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WO2009018088A2 - Imagerie d'alpha-synucléine - Google Patents

Imagerie d'alpha-synucléine Download PDF

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Publication number
WO2009018088A2
WO2009018088A2 PCT/US2008/071017 US2008071017W WO2009018088A2 WO 2009018088 A2 WO2009018088 A2 WO 2009018088A2 US 2008071017 W US2008071017 W US 2008071017W WO 2009018088 A2 WO2009018088 A2 WO 2009018088A2
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WO
WIPO (PCT)
Prior art keywords
compound
synuclein
alpha
substituted
unsubstituted
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Application number
PCT/US2008/071017
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English (en)
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WO2009018088A3 (fr
Inventor
Peter T Lansbury
Craig J. Justman
Leslie Shinobu
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Link Medicine Corporation
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Publication of WO2009018088A2 publication Critical patent/WO2009018088A2/fr
Publication of WO2009018088A3 publication Critical patent/WO2009018088A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • 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
    • 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
    • A61K51/0412—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • 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
    • A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to the treatment of neurodegenerative diseases, particularly synucleinopathies, such as Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA).
  • PD Parkinson's disease
  • DLBD diffuse Lewy body disease
  • MSA multiple system atrophy
  • Synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathologic lesion containing abnormal aggregates of insoluble ⁇ -synuclein protein in selectively vulnerable populations of neurons and glia.
  • Certain evidence links the formation of filamentous aggregates to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders including Parkinson's disease (PD), diffuse Lewy body disease (DLBD), multiple system atrophy (MSA), and disorders of brain iron concentration including pantothenate kinase-associated neurodegeneration (e.g., PANKl).
  • PD Parkinson's disease
  • DLBD diffuse Lewy body disease
  • MSA multiple system atrophy
  • PANKl pantothenate kinase-associated neurodegeneration
  • the current treatment options for these diseases include symptomatic medications such as carbidopa-levodopa, anticholinergics, and monoamine oxidase inhibitors, with widely variable benefit. Even for the best responders, i.e., patients with idiopathic Parkinson's Disease, an initial good response to levodopa is typically overshadowed by drug-induced complications such as motor fluctuations and debilitating dyskinesia, following the first five to seven years of therapy. For the rest of the disorders, the current medications offer marginal symptomatic benefit. Treatment designed to reduce ⁇ - synuclein deposits are of high interest, and a number of strategies (e.g., RNAi, vaccine, small molecule) are already being explored in pre-clinical studies.
  • RNAi RNAi, vaccine, small molecule
  • the present invention stems from recognizing the importance of assessing the levels of ⁇ -synuclein deposits in the central nervous system as an indicator of disease progression in synucleinopathic patients, such as patients with Parkinson's Disease (PD), Diffuse Lewy Body Disease (DLBD), Multiple System Atrophy (MSA), and disorders of brain iron concentration including pantothenate kinase-associated neurodegeneration (e.g., PANKl). Assessing levels of ⁇ -synuclein deposits also allows one to follow treatment of a synucleinopathic subject.
  • the present invention provides radiolabeled compounds that bind to, or otherwise interact with, ⁇ -synuclein.
  • the radiolabeled compounds may be used in vivo or in vitro.
  • the quantity and/or location of bound compound may be determined using an imaging technique known in the art.
  • SPECT or PET imaging is used.
  • Autoradiograms or scintillation counting may also be used to assess the levels of alpha- synuclein deposits in a biological sample or subject.
  • the inventive technique may be useful in assessing various treatment modalities.
  • the invention provides compounds that bind to or interact with ⁇ - synuclein and are labeled with a radioisotope.
  • the radioisotope is suitable for SPECT or PET imaging.
  • the radioisotope is a radioisotope of a halogen such as fluorine (e.g., F- 18), chlorine, bromine (e.g., Br-76), or iodine (e.g., 1-123).
  • fluorine e.g., F- 18
  • chlorine, bromine e.g., Br-76
  • iodine e.g., 1-123.
