WO2013066181A1 - Ligands d'imagerie - Google Patents

Ligands d'imagerie Download PDF

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Publication number
WO2013066181A1
WO2013066181A1 PCT/NL2012/050768 NL2012050768W WO2013066181A1 WO 2013066181 A1 WO2013066181 A1 WO 2013066181A1 NL 2012050768 W NL2012050768 W NL 2012050768W WO 2013066181 A1 WO2013066181 A1 WO 2013066181A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
compound according
pyridinyl
hydrogen
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PCT/NL2012/050768
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English (en)
Inventor
Louise VAN DER WEERD - MEULENKAMP
Rob NABUURS
Vanita VARSHA KAPOERCHAN
Mark Overhand
Marcus Augustinus VAN BUCHEM
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Academisch Ziekenhuis Leiden Lumc
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Publication of WO2013066181A1 publication Critical patent/WO2013066181A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein

Definitions

  • the invention is directed to a compound for use as an imaging ligand for the detection of aggregated amyloid- ⁇ or for use as a medicament.
  • Imaging ligands are used in various imaging methods, such as optical imaging,for example multiphoton microscopy, 19F MRI methods, PET and SPECT imaging.
  • Suitable compounds have a good solubility in aqueous systems and have a good blood-brain barrier (BBB) passage next to a good selectivity for amyloid deposits.
  • BBB blood-brain barrier
  • the compounds will require special properties, such as fluorescence or a radioactive label, to be able to detect them with the specific imaging method for which they are designed.
  • An example of a compound known for use as an imaging ligand for the detection of aggregated amyloid is the optical imaging agent Methoxy X-04 compound as described in Klunk WE, Bacskai BJ, Mathis CA, Kajdasz ST,
  • US-B-7029655 describes (trans, trans)-1 -bromo-2,5-bis-(3- hydroxycarbonyl-4-hydroxy)-stryrylbenzene as a ligand for use in MRI methods for detecting amyloid deposits associated with Alzheimer's disease.
  • WO-A-2007/034757 describes a styrylbenzene derivate which has an effect of inhibiting the coagulation or fibrosis of an amyloid protein. The compound may be used to treat an amyloid related disease.
  • WO-A-2005/042461 describes a styrylbenzene compound which is capable of fluorescent staining of amyloid and which can be used as an amyloid- specific MRI contrast agent.
  • the object of the present invention is to find a compound having similar or even improved affinity to amyloid plaques .
  • R1 and may be the same or different optionally substituted pyridinyl group and wherein R ⁇ is hydrogen or a substituent group comprising at least an oxygen atom and/or a fluor atom.
  • the above compounds can be used as imaging ligands for the detection of aggregated amyloid- ⁇ . Because of their affinity to the aggregated amyloid- ⁇ the compound may also find use as medicament. Further advantages and preferred embodiments will be described below. Apart from ⁇ F for MRI detectability, all developed compounds have fluorescent properties, which make them suitable for optical imaging methods, such as multiphoton microscopy. Further advantages of the invention will be described below.
  • the invention further provides a sensitive and non-invasive method to diagnose Alzheimer's disease at an early stage.
  • MRI methods are based on water signals, but as water is abundant in living systems, background signals can be a problem. ⁇ F is virtually not present in biological systems, and therefore a low background signal is expected, which makes image analysis easier and unambiguous.
  • R1 and R1 may be combinations of an optionally substituted pyridinyl group, wherein the pyridinyl group may be described as below.
  • R1 and R ⁇ are same or different optionally substituted pyridinyl groups. More preferably R1 and
  • R3 are the same optionally substituted pyridinyl group.
  • the pyridinyl groups make the compounds less lipophilic, which translates into better solubility in aqueous systems and an improved blood-brain barrier (BBB) passage.
  • BBB blood-brain barrier
  • Examples of preferred pyridinyl groups are 2- pyridinyl, 3-pyridinyl and 4- pyridinyl. Good results have been observed when both R1 and R ⁇ are 3-pyridinyl.
  • R ⁇ is preferably either hydrogen, a hydroxyl group, alkoxy group having 1 to 5 carbon atoms, preferably 1-2 carbon atoms and more preferably methoxy, or a fluoroalkyi group having 1 to 5 carbon atoms and one to three fluor atoms, preferably 1 -2 carbon atoms and more preferably tri-fluoromethyl or a fluorinated alkoxy group having 1 to 5 carbon atoms of which at least one carbon atom is substituted with 3 fluor atoms. Examples of compounds according to the first embodiment are shown in Figure 2.
