WO2012007510A1 - Composés destinés à la liaison et à l'imagerie de plaques amyloïdes et leur utilisation - Google Patents

Composés destinés à la liaison et à l'imagerie de plaques amyloïdes et leur utilisation Download PDF

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WO2012007510A1
WO2012007510A1 PCT/EP2011/061967 EP2011061967W WO2012007510A1 WO 2012007510 A1 WO2012007510 A1 WO 2012007510A1 EP 2011061967 W EP2011061967 W EP 2011061967W WO 2012007510 A1 WO2012007510 A1 WO 2012007510A1
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group
pyrazol
compound
och
mmol
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PCT/EP2011/061967
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English (en)
Inventor
Ulrike RÖHN
Heribert Schmitt-Willich
Tobias Heinrich
Markus Berger
Ansgar Fitzner
Sabine Krause
Damian Brockschnieder
Thomas Dyrks
Andrea Thiele
Ursula MÖNNING
Ulf Bömer
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds (benzothiazoiopyrazoles and thiazolopyridin-pyrazoles) useful for binding and imaging amyloid deposits and their use in detecting or treating Alzheimer's disease and amyloidoses.
  • AD Alzheimer's disease
  • ⁇ beta-amyloid peptide
  • APP amyloid precursor protein
  • ⁇ peptides are released as soluble proteins and can be detected at low levels in the cerebrospinal fluid (CSF) in normal aging brains.
  • CSF cerebrospinal fluid
  • the ⁇ peptides aggregate and form amyioid deposits in the parenchyma and vasculature of the brain, which can be detected post mortem as diffuse and senile plaques and vascular amyioid during histological examination (for a recent review see: Blennow et al. Lancet. 2006 Jul 29;368(9533):387-403),
  • Alzheimer's disease is becoming a great health and social economical problem all over the world. There are great efforts being made to develop techniques and methods for the early detection and effective treatment of the disease.
  • diagnosis of AD in an academic setting of memory-disorder clinics is approximately 85-90% accurate (Petreila JR et al. Radiology. 2003 226:315-36). It is based on the exclusion of a variety of diseases causing similar symptoms and the careful neurological and psychiatric examination, as well as neuropsychological testing.
  • post mortem histological examination of the brain is still the only definite diagnosis of this disease.
  • amyloid aggregates in the brain are thought to have a big impact on the early detection of AD and differentiation from other dementias.
  • most disease modifying therapies that are under development are aiming at lowering the amyioid load in the brain.
  • imaging the amyioid load in the brain may provide an essential tool for patient stratification and treatment monitoring.
  • amyloid deposits are also known to play a role in amyloidosis, in which amyloid proteins are abnormally deposited in different organs and/or tissues, causing disease. For a recent review see Chiti et al. Annu Rev Biochem, 2006;75:333-66.
  • PET tracers that have been already investigated in humans regarding their binding patterns in brains of AD patients are [F-18]FDDNP (Shoghi-Jadid ef al., Am J Geriatr Psychiatry 2002; 10:24- 35), [C-1 1]PIB (Kiunk et al., Ann Neurol, 2004 55:306-319), [C-1 1]SB-13 (Verhoeff et al., Am J Geriatr Psychiatry 2004; 12:584-595, [F-18]Bay 94-9172 (Rowe et al.
  • the currently most promising PET tracers show a disadvantageous non-specific accumulation, especially in white matter brain regions in AD patients as well as in HC.
  • non-specific background binding interferes with the image quality and could e.g. impair the quantification of amyloid and the diagnosis of very early stages of the disease.
  • the present invention provides novel tracers with high affinity for amyloid ⁇ and rapid elimination of the unspecificaliy bound tracer from the brain. Description of the invention
  • the present invention is directed to compounds that bind to amyloid deposits and are able to pass through the blood-brain barrier, and are therefore useful in diagnosing Alzheimer's disease and amyloidosis in a patient, preferably at an early stage of the disease.
  • the invention is directed to compounds according to formula
  • R 2 is selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , (CH 2 ) m CH 2 X, R 1 ;
  • - R 3 is selected from the group consisting of H, C(0)OH, C(0)0(CH 2 ) n CH 3 , C(0)0(CH 2 ) m CH 2 X, C(0)NH 2 , C(G)NH(CH 2 ) n CH 3 , C(0)NH(CH 2 ) m CH 2 X;
  • R 4 and R 5 are independently selected from the group consisting of H, CH 3 , (CH 2 )nCH 3 , (CH 2 ) n CH 2 X, OH, OCH 3 , 0(CH 2 ) n CH 3 , 0(CH 2 ) n CH 2 X, O-cyclobutyl-X.
  • - W is selected from CH or N - X is selected from the group consisting of 18 F, F, CI, Br, i, 25 l, 123 i, OS0 2 CH 3 , OS0 2 CF 3 , OS0 2 C 4 F 9 , OS0 2 C 6 H 5 , OS0 2 C 6 H 4 CH 3 , OS0 2 C 6 H 4 N0 2 , OS0 2 C 6 H 4 Br, OS0 2 C 6 H 2 (CH(CH 3 ) 2 ) 3 , OS0 2 C 6 H 3 (OCH 3 ) 2;
  • - Y is selected from the group consisting of N0 2 , N + Me 3 , l*aryi, S + aryl 2 ;
  • - Z is selected from the group consisting of H, CF 3, CN, C(0)H, C(0)CH 3 , C(0)0(CH 2 ) n CH 3 ;
  • - m has the meaning of 1-4;
  • n is 0-4; including ail isomeric forms of said compound, including enantiomers and diasteromers as well as racemic mixtures, and any pharmaceuticaiiy acceptable salt, ester, amide, complex or prodrug thereof.
  • - 2 is selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , (CH 2 ) m CH 2 X, R 1 ; - R 3 is selected from the group consisting of H, C(0)OH, C(0)0(CH 2 )nCH 3 , C(0)0(CH 2 ) m CH 2 X, C(0)NH 2 , C(0)NH(CH 2 ) n CH 3 , C(0)NH(CH 2 ) m CH 2 X;
  • R 4 and R 5 are independently selected from the group consisting of H, CH 3 , (CH 2 )nCH 3 , (CH 2 ) n CH 2 X, OH, OCH 3 , 0(CH 2 ) n CH 3 , 0(CH 2 ) n CH 2 X, O-cycoibutyl-X.