  • Any agent that binds ⁇ -synuclein may be used.
  • the agent is a labeled derivative of a tricyclic antidepressant.
  • the agent may be a halogenated tricyclic antidepressant.
  • agents that bind to ⁇ -synuclein include nortriptyline, protriptyline, norclomipramine, maprotiline, imipramine, trimipramine, desipramine, doxepin, amoxapine, amitriptyline, mirtazapine, clomipramine, cyproheptadine, cyclobenzaprine, and lofepramine (see Figure 1). These compounds may be fluorinated, chlorinated, brominated, or idodinated.
  • the aromatic rings of the molecules may be used as sites for halogenation as norclomipramine has a chlorine atom on one of its aromatic rings.
  • the invention provides methods of using the inventive labeled compounds for imaging ⁇ -synuclein or assessing ⁇ -synuclein levels.
  • a biological sample is contacted with an inventive radiolabeled compound at a sufficient concentration to effect binding of the compound to any ⁇ -synuclein present in the sample.
  • the sample is then analyzed to detect bound labeled compound.
  • the detection of ⁇ -synuclein may be quantitative.
  • the invention provides methods of imaging using the labeled compounds of the invention.
  • An amount of the labelled compound effective to bind to or interact with ⁇ -synuclein in the subject is administered to subject.
  • the subject is then images using SPECT or PET imaging to detect ⁇ -synuclein deposits.
  • the brain is imaged.
  • the nervous system is images.
  • the inventive method may be used to diagnose a patient with a synucleinopathy such as Parkinson's Disease. In other embodiments, the inventive method is used to follow disease progression or treatment of a subject.
  • the present invention is a major advance in the diagnosis and treatment of synucleinopathies such as Parkinson's disease, diffuse Lewy Body disease, and multiple system atrophy.
  • the invention provides a system useful for research as well as clinical purposes.
  • the invention is particularly useful in assessing the treatment of a synucleinopathic patient using new treatment modalities such as agents that affect the synthesis, aggregation, deposition, and/or clearance of ⁇ -synuclein.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and ⁇ r ⁇ ws-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, including specific polymorphs, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention.
  • mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are all contemplated by the present invention.
  • mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are all contemplated by the present invention.
  • analogous ratios are contemplated for more complex isomer mixtures.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • protecting group it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound.
  • a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group should be selectively removable in good yield by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction.
  • oxygen, sulfur, nitrogen, and carbon protecting groups may be utilized.
  • Hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), ⁇ -butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), ⁇ -butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxycyclohexyl, A- methoxytetrahydropyranyl (MTHP), 4-methoxyt
  • the protecting groups include methylene acetal, ethylidene acetal, l-?-butylethylidene ketal, 1 -phenylethylidene ketal, (4- methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p- methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1 -methoxyethylid
  • Amino-protecting groups include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10, 10-dioxo-lO, 10, 10, 10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, 1,1-
  • protecting groups are detailed herein. However, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present invention. Additionally, a variety of protecting groups are described in Protective Groups in Organic Synthesis, Third Ed. Greene, T. W. and Wuts, P. G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference. [0015] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties.
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • substituents contained in formulas of this invention refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • the substituent may be either the same or different at every position.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • this invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of infectious diseases or proliferative disorders.
  • stable as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or poly cyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • alkyl includes straight, branched and cyclic alkyl groups.
  • alkyl alkenyl
  • alkynyl alkynyl
  • lower alkyl is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, vinyl, allyl, n-butyl, sec- butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert- pentyl, cyclopentyl, -CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH 2 -cyclohexyl moieties and the like, which again, may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l- yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2- propynyl (propargyl), 1-propynyl, and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom or through a sulfur atom.
  • the alkyl, alkenyl, and alkynyl groups contain 1-20 alipahtic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups contain 1-10 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups contain 1-4 aliphatic carbon atoms.
  • alkoxy include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy, and n-hexoxy.
  • Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • alkylamino refers to a group having the structure -NHR', wherein R is aliphatic, as defined herein.
