチド化合物の製造方法

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WO2011027584A1 (fr) * 2009-09-04 2011-03-10 国立大学法人京都大学 Sonde moléculaire utilisable en imagerie des îlots de langerhans et son utilisation
WO2011040460A1 (fr) * 2009-09-30 2011-04-07 国立大学法人京都大学 Sonde moléculaire pour imagerie d'îlots pancréatiques et utilisation de ladite sonde
US9289516B2 (en) * 2011-03-09 2016-03-22 The General Hospital Corporation Imaging beta cell mass
JP2017504563A (ja) * 2013-07-25 2017-02-09 スローン − ケタリング・インスティテュート・フォー・キャンサー・リサーチ 手術前及び手術中のインスリノーマ診断のための臨床集学的ツール
EP3024500A4 (fr) * 2014-07-25 2017-04-19 Sloan-kettering Institute For Cancer Research Outils d'imagerie multimodalité en pratique clinique pour diagnostics de l'insulinome préopératoire et intra-opératoire

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012108476A1 (fr) * 2011-02-09 2012-08-16 国立大学法人京都大学 Procédé de production d'un polypeptide marqué radioactivement
WO2014084372A1 (fr) * 2012-11-30 2014-06-05 国立大学法人京都大学 Polypeptide et procédé d'imagerie
JPWO2014084372A1 (ja) * 2012-11-30 2017-01-05 国立大学法人京都大学 ポリペプチド及びイメージング方法
US9950083B2 (en) 2012-11-30 2018-04-24 Kyoto University Polypeptide and imaging method
JP2016166151A (ja) * 2015-03-10 2016-09-15 国立大学法人群馬大学 ペプチド化合物及びペプチド化合物の製造方法

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CN102695527B (zh) 2015-03-11
EP2510951A9 (fr) 2014-01-08
JPWO2011071083A1 (ja) 2013-04-22
EP2510951A1 (fr) 2012-10-17
US8980220B2 (en) 2015-03-17
EP2510951B1 (fr) 2016-07-13
CN102695527A (zh) 2012-09-26
JP5700835B2 (ja) 2015-04-15
KR101550006B1 (ko) 2015-09-03
KR20120080653A (ko) 2012-07-17
EP2510951A4 (fr) 2013-05-15

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