  • O-cyclopentyi-X 0(CH 2 CH 2 Q) n CH 2 CH 2 X, NH 2 , NHCH 3 , N(CH 3 ) 2 , NH(CH 2 ) n CH 3 , NH(CH 2 ) m CH 2 X, NCH 3 (CH 2 ) ril CH 2 X, X, Y, Z;
  • - W is selected from CH or N - X is selected from the group consisting of 18 F, F, CI, Br, I, 125 l, 123 l, OS0 2 CH 3 , OS0 2 CF 3 , OS0 2 C 4 F 9 , OS0 2 C 6 H 5 , OS0 2 C 6 H 4 CH 3 , OS0 2 C 6 H 4 N0 2 , OS0 2 C 6 H 4 Br, OS0 2 C 6 H 2 (CH(CH 3 ) 2 ) 3 , OS0 2 C 6 H 3 (OCH 3 ) 2;
  • - Y is selected from the group consisting of N0 2 , N + Me 3 , Taryi, S + aryl 2 ;
  • - Z is selected from the group consisting of H, CF 3, CN, C(0)H, C(0)CH 3 ;
  • - m has the meaning of 1-3;
  • n 0-3;
  • pharmaceutically acceptable salts and prodrugs thereof, and all isomeric forms of said compound, including enantiomers and diasteromers as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof are included. in an even more preferred embodiment,
  • - 1 is selected from the group consisting of H, C(0)CH 3 , C(0)(CH 2 ) crampCH 2 X, C(0)CF 3 , C(0)OC(CH 3 ) 3 , C(0)C 6 H 4 X, C(0)C 6 H 3 YZ, C(0)C 6 H 3 XZ, C(0)OCH 3 , C(0)OCH 2 CH 3 ,
  • R 2 is selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , R 1 ;
  • - R 3 is selected from the group consisting of H, C(0)OH, C(0)G(CH 2 ) r! CH 3 , C(0)0(CH 2 ) m CH 2 X;
  • R 4 and R 5 are independently selected from the group consisting of H, (CH 2 ) n CH 2 X, OH, OCH 3 , 0(CH 2 ) n CH 2 X, O-cyclobutyl-X, 0(CH 2 CH 2 0) n CH 2 CH 2 X, X, Y, Z;
  • - W is selected from CH or N
  • - X is selected from the group consisting of 18 F, F, CI, Br, I, OS0 2 CH 3 , OS0 2 CF 3 , OS0 2 C 4 F 9 , OS0 2 C 6 H 5 , OS0 2 C 6 H 4 CH 3 , OS0 2 C 6 H 4 N0 2 , OS0 2 C 6 H 4 Br, OS0 2 C 6 H 2 (CH(CH 3 ) 2 ) 3 , OS0 2 C 6 H 3 (OCH 3 ) 2;
  • - Y is selected from the group consisting of N0 2 , N + Me 3 , l*aryi, S + aryl 2 ;
  • - Z is selected from the group consisting of H, CF 3, CN, C(0)H;
  • - m has the meaning of 1-2;
  • n 0-2;
  • pharmaceuticaliy acceptable salts and prodrugs thereof and all isomeric forms of said compound, including enantiomers and diasteromers as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof are included.
  • the compound is selected from the group of compounds consisting of
  • the invention also relates to the compound in combination with a suitable counterion.
  • those compound of formula I are preferred that comprise or contain a detectable label, such as a radioactive nuclide.
  • a detectable label such as a radioactive nuclide.
  • histological sections such as fresh frozen samples or paraffin samples can be analyzed.
  • Alkyl refers to a straight or branched chain group consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (iso-propyl), n-butyi, n-pentyl, 1 , 1 -dimethyiethyi (t- butyi), n-heptyl, and the like.
  • Alkoxy refers to a group of the formula -Oalkyl where alky! is as defined above.
  • preferred salts are pharmaceutically acceptable salts of the compounds according to the invention.
  • the invention also comprises saits which for their part are not suitable for pharmaceutical applications, but which can be used, for example, for isolating or purifying the compounds according to the invention.
  • Pharmaceutically acceptable saits of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesuiphonic acid, naphthalene disulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maieic acid and benzoic acid.
  • hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesuiphonic acid, naphthalene disulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid
  • Pharmaceutically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium saits and potassium salts), alkaline earth metal salts (for example calcium saits and magnesium saits) and ammonium salts, derived from ammonia or organic amines having 1 to 18 carbon atoms, such as, by way of example and by way of preference, ethyiamine, diethylamine, triethylamine, ethyldiisopropyiamine, rnonoethano!amine, diethanolamine, triethanolamine, dicyclo- hexyiamine, dimethyiaminoethanoi, procaine, dibenzyiamine, N-methyimorphoiine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts for example sodium saits and potassium salts
  • the present invention also comprises prodrugs of the compounds according to the invention.
  • prodrugs includes compounds which for their part may be biologically active or inactive but which, during the time they spend in the body, are converted into compounds according to the invention (for example metaboiically or hydrolyticaliy).
  • the present invention also comprises hydroiyzabie ester derivatives of the carboxylic acids of the formula (i). These are to be understood as being esters which can be hydrolvzed in physiological media and in particular in vivo by enzymaticai or chemical means to give the free carboxylic acids.
  • esters are preferably straight- chain or branched (CrC 6 )-alkyl esters in which the alkyl group may be substituted by hydroxy!, (C i-C 4 )-alkoxy, amino, mono-(Ci-C 4 )-alkylamino and/or di-(CrC 4 )-alkylamino.
  • Particular preference is given to the methyl or ethyl esters of the compounds of the formula (I).
  • Aryl refers to mono-, bi- or tricyclic aromatic or heteroaromatic ring systems, optionally substituted by one or two aikyl, alkylen, alkynesubstituents and/or alkoxysubstituents.
  • alky! represents a straight-chain or branched aikyl radical having the number of carbon atoms stated in each case.
  • the following radicals may be mentioned by way of example and by way of preference: methyl, ethyl, n-propyi, isopropyi, n-butyl, isobutyl, 1 -methy!propyi, tert-butyl, n-pentyl, isopentyl, 1 -ethylpropyl, 1 -methyibutyl, 2-methyibutyl, 3-mefhylbutyi, n-hexyl, 1 -methylpentyl, 2-mefhylpentyi, 3- methylpentyl, 4-methylpentyl, 3,3-dimethylbutyi, 1 -ethyibutyi, 2-ethyibutyl, 1 ,4- dimethyipentyl, 4,4
  • cycioalkyl represents a monocyclic saturated aikyl radical having 3 to 7 carbon atoms.
  • the following radicals may be mentioned by way of example and by way of preference: cyclopropyl, cyclobutyl, cyclopentyi, cyclohexyl and cycloheptyi.
  • alkoxy represents a straight-chain or branched aikoxy radical having 1 to 4 carbon atoms.