  • the aliphatic group contains 1 -20 aliphatic carbon atoms.
  • the aliphatic group contains 1-10 aliphatic carbon atoms.
  • the aliphatic group employed in the invention contain 1-8 aliphatic carbon atoms.
  • the aliphatic group contains 1-6 aliphatic carbon atoms.
  • the aliphatic group contains 1-4 aliphatic carbon atoms.
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n- butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.
  • dialkylamino refers to a group having the structure -NRR', wherein R and R are each an aliphatic group, as defined herein. R and R' may be the same or different in an dialkyamino moiety.
  • the aliphatic groups contains 1-20 aliphatic carbon atoms. In certain other embodiments, the aliphatic groups contains 1-10 aliphatic carbon atoms. In yet other embodiments, the aliphatic groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the aliphatic groups contains 1-6 aliphatic carbon atoms. In yet other embodiments, the aliphatic groups contains 1-4 aliphatic carbon atoms.
  • dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like.
  • R and R' are linked to form a cyclic structure.
  • cyclic structure may be aromatic or non-aromatic.
  • cyclic diaminoalkyl groups include, but are not limted to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-trianolyl, and tetrazolyl.
  • substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO 2 ; - CN; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 SO 2 CH 3 ; -C(O)R x ; - CO 2 (R x ); -CON(R X ) 2 ; -OC(O)R x ; -OCO 2 R x ; -0C0
  • aryl and heteroaryl refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
  • Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; -F; -Cl; -Br; -I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; - CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 SO 2 CH 3 ; -C(O)R x ; -CO 2 (R x
  • cycloalkyl refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other aliphatic, heteroaliphatic, or hetercyclic moieties, may optionally be substituted with substituents including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; -F; -Cl; -Br; -I; -OH; -NO 2 ; -CN; -CF 3 ; -
  • heteroaliphatic refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
  • heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; -F; -Cl; -Br; -I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; - CH 2 SO 2 CH 3 ; -C(O)R x ; -CO 2 (R x ); -CON(R X ) 2 ; -OC(O)R x ; -CO 2 (R
  • heterocycloalkyl refers to a non- aromatic 5-, 6-, or 7- membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5- membered ring has O to 1 double bonds and each 6-membered ring has O to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring.
  • heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • a "substituted heterocycloalkyl or heterocycle” group refers to a heterocycloalkyl or heterocycle group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; -F; -Cl; -Br; -I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; - CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 SO 2 CH 3 ; -C(O)R x ;
  • Carbocycle The term “carbocycle”, as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is a carbon atom.
  • Independently selected The term “independently selected” is used herein to indicate that the R groups can be identical or different.
  • label As used herein, the term “labeled” is intended to mean that a compound has at least one element, isotope, or chemical compound attached to enable the detection of the compound.
  • labels typically fall into three classes: a) isotopic labels, which may be radioactive or heavy isotopes, including, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 67 Ga, 75 Br, 76 Br, 99m Tc (Tc-99m), 111 In, 123 I, 125 I, 131 I, 169 Yb, and 186 Re; b) immune labels, which may be antibodies or antigens, which may be bound to enzymes (such as horseradish peroxidase) that produce detectable agents; and c) colored, luminescent, phosphorescent, or fluorescent dyes. It will be appreciated that the labels may be incorporated into the compound at any position that does not interfere with the biological activity or characteristic of
  • Tautomers As used herein, the term “tautomers” are particular isomers of a compound in which a hydrogen and double bond have changed position with respect to the other atoms of the molecule. For a pair of tautomers to exist there must be a mechanism for interconversion. Examples of tautomers include keto-enol forms, imine-enamine forms, amide-imino alcohol forms, amidine-aminidine forms, nitroso-oxime forms, thio ketone- enethiol forms, N-nitroso-hydroxyazo forms, nitro- ⁇ cz-nitro forms, and pyridione- hydroxypyridine forms.
