WO2010059905A2 - Ligands d'imagerie - Google Patents

Ligands d'imagerie Download PDF

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Publication number
WO2010059905A2
WO2010059905A2 PCT/US2009/065268 US2009065268W WO2010059905A2 WO 2010059905 A2 WO2010059905 A2 WO 2010059905A2 US 2009065268 W US2009065268 W US 2009065268W WO 2010059905 A2 WO2010059905 A2 WO 2010059905A2
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WO
WIPO (PCT)
Prior art keywords
compound
salt
solvate
formula
compound according
Prior art date
Application number
PCT/US2009/065268
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English (en)
Other versions
WO2010059905A3 (fr
Inventor
Ravi Hegde
Chandan Atreya
Bo Shan
Sudeshna Adak
Original Assignee
General Electric Company
Hammersmith Imanet Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by General Electric Company, Hammersmith Imanet Limited filed Critical General Electric Company
Priority to CN2009801477833A priority Critical patent/CN102223900A/zh
Priority to JP2011537640A priority patent/JP2012509887A/ja
Priority to EP09761111A priority patent/EP2389202A2/fr
Priority to US13/128,418 priority patent/US20110217234A1/en
Publication of WO2010059905A2 publication Critical patent/WO2010059905A2/fr
Publication of WO2010059905A3 publication Critical patent/WO2010059905A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0463—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Definitions