  • the following radicals may be mentioned by way of example and by way of preference: methoxy, ethoxy, n-propoxy, isopropoxy, 1- methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • halogen includes fluorine, chlorine, bromine and iodine. Preference is given to fluorine,
  • radicals in the compounds according to the invention are substituted, the radicals can, unless specified otherwise, be mono- or polysubstituted. in the context of the present invention, the meanings of all radicals which occur more than once are independent of one another. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to substitution with one substifuent.
  • the compounds of the invention may have asymmetric carbon atoms in their structure.
  • the compounds of the invention and their pharmaceutically acceptable salts may therefore exist as single enanfiomers, diastereoisomers, racemates, and mixtures of enantiomers and diastereomers. All such single enantiomers, diastereoisomers, racemates, and mixtures thereof are within the scope of this invention.
  • Another aspect of the invention is the use of a compound of formula I or an otherwise hereby disclosed compound as described above and herein for diagnosing and/or treating Alzheimer's disease and/or amyloidoses in a patient, in particular in a mammal, such as a human.
  • the treatment of a patient with Alzheimer's disease and/or amyloidoses can preferably be performed with a compound of the invention according to formula I that does not bear a radioactive label, but in which Y is e.g. hydrogen.
  • the use of a compound of the invention in the diagnosis is performed using positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance (MR)-speetoscropy or tomography.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MR magnetic resonance
  • Another aspect of the invention is directed to a method of imaging amyloid deposits.
  • Such a method comprises a) administering to a mammal a compound as described above and herein containing a detectable label, and b) detecting the signal stemming from the compound that is specifically bound to the amyloid deposits.
  • the specific binding is a result of the high binding affinity of the compounds of the present invention to the amyloid deposits.
  • the invention is directed to a method of diagnosing a patient with Alzheimer's disease or amyloidoses.
  • This method comprises a) administering to a human in need of such diagnosis a compound of the invention as described above and herein with a detectable label for detecting the compound in the human as described above and herein, and b) measuring the signal from the detectable label arising from the administration of the compound to the human, preferably by using a gamma camera, by positron emission tomography (PET), or by single photon emission computed tomography (SPECT).
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • a further embodiment of the invention includes a diagnostic method for other neurological disorders as Alzheimer's disease comprising the exclusion of Alzheimer's disease in a patient, that method comprising administering a compound of the invention as described above and herein to a patient and applying an imaging method of the invention.
  • a further aspect of the invention refers to a diagnostic composition for imaging amyloid deposits, comprising a radiolabeled compound according to formula I or a compound as described otherwise above or herein.
  • the diagnostic methods of the invention can also be used as post-mortem diagnostic methods using compounds as described above and herein.
  • diagnostic methods of the invention using a compound disclosed above or herein can also be used for monitoring the therapy of Alzheimer's disease, a neurodegenerative disorder or amyloidoses.
  • the diagnostic methods of the invention using a compound described above or herein can also be used in diagnosing neurological disorders other than Alzheimer's disease by excluding Alzheimer's disease.
  • the invention comprises a method of treating or preventing amyloidoses or Alzheimer's disease comprises administering to a human in need of such a treatment a compound of formula I or a compound otherwise described above or herein.
  • a further aspect of the invention refers to a pharmaceutical composition which comprises a compound of the invention as described herein, optionally together with a suitable carrier and/or additive.
  • the compounds of the invention can also be used as tools in screening, for example high throughput screening methods and in vitro assays.
  • Yet another aspect of the invention refers to a method of inhibiting the formation of amyloid or modulating the pathogenicity of amyloid in a mammal.
  • This method comprises administering a suitable compound of formula I as described herein in an amount that is effective to inhibit the formation of amyloidogenic aggregates or to modulate the pathogenicity of amyloidogenic aggregates.
  • the invention also refers to a method for synthesizing a compound of the invention according to formula I as described herein.
  • the general synthetic methods of the compounds of the invention are as follows. F-18 radiolabeling
  • a further aspect of the invention refers to a method of radiofluorination of a compound of formula I for the manufacture of radiolabeled compound of formula I comprising the step of reacting a compound of formula I with a fiuorination agent.
  • Useful Radiofluorination methods are well known to the person skilled in the art.
  • the fiuorination agent is 4,7, 13, 16,21 ,24-Hexaoxa-1 , 10 diazabicyclo[8.8.8]-hexacosane K 18 F (crownether salt Kryptofix K 18 F), K 18 F, H 18 F, KH 18 F 2 or tetraalkylammonium salt of 18 F, More preferably, fiuorination agent is K 18 F, H 18 F, or KH 18 F 2 .
  • the solvents used can be Dimethylformamide, DMF, Dimethylsuifoxyde, DMSO, Acetonitrile, eCN, Dimethyiacetamide, DMA, DMAA etc., preferably DMSO, MeCN or DMF.
  • the solvents can also be a mixture of solvents as indicated above.
  • radiolabeling procedures are well known to the person skilled in the art.
  • radiolabeling can be performed as described in the following.
  • [F-18]F!uoride can be produced by proton bombardment in a cyclotron using a silver target (1 mL) filled with [0-18] water for the 18 0 (p,n) 18 F reaction.
  • the aqueous [F- 18]fluoride can be passed through a cartridge (e.g. QMA-resin cartridge Waters, Sep Pak Light QMA Part.No.: WAT023525 ).
  • the trapped [F-18]fluoride can then be eiuted from the cartridge by adding e.g.
  • Kryptofix is 4,7, 13, 18,21 ,24-Hexaoxa-1 , 10-diazabicyclo[8.8.8]hexacosane
  • the nucleophilic substitution of the precursor works preferably in the presence of a base such as NBu 4 OH, (NBu 4 ) 2 C0 3 , NBu 4 HC0 3 , K 2 C0 3 , Cs 2 C0 3 etc. and at elevated temperatures.
  • the addition of crown ethers such as Kryptofix (K2.2.2) can influence the reaction positively, especially in the presence of K 2 C0 3 as the base.
  • the potassium fluoride Kryptofix complex is preferably dried by repeated azeotropic distillation with sequential addition of acetonitrile. Solvents such as acetonitrile, DMF, DMSO etc. can be used as a reaction solvent.
  • the labeling product can be purified by solid phase extraction using cartridges. Preferred cartridges are Sep-Pak Plus C18 cartridge (Waters, WAT020515). The cartridge can be rinsed with water and the compound can be e!uted with acetonitri!e. The eluted compound can be diluted with water and can then be subjected to preparative HPLC purification.
  • Preferred HPLC columns are reversed phase columns such as Gemini 5 ⁇ C 18 1 10 A, 250 * 10 mm (Phenomenex, 00G-4435-NQ). Mixtures of buffer solution, acids, water etc. with organic solvents such as acetonitrile, methanol, ethanol etc. can be used as mobile.