  • Non-chemical terms used throughout the specification include: [0033] "Animal”: The term animal, as used herein, refers to humans as well as non- human animals, including, for example, mammals, birds, reptiles, amphibians, and fish.
  • the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a primate, a non-human primate, or a pig).
  • the animal may be at any stage of development.
  • a non-human animal may be a transgenic animal.
  • Bind or “binding”: The term “bind” or “binding” refers to any interaction or association between the radiolabeled compound and ⁇ -synuclein. In certain embodiments, the binding is non-covalent. The binding preferably provides for quantitative measure of ⁇ - synuclein in a biological sample or subject.
  • Bio sample is broadly defined to include any cell, tissue, biological fluid, organ, multi-cellular organism, and the like.
  • a biological sample may be derived, for example, from cells or tissue cultures in vitro.
  • a biological sample may be derived from a living organism or from a population of single-cell organisms.
  • a biological sample may be a live tissue such as live bone.
  • biological sample is also intended to include samples such as cells, tissues or biological fluids isolated from a subject, as well as samples present within a subject.
  • the "effective amount” of an agent refers to an amount sufficient to bind alpha-synuclein to obtain a detectable signal upon imaging.
  • the effective amount of a compound of the invention may vary depending on such factors as the affinity of the agent for alpha- synuclein, the pharmacokinetics of the compound, the disease being detected, the mode of administration, and the patient.
  • Polynucleotide or “oligonucleotide” refers to a polymer of nucleotides.
  • the polymer may include natural nucleosides (i.e., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine), nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-
  • a "protein” or “peptide” comprises a polymer of amino acid residues linked together by peptide bonds.
  • a protein may refer to an individual protein or a collection of proteins. Inventive proteins preferably contain only natural amino acids, although non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and/or amino acid analogs as are known in the art may alternatively be employed.
  • amino acids in an inventive protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc.
  • a protein may also be a single molecule or may be a multi-molecular complex.
  • a protein may be just a fragment of a naturally occurring protein or peptide.
  • a protein may be naturally occurring, recombinant, or synthetic, or any combination of these.
  • Synucleinopathic subject refers to a subject that is affected by or at risk of developing a synucleinopathy (e.g. predisposed, for example genetically predisposed, to developing a synucleinopathy) and/or any neurodegenerative disorders characterized by pathological synuclein aggregations.
  • a synucleinopathy e.g. predisposed, for example genetically predisposed, to developing a synucleinopathy
  • any neurodegenerative disorders characterized by pathological synuclein aggregations e.g. predisposed, for example genetically predisposed, to developing a synucleinopathy
  • DLBD Diffuse Lewy Body disease
  • MSA Multiple System Atrophy
  • Treatment includes prophylaxis and therapy, and includes managing a synucleinopathic subject's symptoms and halting the progression of the synucleinopathy.
  • Treatment includes preventing, slowing, stopping, or reversing (e.g., curing) the development of a synucleinopathy, and/or the onset of certain symptoms associated with a synucleinopathy in a subject with, or at risk of developing, a synucleinopathy or a related disorder.
  • Therapy includes preventing, slowing, stopping or reversing (e.g., curing) the accumulation of ⁇ -synuclein in a subject with a synucleinopathy. Therapy also includes decreasing the amount of accumulated ⁇ -synuclein in a subject with a synucleinopathy.
  • Figure IA and IB Chemical structures of various tricyclic antidepressants that may be labeled with radioisotopes and used in PET or SPECT imaging.
  • Nortriptyline binds to ⁇ -synuclein and affects the rate of structure formation in the presence of HFIP.
  • Figure 3 Protriptyline and Maprotiline bind to ⁇ -synuclein and affect the rate of structure formation in the presence of HFIP. Monitoring of Thioflavin T fluorescence.
  • Norclomipramine and Nordoxepin bind to ⁇ -synuclein and affect the rate of structure formation in the presence of HFIP. Monitoring of Thioflavin T fluorescence.