  • the present invention relates to the field of medical diagnostics and imaging using positron emission tomography (PET) and provides compounds and methods for visualising central nervous system (CNS) receptors.
  • PET positron emission tomography
  • CNS central nervous system
  • this invention relates to naphthoxazine derivatives which are selective ligands forthe dopamine D2 receptor and which carry an 18 F-radiolabel suitable for imaging with PET.
  • the compounds of the present invention are thus useful for in vivo diagnostics and in vivo imaging of the dopamine D2 receptor.
  • Dopamine is an important neurotransmitter in the human brain. Dysfunctions of dopamine neurotransmission are implicated in many neurological and psychiatric disorders - for example, schizophrenia, Parkinson's Disease, psychosis, anxiety, and Attention Deficit Hyperactivity Disorder (ADHD). In addition to its role in the CNS, dopamine agonists may also be used to increase cardiac output and blood pressure in patients with shock and heart failure. Current evidence indicates that changes in the receptors which mediate dopamine transmission are associated with particular CNS (central nervous system) disorders. Dopamine receptors fall into two main types : Dl- like and D2-like receptors, within which there are several receptor sub-types. Study of the D2 dopamine receptor is considered particularly valuable for assistance in diagnosis and therapy monitoring of the neurological disorders mentioned, as well as for clinical research on healthy human volunteers and for therapeutic drug development trials.
  • R is Ci- ⁇ lkyl in which one hydrogen atom on the alkyl chain is replaced with fluoro or radioactive fluoro. But these compounds have performed poorly in vivo and ex vivo.
  • the present invention seeks to provide detectably labelled ligands suitable for studying the dopamine D2 receptor in vivo having improved properties over those in the prior art.
  • R 1 is Ci-ealkyl; one of R 2 and R 3 is [ 18 F]fluoro and the other is hydrogen.
  • R 1 is preferably ethyl, n-propyl, or iso-propyl; and is most preferably n-propyl.
  • R 1 , R 2 , and R 3 are as defined above for formula
  • Preferred specific compounds of formula (I) include:
  • Said compounds of formula (Ia), Compound 1, and Compound 2 or a salt or solvate thereof, are suitably in substantially pure form.
  • Suitable salts according to the invention include (i) physiologically acceptable acid addition salts such as those derived from mineral acids, for example hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and those derived from organic acids, for example tartaric, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, succinic, methanesulphonic, and para- toluenesulphonic acids; and (ii) physiologically acceptable base salts such as ammonium salts, alkali metal salts (for example those of sodium and potassium), alkaline earth metal salts (for example those of calcium and magnesium), salts with organic bases such as triethanolamine, N-methyl-D-glucamine, piperidine, pyridine, piperazine, and morpholine, and salts with amino acids such as arginine and lysine.
  • physiologically acceptable acid addition salts such as those derived from mineral acids
  • Suitable solvates according to the invention include those formed with ethanol, water, saline, physiological buffer and glycol.
  • alkyl either alone or as part of another term means a straight, branched or cyclic alkyl group.
  • the compounds of formula (I) have use as PET Iigands forthe D2 receptor. Therefore, according to a further aspect of the invention, there is provided a compound of formula (I) as defined above, or a salt or solvate thereof, for use in medicine, particularly for use in an in vivo PET diagnostic or imaging method.
  • a compound of formula (I) as defined above, or a salt or solvate thereof may also be used to image the D2 receptor in healthy human volunteers for example for clinical research purposes.
  • a method for detection of D2 receptors in a subject comprising: (i) administration of a compound of formula (I) as defined above, or a salt or solvate thereof to said subject; and (ii) detecting uptake of said compound by in vivo PET imaging.
  • Such a method provides information and data having utility in the diagnosis and clinical research of D2-mediated disorders.
  • the subject is a mammal, most suitably a human who has or is suspected of having a D2-mediated disorder.
  • the method may be performed quantitatively such that the amount or change in amount of D2 receptors or the density or change in density of receptors in the high-affinity D2 H
  • the method may be used to locate D2 receptors.
  • a method for detection of D2 receptors in a subject comprising:
  • step (ii) detecting uptake of said compound of formula (I) administered in step (i) by in vivo PET imaging;
  • step (iii) allowing a suitable amount of time to pass such that the compound administered in step (i) has radioactively decayed; then (iv) administration of an effective amount of either (a) a non-radiolabelled dopamine agonist or dopamine mimetic, or (b) a non-radiolabelled dopamine depletor, and contemporaneous administration of a compound of formula (I) or a salt or solvate thereof as defined in step (i) ; (v) detecting uptake of said compound of formula (I) administered in step (iv) by in vivo PET imaging.
  • step (iii) is suitably over 10 hours, more suitably at least 16 hours, and more suitably is around 24 hours such that the PET signal from the compound of formula (I) administered in step (i) is no longer detectable.
  • a method for detection of D receptors in a subject comprising: (i) administration of a compound of formula (I) as defined above, or a salt or solvate thereof to said subject;
  • step (ii) detecting uptake of said compound of formula (I) administered in step (i) by in vivo PET imaging;
  • step (iv) detecting uptake of said compound of formula (I) administered in step (i) by in vivo PET imaging.
  • dopamine mimetic means a compound which has a biological activity similar to dopamine or which causes a release of dopamine.
  • the non-radiolabelled dopamine agonist or dopamine mimetic used in the above methods is suitably selected from amphetamine, (+1-PHNO, apomorphine and congeners thereof (for example, N- propyl-norapomorphine) and an aminotetralin (such as dihydroxy-2-dimethyl- aminotetralin).
  • the non-radiolabelled dopamine agonist or dopamine mimetic used in the above methods is amphetamine.
  • non-radiolabelled dopamine depletor is a compound which temporarily and acutely decreases the availability of dopamine in the subject, for example by inhibiting synthesis or release of endogenous dopamine, and is for example a tyrosine hydroxylase inhibitor such as alpha-methyl-para-tyrosine (AMPT).
  • AMPT alpha-methyl-para-tyrosine
  • Constant administration in the above method means that both compounds are administered to the subject such that they are both biologically active in the subject at the same time.