  • the solution can then be diluted with e.g. water to be passed through a cartridge for concentration and solvent change.
  • alkyl-F-18 compounds of general formula I are e.g. iodides and bromides and the like whose conversion to the respective fluorides is also known in the art (J. March, see above).
  • Precursors for aryl-F-18 compounds of general formula I are e.g. aryi or heteroaryi bromides, nitro compounds, trialkyl ammonium, aryliodonium which can be converted to the respective F-18 compounds of this invention by methods known in the art (L. Cai, S. Lu, V. Pike, Eur. J. Org, Chem 2008, 2853-2873). Starting materials for these precursors are commercially available or can be synthesized by methods known in the art (R.C. Larock, Comprehensive Organic Transformations, VCH Publishers 1989).
  • a further aspect of the invention refers to a kit comprising a non-radiolabeled compound of the invention, the compound optionally being in a dry condition or having an inert, pharmaceutically acceptable carrier and/or solvent and/or auxiliary substances added.
  • the compounds according to the invention can act system icaily and/or locally.
  • they can be administered in a suitable manner, such as, for example, orally, parenteraliy, pulmonally, nasaliy, sublinguaiiy, lingualiy, buccally, rectaliy, dermaliy, transdermal, conjunetivaliy, otieally or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • suitable administration forms which work in accordance with the prior art and release the compounds according to the invention rapidly and/or in modified form and which comprise the compounds according to the invention in crystalline and/or amorphicized and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example with enteric coats or coats which dissolve in a delayed manner or are insoluble and which control the release of the compounds according to the invention), films/wafers or tablets which dissolve rapidly in the oral cavity, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar- coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration may take place by circumventing a bioabsorption step (for example intravenously, infraarterially, intracardially, intraspinaiiy or intraiumbarly), or with bioabsorption (for example intramuscularly, subcutaneous! 1 /, intracutaneously, percutaneously or intraperitoneaily).
  • a bioabsorption step for example intravenously, infraarterially, intracardially, intraspinaiiy or intraiumbarly
  • bioabsorption for example intramuscularly, subcutaneous! 1 /, intracutaneously, percutaneously or intraperitoneaily.
  • Administration forms suitable for parenteral administration are inter alia preparations for injection or infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • Suitable for other administration routes are, for example, medicaments suitable for inhalation (inter alia powder inhalers, nebulizers), nose drops, solutions or sprays, tablets to be administered lingualiy, sublinguaiiy or buccaliy, films/wafers or capsules, suppositories, preparations to be administered to ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example plasters), milk, pastes, foams, powders for pouring, implants or stents.
  • medicaments suitable for inhalation inter alia powder inhalers, nebulizers
  • nose drops tablets to be administered lingualiy, sublinguaiiy or buccaliy
  • films/wafers or capsules films/wafers or capsules
  • suppositories preparations to be administered to ears or eyes
  • vaginal capsules aqueous suspensions
  • the compounds according to the invention can be converted into the administration forms mentioned. This can be carried out in a manner known per se by mixing with inert non-toxic pharmaceutically suitable auxiliaries.
  • auxiliaries include inter alia carriers (for example microcrysfailine cellulose, lactose, mannitoi), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyi sulphate, polyoxysorbitan oieate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants, such as, for example, ascorbic acid), colorants (for example inorganic pigments, such as, for example, iron oxides), and flavour and/or odor corrigents.
  • carriers for example microcrysfailine cellulose, lactose, mannitoi
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyi sulphate, polyoxysorbitan oieate
  • binders for example polyvinylpyrrol
  • Another aspect of this invention is related to methods of preparing compounds of the general formula ⁇
  • the radio-labeling of the benzothiazol-pyrazole labeling precursor 22 is shown in scheme 4.
  • Treatment of 22 with F-18 potassium fluoride and Kryptofix 222 in DMSO/MeCN gave the F-18 fluoroalkylated compound 13 F-39.
  • Fluoroalkylated compounds can also be synthesized by indirect labeling as exemplified in scheme 5, Compound 8 F-41 was synthesized by conversion of compound 11 with F- 18 fluoromethyl tosylate Compounds 18 F-39 and 18 F-40 could be synthesized accordingly via the corresponding F-18 fiuoroaikyi tosyiates.
  • Fig. 1 summarizes exemplified compounds.
  • C(0)heteroraryl is selected from the group consisting of H, C(0)CH 3 , C(0)(CH 2 ) n CH 2 X, C(0)CF C(0)OC(CH 3 ) 3 , C(0)C 6 H4X, C(0)C 6 H3XZ, C(0)heteroraryl, substituted C(0)heteroraryl - R 2 is selected from the group consisting of H, CH 3 , (CH 2 )nCH 3 , (CH 2 ) m CH 2 X, R 1 ;
  • R 3 is selected from the group consisting of H, C(0)OH, C(0)0(CH 2 )nCH 3 , C(0)0(CH 2 ) m CH 2 X, C(0)NH 2 , C(0)NH(CH 2 ) n CH 3 , C(0)NH(CH 2 ) m CH 2 X;
  • R 4 and R 5 are independently selected from the group consisting of H, CH 3 , (CH 2 )nCH 3 , (CH 2 )nCH 2 X, OH, OCH 3 , 0(CH 2 ) n CH 3 , 0(CH 2 ) n CH 2 X, O-cyciobufyl-X, O-cyclopentyi-X, O-cyclohexyl-X, 0(CH 2 CH 2 0) n CH 2 CH 2 X, SH, SCH 3 , S(CH 2 ) n CH 3 , S(CH 2 ) n CH 2 X, NH 2 , NHCH 3 , N(CH 3 ) 2 , NH(CH 2 ) n CH 3 , NH(CH 2 ) m CH 2 X, NCH 3 (CH 2 ) m CH 2 X, X, Z;
  • - W is selected from CH or N
  • - X is selected from the group consisting of F, 18 F, I, 25 l, 123 l ;
  • - Z is selected from the group consisting of H, CF 3, CN, C(0)H, C(0)CH 3 , C(0)0(CH 2 ) n CH 3 ;
  • - m has the meaning of 1-4;
  • n has the meaning of 0-4; including ail isomeric forms of said compound, including enantiomers and diasteromers as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof, wherein the formula comprises only one X.