  • Desipramine and Trimipramine bind to ⁇ -synuclein and affect the rate of structure formation in the presence of HFIP. Monitoring of Thioflavin T fluorescence.
  • FIG. 7 Clomipramine and Imipramine bind to ⁇ -synuclein and affect the rate of structure formation in the presence of HFIP. Monitoring of Thioflavin T fluorescence.
  • Figure 9 Nortriptyline delays aggregation of ⁇ -synuclein in a dose-dependent manner. Recombinant ⁇ -synuclein (70 ⁇ M) was incubated in the presence of solvent alone (solid line), nortriptyline at 0.1 ⁇ M (open squares), 50 ⁇ M (open cirlces), or 200 ⁇ M (open diamonds).
  • Figure 10 Nortriptyline decreases ⁇ -synuclein neurotoxicity in dopaminergic neurons.
  • Midbrain cultures from embryonic mice were infected with a recombinant lentivirus encoding A53T human ⁇ -synuclein (A53T) or a control virus (control), then treated for 3 days.
  • the percent Tyrosine-Hydroxylase-positive neurons (TH+ cells) was determined as described.
  • Figure 11 Nortriptyline binding affects the accumulation of ⁇ -synuclein in transgenic mice. Quantification of ⁇ -synuclein by ELISA in the cytoplasmic (black bars) and membrane fraction (white bars) in three month old ⁇ -synuclein transgenic mice treated for 30 days. A. Cortex. B. Hippocampus. *, p ⁇ 0.05; **, p ⁇ 0.01, T-test. [0052] Figure 12. Nortriptyline binding affects the accumulation of ⁇ -synuclein in transgenic mice. Number of cells positive for ⁇ -synuclein immunoreactivity in three month old ⁇ -synuclein transgenic mice treated for 30 days. A. Cortex. B. Hippocampus. ** p ⁇ 0.01, *** P ⁇ 0.001, T-test.
  • Figure 13 Hippocampus of three month old ⁇ -synuclein transgenic mice treated for 30 days with vehicle or Nortriptyline. Immunofluorescence analysis of brain sections immunostained for human ⁇ -synuclein (green) and NeuN (red).
  • Figure 14 Nortriptyline binding affects the accumulation of ⁇ -synuclein in transgenic mice. Number of cells positive for human ⁇ -synuclein immunoreactivity six- month-old ⁇ -synuclein transgenic mice treated for 30 days. A. Cortex. B. Hippocampus. * p ⁇ 0.05, ** p ⁇ 0.01, *** P ⁇ 0.001, one-way ANOVA with Newman-Keuls comparison post-hoc test.
  • alpha-synuclein is an invariant feature of synucleinopathies such as Parkinson's disease that is temporally and antomically linked to symptom progression.
  • Treatment designed to reduce alpha-synuclein deposits are of high interest, and a number of such strategies using RNAi technology, vaccines, or small molecules are currently being explored pre-clinically. Assessing the success of these strategies will be aided by the efficient imaging of alpha-synuclein deposits in a biological sample, experimental animal, or human subject.
  • the magnitude, extent, and rate of change in alpha-synuclein deposits effected by these new therapeutic approaches will soon become the critical question in moving these approaches into the clinic.
  • the present invention for imaging alpha-synuclein deposits or quantitating alpha-synuclein deposits in the nervous system of a subject was developed.
  • the invention provides a system for imaging and/or assessing the levels of ⁇ - synuclein in a biological sample or a subject.
  • Compounds known to bind or interact with ⁇ - synuclein are labeled with a radioisotope to form scintigraphic biomarkers useful in imaging (e.g., SPECT and PET imaging).
  • the invention includes such labeled alpha-synuclein binding agents and pharmaceutical compositions thereof.
  • the invention also includes methods of using the inventive compounds and compositions in diagnosing and following disease progression or treatment in a subject (e.g., humans) including experimental animals.
  • the inventive imaging methods may be combined with methods of treating a synucleinopathy.
  • inventive compound, compositions, kits, and methods may be used to diagnose or follow the progression of a synucleinopathy.