  • both compounds are administered substantially at the same time i.e. within 30 minutes of each other , or in a single composition comprising both compounds.
  • the compounds of formula (I) or salt or solvate thereof are useful for in vivo imaging of D2 receptors and thus have utility in the imaging or diagnosis of D2- mediated disorders.
  • D2-mediated disorders means neurological and psychiatric disorders such as schizophrenia, Parkinson's disease, psychosis, anxiety, and ADHD.
  • One important D2-mediated disorder is schizophrenia.
  • a compound of formula (I) or a salt or solvate thereof for use in the in vivo diagnosis or imaging of a D2-mediated disorder.
  • a method for the in vivo diagnosis or imaging of a D2- mediated disorder in a subject comprising administration of a compound of formula (I) or a salt or solvate thereof and detecting the uptake of said compound by an in vivo PET imaging technique.
  • the method is especially preferred for the in vivo diagnosis or imaging of schizophrenia, Parkinson's disease, psychosis, anxiety, or ADHD.
  • a method for in vivo imaging of a D2- mediated disorder in a subject preferably a human, to whom of a compound of formula (I) or a salt or solvate thereof has been pre-administered and detecting the uptake of said compound by an in vivo PET imaging technique.
  • the invention further provides a method of monitoring the effect of treatment of a subject, preferably a human with a drug to combat a D2- mediated disorder, said method comprising administering to said subject a compound of formula (I) or a salt or solvate thereof and detecting the uptake of said compound by an in vivo PET imaging technique such as the methods described above, said administration and detection optionally but preferably being effected repeatedly, e.g. before, during and after treatment with said drug.
  • a compound of formula (I) or a salt thereof is preferably administered for in vivo use in a pharmaceutical formulation comprising the compound of the invention and a pharmaceutically acceptable excipient.
  • a "pharmaceutical formulation” is defined in the present invention as a formulation comprising compound of formula (I) ora salt or solvate thereof in a form suitable for administration to humans. Administration is preferably carried out by injection of the formulation as an aqueous solution.
  • Such a formulation may optionally contain further ingredients such as buffers; pharmaceutically acceptable solubilisers (e.g. cyclodextrins or surfactants such as Pluronic, Tween or phospholipids); pharmaceutically acceptable stabilisers or antioxidants (such as ascorbic acid, gentisic acid or para-aminobenzoic acid).
  • the effective in vivo dose of a compound of formula (I), (Ia) or a salt thereof will vary depending on the exact compound to be administered, the weight of the patient, and other variables as would be apparent to a physician skilled in the art. Generally, the dose would lie in the range 0.001 ⁇ g/kg to 10 ⁇ g /kg, preferably 0.01 ⁇ g /kg to 1.0 ⁇ g/kg.
  • R 1 is as defined for the compound of formula (I)
  • one of R 4 and R 5 is hydrogen and the other is a leaving group (such as a Ci- ⁇ alkyl-.
  • Ci-ehaloalkyl- or aryl- sulphonate suitably methanesulphonate, p-toluenesulphonate, ortrifluoromethylsulphonate
  • R 5 is hydrogen or preferably methyl.
  • protecting groups may be required during synthesis of a compound of formula (I) to prevent unwanted side- reactions. Suitable protecting groups may be found in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc. which describes methods for incorporating and removing such protecting groups.
  • Fluorination of a compound of formula (II) may be effected by conventional [ 18 F]radiofluoriation techniques.
  • [ 18 F]fluoride is conveniently prepared from 18 O- enriched water using the (p.n)-nuclear reaction, (Guillaume et a/, Appl. Radiat. Isot. 42 (1991) 749-762) and generally isolated as a salt such as Na 18 F, K 18 F, Cs 18 F, tetraalkylammonium [ 18 F]fluoride, ortetraalkylphosphonium 18 F fluoride.
  • a phase transfer catalyst such as an aminopolyether or crown ether, for example, 4,7,13,16,21,24 hexaoxa-l,10-diazabicyclo[8,8,8] hexacosane (Kryptofix 2.2.2) may be added and the reaction performed in a suitable solvent. These conditions give reactive fluoride ions.
  • a free radical trap may be used to improve fluoridation yields, as described in WO 2005/061415 .
  • the term "free radical trap" is defined as any agent that interacts with free radicals and inactivates them.
  • a suitable free radical trap for this purpose may be selected from 2,2,6,6-Tetramethylpiperidine-N-Oxide (TEMPO), 1,2-diphenylethylene (DPE), ascorbate, para-amino benzoic acid (PABA), a-tocopherol, hydroquinone, di-t-butyl phenol, ⁇ - carotene and gentisic acid.
  • TEMPO 2,2,6,6-Tetramethylpiperidine-N-Oxide
  • DPE 1,2-diphenylethylene
  • PABA para-amino benzoic acid
  • hydroquinone hydroquinone
  • di-t-butyl phenol di-t-butyl phenol
  • ⁇ - carotene gentisic acid
  • the treatment with fluoride may be effected in the presence of a suitable organic solvent such as acetonitrile, dimethylformamide, dimethylsulphoxide, dimethyl ⁇ cet ⁇ mide, tetr ⁇ hydrofur ⁇ n, diox ⁇ n, 1,2 dimethoxyeth ⁇ ne, sulphol ⁇ ne, N- methylpyrolidininone, or in an ionic liquid such as an imidazolium derivative (for example l-ethyl-3-methylimidazolium hexafluorophosphate), a pyridinium derivative (for example, l-butyl-4-methylpyridinium tetrafluoroborate), a phosphonium compound, or tetralkylammonium compound at a non-extreme temperature, for example, 15°C to 180°C, preferably at elevated temperature, such as 80°C to 150°C, for example around 120°C.
  • a suitable organic solvent such as acetonitrile,
  • the tosylate precursor is prepared according to Scheme 2 above.
  • the starting materials in scheme 1 are commercially available from Aldrich and the starting material in scheme 2 may be synthesized according to the methods of scheme 1.
  • [ 18 F]fluoride (in 200 ⁇ L enriched 95% 18 O water), 2.5mg of Kryptofix 2.2.2 (in 0.5mL acetonitrile) and 50 ⁇ L 0.1M K2CO3 are added to a glassy carbon reaction vessel. The solution is then evaporated to dryness using a stream of nitrogen and heating the reaction vessel to 100°C for 15 minutes.
  • 2 x ImL acetonitrile is added to the reaction vessel at 5 minutes and 10 minutes respectively to aid azeotropic drying.
  • the reaction vessel is cooled to room temperature and the tosylate precursor in ImL anhydrous dimethyl sulfoxide is added.
  • the reaction is sealed and heated for 10 minutes at 130°C.
  • the crude mixture is analyzed by HPLC and TLC.
  • the specific ligand binding to the receptors is defined as the difference between the total binding and the nonspecific binding determined in the presence of an excess of unlabelled ligand. The results are expressed as a percent of control specific binding