  • R 1 is selected from the group consisting of H, C(0)CH 3 , C(0)(CH 2 ) n CH 2 X, C(0)CF 3 , C(0)OC(CH 3 ) 3 , C(0)C 6 H 4 X, C(0)C 6 H 3 XZ, C(0)heteroraryl, substituted C(0)heteroraryl;
  • R 2 is selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , (CH 2 ) m CH 2 X, R 1 ;
  • R 3 is selected from the group consisting of H, C(0)OH, C(0)0(CH 2 ) r! CH 3 , C(0)0(CH 2 ) m CH 2 X, C(0)NH 2 , C(0)NH(CH 2 ) n CH 3 , C(0)NH(CH 2 ) m CH 2 X;
  • R 4 and R are independently selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , (CH 2 ) n CH 2 X, OH, OCH 3 , 0(CH 2 ) n CH 3 , 0(CH 2 ) n CH 2 X, O-cyciobutyl-X, O-cyclopentyi-X, 0(CH 2 CH 2 0) n CH 2 CH 2 X, NH 2 , NHCH 3 , N(CH 3 ) 2 , NH(CH 2 ) n CH 3 , NH(CH 2 ) m CH 2 X,
  • - W is selected from CH or N
  • - X is selected from the group consisting of F, 18 F, I, 25 l, 123 i ;
  • - Z is selected from the group consisting of H, CF 3, CN, C(0)H, C(0)CH 3 ;
  • - m has the meaning of 1-3;
  • n has the meaning of 0-3; including ail isomeric forms of said compound, including enantiomers and diasteromers as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof, wherein the formula comprises only one X.
  • R 1 is selected from the group consisting of H, C(0)CH 3 , C(0)(CH 2 ) I1 CH 2 X, C(0)CF 3 , C(0)OC(CH 3 ) 3 , C(0)C 6 H 4 X, C(0)C 6 H 3 XZ;
  • R 2 is selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , R ;
  • R 3 is selected from the group consisting of H, C(0)OH, C(0)0(CH 2 )nCH 3 , C(0)0(CH 2 ) m CH 2 X;
  • R 4 and R 5 are independently selected from the group consisting of H, (CH 2 ) n CH 2 X, OH, OCH 3 , 0(CH 2 ) n CH 2 X, O-cyclobutyl-X, 0(CH 2 CH 2 0) felicitCH 2 CH 2 X, X, Z;
  • - W is selected from CH or N
  • - X is selected from the group consisting of F, 18 F ;
  • - Z is selected from the group consisting of H, CF 3 _ CN, C(0)H;
  • - m has the meaning of 1-2;
  • n has the meaning of 0-2, including ail isomeric forms of said compound, including enantiomers and diasteromers as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof, wherein the formula comprises only one X.
  • R 1 is selected from the group consisting of H, C(0)CH 3 , C(0)(CH 2 )nCH 2 X, C(0)CF 3 , C(0)OC(CH 3 ) 3 , C(0)C 6 H 4 X, C(0)C 6 H 3 YZ, C(0)C 6 H 3 XZ, C(0)heteroraryl, substituted
  • R 2 is selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , (CH 2 ) m CH 2 X, R 1 ;
  • R 3 is selected from the group consisting of H, C(0)OH, C(0)0(CH 2 ) n CH 3 , C(0)0(CH 2 )mCH 2 X, C(0)NH 2 , C(0)NH(CH 2 ) n CH 3 , C(0)NH(CH 2 ) rn CH 2 X;
  • R 4 and R 5 are independently selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , (CH 2 ) n CH 2 X, OH, OCH 3 , 0(CH 2 ) n CH 3 , 0(CH 2 ) n CH 2 X, O-cyciobutyl-X, O-cyclopentyl-X,
  • O-cyclohexyl-X 0(CH 2 CH 2 0) n CH 2 CH 2 X, SH, SCH 3 , S(CH 2 ) n CH 3 , S(CH 2 ) n CH 2 X, NH 2 , NHCH 3 , N(CH 3 ) 2 , NH(CH 2 ) n CH 3 , NH(CH 2 ) m CH 2 X, NCH 3 (CH 2 ) rn CH 2 X, X, Y, Z;
  • - W is selected from CH or N - X is selected from the group consisting of F, CI, Br, 1, OS0 2 CH 3 , OS0 2 CF 3 , OSO 2 C 4 F 9 , OS0 2 C 6 H 5 , OS0 2 C 6 H 4 CH 3 , OS0 2 C 6 H 4 N0 2 , OS0 2 C 6 H 4 Br, OS0 2 C 6 H 2 (CH(CH 3 ) 2 ) 3 , OS0 2 C 6 H 3 (GCH 3 ) 2; - Y is selected from the group consisting of N0 2 , N + Me 3 , l*aryi, S + aryl 2 ;
  • - Z is selected from the group consisting of H, CF 3, CN, C(0)H, C(0)CH 3 , C(0)0(CH 2 ) n CH 3 ;
  • - m has the meaning of 1-4;
  • n has the meaning of 0-4; including ail isomeric forms of said compound, including enantiomers and diasteromers as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof, wherein the formula comprises only one X,
  • R 2 is selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , (CH 2 ) m CH 2 X, R 1 ;
  • R 3 is selected from the group consisting of H, C(0)OH, C(0)0(CH 2 )nCH 3 , C(0)0(CH 2 ) m CH 2 X, C(0)NH 2 , C(0)NH(CH 2 ) n CH 3 , C(0)NH(CH 2 ) m CH 2 X;
  • R 4 and R 5 are independently selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , (CH 2 ) n CH 2 X, OH, OCH 3 , 0(CH 2 ) n CH 3 , 0(CH 2 ) n CH 2 X, O-cyciobutyl-X, O-cyclopentyl-X, 0(CH 2 CH 2 0) n CH 2 CH 2 X, NH 2 , NHCH 3 , N(CH 3 ) 2 , NH(CH 2 ) n CH 3 , NH(CH 2 ) rfi CH 2 X, NCH 3 (CH 2 ) m CH 2 X, X, Y, Z;
  • - W is selected from CH or N - X is selected from the group consisting of F, CI, Br, 1, OS0 2 CH 3 , OS0 2 CF 3 , OSO2C4F9, OS0 2 C 6 H 5 , OS0 2 C 6 H 4 CH3, OSG 2 C 6 H 4 N0 2 , OS0 2 C 6 H 4 Br, OS0 2 C 6 H 3 (OCH 3 ) 2;
  • - Y is selected from the group consisting of N0 2 , N + Me 3 , Taryl, S + aryl 2 ;
  • - Z is selected from the group consisting of H, CF 3, CN, C(0)H, C(0)CH 3 ;
  • - m has the meaning of 1-3;
  • n has the meaning of 0-3; including ail isomeric forms of said compound, including enantiomers and diasteromers as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof wherein the formula comprises only one X,
  • R 1 is selected from the group consisting of H, C(0)CH 3 , C(0)(CH 2 ) n CH 2 X, C(0)CF 3 , C(0)OC(CH 3 ) 3 , C(0)C 6 H 4 X, C(0)C 6 H 3 YZ, C(0)C 6 H 3 XZ, C(0)OCH 3 , C(0)OCH 2 CH 3 , C(0 ⁇ OCH 2 C 6 H5, Frnoc;
  • R 2 is selected from the group consisting of H, CH 3 , (CH 2 ) n CH 3 , R ;
  • R 3 is selected from the group consisting of H, C(0)OH, C(0)0(CH 2 )nCH 3 , C(0)0(CH 2 ) m CH 2 X;
  • R 4 and R 5 are independently selected from the group consisting of H, (CH 2 ) n CH 2 X, OH, OCH 3 , 0(CH 2 ) n CH 2 X, O-cyclobutyi-X, 0(CH 2 CH 2 0) n CH 2 CH 2 X, X, Y, Z;
  • - W is selected from CH or N
  • - X is selected from the group consisting of F, CI, Br, I, OS0 2 CH 3 , OS0 2 CF 3 , OS0 2 C 4 F g , OS0 2 C 6 H 5 , OS0 2 C 6 H 4 CH 3;
  • - Y is selected from the group consisting of N0 2 , N + Me 3 , l + aryl, S + aryi 2 ;
  • - Z is selected from the group consisting of H, CF 3, CN, C(0)H;
  • - m has the meaning of 1-2;
  • n has the meaning of 0-2, including ail isomeric forms of said compound, including enantiomers and diasteromers as well as raeemic mixtures, and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof, wherein the formula comprises only one X,
  • a compound according to count 12 as a compound for diagnostic imaging of a disease selected from the group of diseases comprising Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis.