  • the invention is also directed to compositions comprising the above compound and especially directed to pharmaceutical compositions comprising the above compound, salt or solvate thereof and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
  • the compound may be
  • the compound after purification, may be diluted with water or water containing such as, but not limited to, sodium hydroxide or hydrogen chloride.
  • the diluted fraction as prepared is trapped on a Seppak® like, but not limited to, C18, tC18, Silica or an Oasis Seppak® and the compound is preferably eluted from the Seppak® with a solvent suitable for injection in vivo, like ethanol.
  • the obtained eluate is preferable diluted with pharmaceutically acceptable buffers such as, but not limited to 0.9% sodium chloride, sodiumdihydrogenphosphate 7.09 mM in 0.9 % sodiumchloride or citrate buffer, pharmaceutically acceptable solubilisers such as, but not limited to, ethanol, tween or phospholipids and/or with pharmaceutically acceptable stabilizers or antioxidants such as, but not limited to, ascorbic acid, gentisic acid or p-aminobenzoic acid.
  • pharmaceutically acceptable buffers such as, but not limited to 0.9% sodium chloride, sodiumdihydrogenphosphate 7.09 mM in 0.9 % sodiumchloride or citrate buffer
  • pharmaceutically acceptable solubilisers such as, but not limited to, ethanol, tween or phospholipids
  • pharmaceutically acceptable stabilizers or antioxidants such as, but not limited to, ascorbic acid, gentisic acid or p-aminobenzoic acid.
  • the invention is directed to a compound for use as an imaging ligand for the detection of aggregated amyloid- ⁇ in an in vivo diagnosis.
  • the invention is directed to the use of the above compound or a formulation comprising the compound as an imaging ligand for the detection of aggregated amyloid- ⁇ , preferably in an in vivo diagnosis. More preferably to the use in a method for in vivo diagnosis of an amyloid related disease in a subject, preferably a human, comprising administration of the above compound or formulation, suitably a pharmaceutical formulation comprising the compound and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluents, and performing an imaging method. All compounds or formulations have fluorescent properties, making them suitable for optical imaging techniques, such as but not limited to multiphoton microscopy, in vivo fluorescence imaging and fluorescence microscopy. The invention is thus also directed to a method wherein the imaging method is an optical imaging method.
  • the compound comprises one or more substituent groups comprising one or more fluor atoms.
  • a further preferred imaging method is positron emission tomography (PET) or single photon emission computed tomography (SPECT). These methods use radiolabeled compounds.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the compound has one or more substituent groups such as, but not limited to, one or more of
  • the compound has a group
  • R2 comprising one or one I ⁇ F atom.
  • radiolabeled compounds can be advantageously used as diagnostic imaging agents for in vivo imaging of aggregated amyloid- ⁇ using said PET and SPECT methods.
  • the compounds described above or pharmaceutical compositions comprising said compound may also be used as a medicament. More preferably the compounds described above or compositions comprising said compound are used in treating or prevention of Alzheimer's disease, mild cognitive impairment, Down's syndrome, mild cognitive impairment in Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease.
  • the use is prevention or treatment of Alzheimer's disease.
  • R1 and R ⁇ may be the same or different optionally substituted
  • R ⁇ is hydrogen or a substituent group comprising at least an oxygen atom or a fluor atom.
  • R.1 and R ⁇ are different or more preferably the same optionally substituted 3-pyridinyl group.
  • the pyridinyl groups make the compounds less lipophilic, which translates into better solubility in aqueous systems and an improved blood-brain barrier (BBB) passage.
  • BBB blood-brain barrier
  • R ⁇ is preferably either hydrogen, a hydroxyl group, alkoxy group having 1 to 5 carbon atoms, preferably 1 -2 carbon atoms and more preferably methoxy, or a fluoroalkyl group having 1 to 5 carbon atoms and one to three fluor atoms, preferably 1 -2 carbon atoms and more preferably tri-fluoromethyl or a fluorinated alkoxy group having 1 to 5 carbon atoms of which at least one carbon atom is substituted with 3 fluor atoms.
  • R ⁇ is preferably a hydrogen, a methoxy or a tr-fluoromethyl group.
  • the invention shall be illustrated with the below non-limiting examples.
  • the examples will include the synthesis of a set of compounds in Example 1 , a comparison of the properties of said compounds in Example 2 and Examples 3 and 4 illustrating the use of said compound as ligand for the detection of