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention porte sur des dérivés de naphtoxazine qui sont des ligands sélectifs pour le récepteur D2 de la dopamine et qui portent un radiomarqueur 18F approprié pour une imagerie par tomographie par émission de positons (PET). Les composés de la présente invention sont ainsi utiles pour un diagnostic in vivo et une imagerie in vivo du récepteur D2 de la dopamine.
PCT/US2009/065268 2008-11-24 2009-11-20 Ligands d'imagerie WO2010059905A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN2009801477833A CN102223900A (zh) 2008-11-24 2009-11-20 用于多巴胺d2受体的成像配体
JP2011537640A JP2012509887A (ja) 2008-11-24 2009-11-20 イメージングリガンド
EP09761111A EP2389202A2 (fr) 2008-11-24 2009-11-20 Ligands d'imagerie
US13/128,418 US20110217234A1 (en) 2008-11-24 2009-11-20 Imaging ligands

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US11725408P 2008-11-24 2008-11-24
GB0821432.2 2008-11-24
US61/117,254 2008-11-24
GBGB0821432.2A GB0821432D0 (en) 2008-11-24 2008-11-24 Imaging ligands

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WO2010059905A2 true WO2010059905A2 (fr) 2010-05-27
WO2010059905A3 WO2010059905A3 (fr) 2010-08-26

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WO (1) WO2010059905A2 (fr)

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US20150031768A1 (en) * 2011-08-19 2015-01-29 The Trustees Of Princeton University C-halogen bond formation
SG11201908066XA (en) * 2017-03-07 2019-09-27 Nihon Mediphysics Co Ltd Radioactive fluorine-labeled precursor compound, and method for producing radioactive fluorine-labeled compound using same
DE102019112040A1 (de) * 2019-05-08 2020-11-12 Helmholtz-Zentrum Dresden - Rossendorf E.V. 3-(4-Amino-2-methoxyphenyl)-2-cyanoacrylsäure-Derivate und deren Verwendung als Präkursoren für die Herstellung radiochemischer Verbindungen

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080115A2 (fr) * 1981-11-20 1983-06-01 Merck & Co. Inc. Hexahydronaphth(1,2-b)-1,4-oxazines, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4540691A (en) * 1984-04-13 1985-09-10 Nelson Research & Development Co. Dopamine agonists and use thereof
WO1991019719A1 (fr) * 1990-06-15 1991-12-26 Whitby Research, Inc. Naphtoxazines substituees utiles comme dopaminergiques
WO1993024471A1 (fr) * 1992-06-02 1993-12-09 Whitby Research, Inc. Naphtoxazines substitues efficaces en tant que dopaminergiques
WO2006047861A1 (fr) * 2004-11-03 2006-05-11 Clera Inc. Methode de detection de recepteurs de la dopamine a l'etat fonctionnel d2high
WO2006084368A1 (fr) * 2005-02-14 2006-08-17 Clera Inc. Phno fluorée et analogues de ladite substance

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080115A2 (fr) * 1981-11-20 1983-06-01 Merck & Co. Inc. Hexahydronaphth(1,2-b)-1,4-oxazines, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4540691A (en) * 1984-04-13 1985-09-10 Nelson Research & Development Co. Dopamine agonists and use thereof
WO1991019719A1 (fr) * 1990-06-15 1991-12-26 Whitby Research, Inc. Naphtoxazines substituees utiles comme dopaminergiques
WO1993024471A1 (fr) * 1992-06-02 1993-12-09 Whitby Research, Inc. Naphtoxazines substitues efficaces en tant que dopaminergiques
WO2006047861A1 (fr) * 2004-11-03 2006-05-11 Clera Inc. Methode de detection de recepteurs de la dopamine a l'etat fonctionnel d2high
WO2006084368A1 (fr) * 2005-02-14 2006-08-17 Clera Inc. Phno fluorée et analogues de ladite substance

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VASDEV ET AL: "Syntheses and in vitro evaluation of fluorinated naphthoxazines as dopamine D2/D3 receptor agonists: radiosynthesis, ex vivo biodistribution and autoradiography of [<18>F]F-PHNO" NUCLEAR MEDICINE AND BIOLOGY, ELSEVIER, NY, US LNKD- DOI:10.1016/J.NUCMEDBIO.2006.11.001, vol. 34, no. 2, 15 February 2007 (2007-02-15), pages 195-203, XP005890920 ISSN: 0969-8051 cited in the application *

Also Published As

Publication number Publication date
US20110217234A1 (en) 2011-09-08
JP2012509887A (ja) 2012-04-26
EP2389202A2 (fr) 2011-11-30
GB0821432D0 (en) 2008-12-31
WO2010059905A3 (fr) 2010-08-26
CN102223900A (zh) 2011-10-19

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