  • a pharmaceutical or diagnostic composition comprising a 18 F radioactively labelled compound according to counts 1 - 4, 10 or 1 1 and a pharmaceutically acceptable carrier.
  • a method for the preparation of a 18 F radiofiuorinafed compound according to counts 1 - 4, 10 or 1 1 the method comprising reacting a suitable precursor molecule of counts 5 - 7, or 9 with a radiofluorinating agent.
  • a method according to count 16 for the preparation of a compound according to count 10 the method comprising reacting a suitable precursor molecule of count 9 with a radiofluorinating agent,
  • a method for diagnosing a disease in a mammal selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis comprising administering a radioactively labelled compound of counts 1 - 4, 10, 1 1 , 12, or 13 or a composition according to count 15 or 16 to said mammal, imaging said mammal and detecting the signal.
  • a radioactively labelled compound of counts 1 - 4, 10, 1 1 1 , 12, or 13 or a composition according to count 15 or 16 to said mammal, imaging said mammal and detecting the signal.
  • a method of imaging amyloid plaques in a mammal comprising administering a compound according to counts 1 - 4, 10, 1 1 , 12 or 13, a composition according to counts 15 or 16 to said mammal, imaging said mammal and detecting the signal.
  • Fig. 1 list of compounds prepared.
  • Fig. 2 HPLC chromatogram of compound [18FJ-39.
  • Fig. 3 HPLC chromatograms of compound [18FJ-40 in comparison with compound 16.
  • Fig. 4 HPLC chromatograms of [18F]MeBr and compound [18F]-41 in comparison with compound 15.
  • Fig. 5 HPLC chromatograms compound [18FJ-42 in comparison with compound 4.
  • Fig. 6 HPLC chromatograms of compound [18FJ-43 in comparison with compound 36.
  • Fig. 7 Autoradiographical analysis of binding of compound 18 F-39 to brain sections from cortex of Alzheimer ' s disease patients (AD) and controls without ⁇ plaques (HC) (healthy control). Blocking of specific signals was performed with an excess of cold compound. Arrows point to plaque-specific signals.
  • Fig. 8 Autoradiographical analysis of binding of compound 13 F-40 to brain sections from cortex of Alzheimer ' s disease patients (AD) and controls without ⁇ plaques (HC) (healthy control). Blocking of specific signals was performed with an excess of cold compound. Arrows point to plaque-specific signals.
  • Fig. 9 Autoradiographical analysis of binding of compound 18 F-41 to brain sections from cortex of Alzheimer ' s disease patients (AD) and controls without ⁇ plaques (HC) (healthy control). Blocking of specific signals was performed with an excess of cold compound. Arrows point to plaque-specific signals.
  • Fig. 10 Autoradiographical analysis of binding of compound 8 F-43 to brain sections from cortex of Alzheimer ' s disease patients (AD) and controls without ⁇ plaques (HC) (healthy control). Blocking of specific signals was performed with an excess of cold compound. Arrows point to plaque-specific signals.
  • Benzoyl chloride (18.5 g, 132 mmol) was added to a solution of ammonium thiocyanate (12 g, 158 mmol) in acetone (350 mL) over 5 minutes and the mixture was refluxed for 15 minutes.
  • 3-Bromo-4-fluoroaniline 25 g, 132 mmol was added to the mixture at 40 and refluxing was continued for 30 minutes.
  • the hot solution was poured over ice (400 mL) and the mixture was stirred for 5 minutes until a precipitate formed, which was collected by filtration and washed with 50% methanol in water (50 mL).
  • Benzoyl chloride (1.53 g, 10.8 mmol) was added to a solution of ammonium thiocyanate (0.94 g, 12.4 mmol) in acetone (17 mL) over 5 minutes and the mixture was refluxed for 15 minutes.
  • 2-Bromo-4-fluoro-5-(trifiuoromethyl)aniline 2.0 g, 7.7 mmol
  • acetone 14 mL
  • the hot solution was poured over ice (100 mL) and the mixture was stirred for 5 minutes until a precipitate formed, which was collected by filtration and washed with 50% methanol in water (30 mL).
  • Benzoyl chloride (6.4 mL, 54.9 mmol) was added to a solution of ammonium thiocyanate (5.0 g, 65.5 mmol) in acetone (174 mL) and the mixture was refluxed for 15 minutes.
  • 1 ,5-Dibromo-4-nitroaniline (1 1 .6 g, 39.2 mmol, C. Wang ei ai. Synthesis 2003, 13, 2089-2095) was added to the mixture at 4G and r efluxing was continued for 14 hours.
  • the hot solution was poured over ice (2000 mL) and the mixture was stirred for 5 minutes until a precipitate formed, which was collected by filtration and washed with 50% methanol in water (100 mL).
  • Toiuene-4-suifonic acid 3-[2-(3-amino-pyrazol-1 -yi)-benzothiazol-6-yloxy] ⁇ cyclobutyi ester 4d (35 mg, 0.077) was solved in THF (1 mL).