  • Reactions were monitored by thin layer chromatography on aluminum coated silica sheets (Merck, silica 60 F254), using visualization either with iodine, or spraying with a solution of 25 g ( ⁇ 10 g (NH4)4Ce(S04)4 in 100 ml H2SO4 and 900 ml H2O, or a solution of 20% H2SO4 in ethanol, followed by charring at -150 °C.
  • the high resolution mass spectrometer was calibrated prior to
  • LC-MS analysis was performed on a Finnigan Surveyor HPLC system with a Gemini C18 50 ⁇ 4.6 mm column (3 micron, Phenomenex, Torrance, CA, USA) (detection at 200-600 nm), coupled to a Thermo Finnigan LCQ Advantage Max mass spectrometer (Breda, The Netherlands) with electrospray ionization (ESI; system 1 ) was used, with the same buffers as described above.
  • ESI electrospray ionization
  • the compounds according to the first embodiment are preferably prepared by a scheme as illustrated in Figure 1 . Reference will be made to this scheme in describing this Example. This example describes the synthesis wherein R1 and R 3 are 4-pyridinyl groups and R ⁇ is hydrogen.
  • Tetraethyl 1 ,4-xylylene diphosphonate (34 in Figure 1 ) was obtained as white fluffy powder (5.6 g, 14.8 mmol, 74% over two steps) and had the following properties: H NMR (CDCI3, 400 MHz) ⁇ 7.25 (s, 4H); 4.07-3.95 (m,
  • LogP values were determined for some of the compounds.
  • the LogP value is an indicator for Blood Brain Barrier (BBB) passage.
  • LogP determinations were performed using literature procedures (Benhaim, D.; Grushka, E. J. Chrom. A 2008, 1209, 1 1 1 -1 19).
  • Table 2 shows some results for the LogP values and % intensity relative to the prior art MethX04 dye which are relevant for a dye for the detection of aggregated amyloid- ⁇ .
  • Affinity for amyloid plaque was assessed qualitatively by staining human and mouse brain sections with the developed compounds.
  • Solutions of the compounds (1 , 10 and 100 ⁇ ) were applied to brain slices of APP/PS1 mice bearing ⁇ plaques and human AD sections.
  • Fluorescence microscopy was used to score the specificity for amyloid plaque based on the compounds' fluorescence, and to assess non-specific background staining.
  • FIG. 3 A compound according to Figure 3a was used to stain amyloid plaque in APP/PS1 mouse brain. Direct staining of tissue sections showed high affinity and specificity of this compound for amyloid plaque with fluorescence microscopy. See results in Figure 3B.
  • Ki values were assessed by a competition assay on fibrilized synthestic ⁇ 1 -40, as well as on APP/PS1 mouse brain homogenates to test the properties of the compound according to Figure 3A.
  • the competing amyloid- targeting ligand was 3H-Chrysamine G, a known amyloid-binding ligand.
  • the mixture was sonicated for 10 min, and the assay was subsequently initiated by the addition of 50 ⁇ synthetic ⁇ 1 -40 fibrils, to achieve final concentrations of 5 nM [3H]Chrysamine-G and 50 nM fibrils.
  • Identical experiments were performed using mouse brain cortex homogenate instead of synthetic ⁇ 1 -40 fibrils.
  • Nonspecific binding was determined in the presence of 1 ⁇ M-X04. Incubations were terminated after 1 h via filtration through Whatman GF/B filters (pre-soaked in binding buffer), using a 48-well Brandel harvester.
  • the filters were washed two times with 3 ml of ice-cold binding buffer (pH 7.0), and radioactivity was determined by liquid scintillation spectrometry in 5 ml of Optiphase-HiSafe 3, at an efficiency of 40 %.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un composé ou son sel ou son solvate, à utiliser en tant que ligand d'imagerie pour la détection d'amyloïde-β agrégé ou en tant que médicament selon la formule (I): Dans ladite formule, R1 et R3 peuvent représenter le même groupe pyridinyle éventuellement substitué ou un groupe pyridinyle éventuellement substitué différent, et R2 représente un hydrogène ou un groupe substituant comprenant au moins un atome d'oxygène ou un atome de fluor.
PCT/NL2012/050768 2011-11-04 2012-11-02 Ligands d'imagerie WO2013066181A1 (fr)

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NL2007714 2011-11-04
NL2007714A NL2007714C2 (en) 2011-11-04 2011-11-04 Imaging ligands.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109776583A (zh) * 2019-01-25 2019-05-21 郑州大学 一种吡啶类链状共轭体系分子衍生物及其制备方法和应用

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US7029655B2 (en) 2000-10-04 2006-04-18 California Institute Of Technology Magnetic resonance imaging agents for in vivo labeling and detection of amyloid deposits
WO2005042461A1 (fr) 2003-10-30 2005-05-12 Dojindo Laboratories Compose presentant une affinite avec l'amyloide
WO2007034757A1 (fr) 2005-09-20 2007-03-29 Fuence Co., Ltd. Remède pour des maladies amyloïdes et médicament pour le suivi de celles-ci
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109776583A (zh) * 2019-01-25 2019-05-21 郑州大学 一种吡啶类链状共轭体系分子衍生物及其制备方法和应用

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