  • TBAF 36 mg, 0.1 1 mmol was added and the reaction mixture was stirred at 75 ⁇ for 5h. The mixture was concentrated and the residue was purified by chromatography on silica gel to give 10 mg (43%) of 17.
  • Toluene-4-sulfonic acid 2-[2-(3-aminopyrazol-1 -yl)benzothiazol-6-yloxy]ethyl ester 18 (100 mg, 0.23 mmol) was solved in dichloromethane (3 mL). Boc 2 0 (200 mg, 0.93 mmol), triethyiamine (94 mg, 0.93 mmol) and DMAP (6 mg, 0.05 mmol) were added. The reaction mixture was stirred at SO'C for 4h and concentrated. The residue was purified by chromatography on siiica gel to yieid 88 mg (60%) of 22.
  • N-[1 -(6-Bromo-benzofhiazol-2-yl)-1 H-pyrazol-3-yi]-acetamide 23 (155 mg, 0.46 mmol) was suspended in DMF (2mL).
  • Pd(Ph 3 ) 4 106 mg, 0.092 mmoi
  • potassium carbonate 0.8 mL, 2.4 mmol, 3M in water
  • Methanesuifonic acid 3-[2-(3-amino-pyrazol-1-yl)-benzothiazoi-6-ylj-propyl ester 24 (80 mg, 0.2 mmol) was solved in THF (3 mL).
  • TBAF (96 mg, 0.3 mmol) was added and the reaction mixture was stirred at 75 ⁇ for 5h and con centrated. The residue was purified by chromatography on silica gel to give 30 mg (47%) of 25.
  • N- ⁇ 1-[6-(3-Fluoropropyl)-benzothiazol-2-yl]-1 H-pyrazol-3-yl ⁇ acetamide 25 (30 mg, 0.09 mmol) was stirred for 48 hours in 0.5 M solution of sodium hydroxide in ethanol (0.5 mi, 0.25 mmol) and then heated to 40 ⁇ for 8 hours. (3 mL). The reaction mixture was neutralized with 1 M hydrochloric acid and concentrated. The residue was purified by chromatography on silica gel to give 3.7 mg (14 %) of compound 26.
  • Benzoyl chloride (5.8 mL, 50 mmol) was added to a solution of ammonium thiocyanate (4.35 g, 57 mmol) in acetone (79 mL) and the mixture was refluxed for 15 minutes.
  • 6- Fluoropyridin-3-amine (4.0 g, 35.7 mmol) in acetone (52 mL) was added to the mixture at 40 and refluxing was continued for 1 ,5 hours.
  • the hot solution was poured over ice water (400 mL) and the mixture was stirred for 5 minutes until a precipitate formed, which was collected by filtration and washed with 50% methanol in water (50 mL).
  • Benzoyl chloride (1 .9 rnL, 16.7 mmol) was added to a solution of ammonium thiocyanate (1 .45 g, 19.1 mmol) in acetone (21 mL) and the mixture was refiuxed for 15 minutes.
  • 3-Amino ⁇ 2,6-dibromopyridine (3.0 g, 1 1 .9 mmol, Parlow, J. J.; South, . S. Tetrahedron 2003, 59, 7695 - 7702) in acetone (26 mL) was added to the mixture at 40 and refiuxing was continued for 1 .5 hours.
  • 6-Bromo-2-chlorothiazolo[5,4-b]pyridine (580 mg, 2.3 mmo!) in DMF (14 ml_) and acetoniirile (14 mL) was added to a stirred suspension of caesium carbonate (482 mg, 3.5 mmo! and 1 H-pyrazoi-3-amine (212 mg, 2.6 mmol) in DMF (9 mL) and acetonitri!e (9 mL) and heated to 7QO lor 4 hours, while additi onal portions of caesium carbonate (241 mg, 1 .7 mmol) were added after 15, 30, 45, 60, 75, 150, 165 and 180 minutes.
  • Benzoyl chloride (284 mg, 2.0 mmol) was added to a solution of ammonium thiocyanate (176 mg, 2.3 mmol) in acetone (3 mL) and the mixture was refluxed for 15 minutes.
  • 3- Amino-2,6-diiodopyridine (0.5 g, 1 .45 mmol, ) in acetone (2.7 mL) was added to the mixture at room temperature and stirring was continued for 3 hours. The solution was poured into ice water and the mixture was stirred for 5 minutes until a precipitate formed, which was collected by filtration and washed with 50% methanol in water.
  • the forming precipitate was collected by filtration and washed with water.
  • the precipitate was triturated with dichloromethane and additionally purified by preparative thin layer chromatography on silica gel (ethyl acetate in dichloromethane 30% + 1 % triethylamine) to yield 10 mg of the title compound.
  • [ 18 F]fluoride (7,4 GBq) was trapped on a preconditioned QMA cartridge (Waters). The activity was eluted using 1 .5 mL kryptofix solution (5 mg K222, rng K 2 C0 3i 1 .25 mL MeCN, 0.25 mL water) and the solvent was removed at 120 ⁇ under gentle nitrogen steam and more MeCN (2 x 1 mL) was added and evaporated as before. The precursor 22 (1 .5 mg in 150 ⁇ . DMSO + 100 ⁇ MeCN) was added and the resulting solution was stirred for 10 min at 120 ⁇ , Aqueous HCi (1 M, 1 mL) was added to the mixture and stirred for additional 5 min at 1 10 ⁇ .
  • the collected HPLC fraction was diluted with 50 mL water, passed through a preconditioned tC18 plus cartridge.
  • the cartridge was washed with 5 mL water and eluted with 2 mL EtOH to deliver 716 MBq of the final product [ 18 F]-39 (14%, corrected for decay, radiochemical purity > 98%) after an aliover synthesis time of 63 min.
  • Aqueous [ 18 FJF!uoride (8.1 GBq) was trapped on a QMA cartridge (Waters) and eluted with 5 mg K2.2.2 in 0,95ml MeCN +1 mg K 2 C0 3 in 50 ⁇ water into a reaction vessel. The solvent was removed by heating at 120 for 10 min under a stream of nitrogen. Anhydrous MeCN (1 ml) was added and evaporated as before. A solution of starting material 20 (2 mg) in 500 ⁇ anhydrous MeCN was added.
  • the crude product was purified by preparative HPLC: ACE 5-C18- HL 250mmx10rnrn; isocratic, 48% acetonitrile in 0.1 % trifluoroacetic acid, flow: 4 ml/min; t R ⁇ 15 min.
  • the collected HPLC fraction was diluted with 40 mL water and immobilized on a Sep-Pak light C18 cartridge (Waters), which was washed with 5 mL water and eluted with 1 mL ethanoi to deliver 471 MBq product (1 1 %, corrected for decay; radiochemical purify >97.5 %) in 1000 ⁇ EtOH in a overall synthesis time of 60 min.
  • Aqueous [ 18 F]Fiuoride (3 GBq) was trapped on a QMA cartridge (Waters) and eluted with 15mg K2.2.2 in 0.95 mL MeCN / 2.7mg K 2 C0 3 in 50 ⁇ water into the reaction vessel. The solvent was removed by heating at 140°C for 10 min under a stream of nitrogen. Anhydrous MeCN (1 mL) was added and evaporated as before. A solution of dibromo-methane (100 ⁇ _) in 1000 ILanhydrous MeCN was added. After heating at 130 ⁇ for 5 min the crude reaction mixture was all owed to cool down to room temperature. By bubbling a stream of nitrogen through the reaction mixture.
  • [ 18 F]Bromo- fluoro-methane was purified by distillation through several SepPak Silica Plus cartridges (Waters) and trapped in 800 ⁇ _ DMSO in 5 mL Weaton V-vial.
  • reaction mixture was diluted wi th 4 mL H 2 0/MeCN (+0, 1 % TFA) 65:35 and eventually purified by preparative HPLC: ACE 5-C18-HL 25Qmmx10mm; isocratic, 35% acetonitrile in 0.1 % trifluoroacetic acid, flow: 4 mL/min; t R ⁇ 20 min.
  • the collected HPLC fraction was diluted with 40ml water and immobilized on a Sep-Pak light C18 cartridge (Waters), which was washed with 5 mL water and eluted with 1 mL ethanoi to deliver 220 MBq product (16%, corrected for decay; radiochemical purify >99%) in 1000 ⁇ L ⁇ EtOH in a overall synthesis time of 1 10 min.
  • Aqueous [ 18 FjFluoride (1 .8 GBq) was trapped on a QMA cartridge (Waters, Sep Pak Light QMA Part.No.: WAT023525 ) and eluted with 1 .5 mL K 222 /K 2 C0 3 solution (5 mg K 222 in 0.95 mL MeCN, 1 mg K 2 C0 3 in 0.05 mL water) into the reaction vessel.
  • the solvent was removed by heating at 120 for 10 min under a stream of nitrogen.
  • Anhydrous MeCN (1 mL) was added and evaporated as before.
  • a solution of precursor 6 (2.5 mg) in 500 ⁇ anhydrous DMF was added.
  • the collected HPLC fraction was diluted with 40mL water and immobilized on a Sep-Pak tC18 plus short: Waters; Part.No.: WAT038810, which was washed with 5 mL water and eiuted with 1 mL ethanol to deliver the 650 MBq of the F-18 labeled product (13 % rc. yield, corrected for decay; >99% HPLC) in 1000 ⁇ EtOH in a overall synthesis time of -80 min.
  • a competition assay with a tritiated amyloid ligand was performed in 96-weli plates (Greiner bio-one; Cat. 651201 ; Lot. 06260130) using brain homogenate from AD patients.
  • Homogenates were prepared by homogenizing (Ultra-Turrax, setting 2, 30 s, 24000 rpm) dissected frontal cortex containing grey matter and white matter from AD patients in phosphate buffered saline (PBS, pH 7.4). The homogenate with a concentration of 100 mg wet tissue/mi was divided into aliquots of 300 ⁇ and stored at -80 .
  • Frozen sections sliced at 18 ⁇ thickness on a cryostate (Leica, Germany) and paraffin sections, sliced on a sliding microtom (Leica) at a thickness of 6 m, were mounted onto glass slides (Superfrost Plus, Fa.Menzei, Braunschweig Germany). Frozen sections were allowed to adhere to the slides for several nights at -20 . The paraffin sections were deparaffinized using routine histological methods. For binding studies sections were incubated with the F-18 labeled test compound at 10 Bq/ ⁇ diluted in 25m Hepes buffer, pH 7.4, 0, 1 % BSA (200-300 ⁇ /slide) for 1 ,5 hour at room temperature in a humidified chamber.
  • Biodistribution and excretion studies were performed in male N Ri mice (body weight app. 30 g; 3 animals per time point). The animals were kept under normal laboratory conditions at a temperature of 22 ⁇ 2 ⁇ and a dark/ light rhythm of 12 hours. Food and water were provided ad iibitium. During an acclimation period of at least 3 days before the beginning of the study animals were clinically examined to ascertain the absence of abnormal clinical signs.
  • Tabei 2 Brain uptake and brain wash-out of compounds expressed as percentage of injected dose per gram tissue [%ID/g]. The F-18 signal was detected at 2 min and 30 min after compound administration to mice. Note the favourable high brain uptake and fast wash-out from healthy mouse brain, which is devoid of plaques.
  • the tracers 18 F-4Q and 18 F-43 show an advantageous rapid eiimination of the unspecific radioactive signal from the brain.

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Abstract

La présente invention concerne de nouveaux composés (benzothiazolopyrazoles et thiazolopyridin-pyrazoles) utiles dans la liaison et l'imagerie de dépôts amyloïdes et leur utilisation dans la détection ou le traitement de la maladie d'Alzheimer et de l'amyloïdose.
PCT/EP2011/061967 2010-07-14 2011-07-13 Composés destinés à la liaison et à l'imagerie de plaques amyloïdes et leur utilisation WO2012007510A1 (fr)

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JP2017528519A (ja) * 2014-08-29 2017-09-28 シーエイチディーアイ ファウンデーション，インコーポレーテッド ハンチントンタンパク質のイメージング用プローブ
WO2017214005A1 (fr) 2016-06-06 2017-12-14 Bristol-Myers Squibb Company Dérivés de 2-(benzothiazol-2-yl)-2-cyano-acétamide et leur utilisation en tant qu'inhibiteurs de la lipase endothéliale
CN112778175A (zh) * 2020-12-30 2021-05-11 四川大学华西医院 环丁烯衍生物的制备方法及其在制备荧光标记试剂中的应用

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EP4001277A3 (fr) * 2016-03-11 2022-09-14 AC Immune SA Composes bicycliques pour le diagnostic et le traitement
KR20220151042A (ko) * 2016-03-11 2022-11-11 에이씨 이뮨 에스에이 진단 및 치료를 위한 바이사이클릭 화합물
KR102646115B1 (ko) 2016-03-11 2024-03-12 에이씨 이뮨 에스에이 진단 및 치료를 위한 바이사이클릭 화합물
WO2017214005A1 (fr) 2016-06-06 2017-12-14 Bristol-Myers Squibb Company Dérivés de 2-(benzothiazol-2-yl)-2-cyano-acétamide et leur utilisation en tant qu'inhibiteurs de la lipase endothéliale
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