  • the inventive system is used to assess a treatment of a synucleinopathy in a patient.
  • Synucleinopathies are neurodegenerative disease that share a commong pathologic lesion containg ⁇ -synuclein deposits.
  • Synucleins are small proteins (123 to 143 amino acids) characterized by repetitive imperfect repeats SEQ ID NO: 8 (KTKEGV) distributed throughout most of the amino terminal half of the polypeptide in the acidic carboxy -terminal region.
  • SEQ ID NO: 8 There are three human synuclein proteins termed ⁇ , ⁇ , and ⁇ , and they are encoded by separate genes mapped to chromosomes 4221.3-q22, 5q23 and 10q23.2-q23.3, respectively.
  • synuclein protein synoretin has a close homology to ⁇ -synuclein and is predominantly expressed within the retina, ⁇ -synuclein, also referred to as non-amyloid component of senile plaques precursor protein (NACP), SYNl or synelfin, is a heat-stable, "natively unfolded" protein of poorly defined function. It is predominantly expressed in the central nervous system (CNS) neurons where it is localized to presynaptic terminals.
  • CNS central nervous system
  • Electron microscopy studies have localized ⁇ -synuclein in close proximity to synaptic vesicles at axonal termini, suggesting a role for ⁇ -synuclein in neurotransmission or synaptic organization, and biochemical analysis has revealed that a small fraction of ⁇ -synuclein may be associated with vesicular membranes but most ⁇ -synuclein is cytosolic. [0059] Genetic and histopathological evidence supports the idea that ⁇ -synuclein is the major component of several proteinaceous inclusions characteristic of specific neurodegenerative diseases.
  • Pathological synuclein aggregations are restricted to the ⁇ - synuclein isoforms, as ⁇ and ⁇ synucleins have not been detected in these inclusions.
  • the presence of ⁇ -synuclein positive aggregates is disease specific.
  • Lewy bodies, neuronal fibrous cytoplasmic inclusions that are histopathological hallmarks of Parkinson's Disease (PD) and Diffuse Lewy Body disease (DLBD) are strongly labeled with antibodies to ⁇ - synuclein.
  • Dystrophic ubiquitin-positive neurites associated with PD pathology termed Lewy neurites (LN) and CA2/CA3 ubiquitin neurites are also ⁇ -synuclein positive.
  • ⁇ -synuclein is likely the major component of glial cell inclusions (GCIs) and neuronal cytoplasmic inclusions in MSA and Hallervorden-Spatz disease (brain iron accumulation type 1).
  • ⁇ -synuclein immunoreactivity is also present in Alzheimer's disease, prion diseases (scrapie, mad cow disease, Gerstmann- Strassler Schenker, Creutzfeld Jakob disease, etc.), amyotrophic lateral sclerosis, Huntington's disease, and other neurodegenerative disorders.
  • ⁇ -synuclein is the actual building block of the fibrillary components of LBs, LNs and GCIs. Immunoelectron microscopic studies have demonstrated that these fibrils are intensely labeled with ⁇ -synuclein antibodies in situ. Sarcosyl-insoluble ⁇ -synuclein filaments with straight and twisted morphologies can also be observed in extracts of DLBD and MSA brains. Moreover, ⁇ -synuclein can assemble in vitro into elongated homopolymers with similar widths as sarcosyl-insoluble fibrils or filaments visualized in situ.
  • Polymerization is associated with a concomitant change in secondary structure from random coil to anti-parallel ⁇ -sheet structure consistent with the Thioflavine-S reactivity of these filaments.
  • the PD-association with ⁇ -synuclein mutation, A53T may accelerate this process, as recombinant A53T ⁇ -synuclein has a greater propensity to polymerize than wild-type ⁇ -synuclein.
  • This mutation also affects the ultrastructure of the polymers; the filaments are slightly wider and are more twisted in appearance, as if assembled from two protofilaments.
  • the A30P mutation may also modestly increase the propensity of ⁇ -synuclein to polymerize, but the pathological effects of this mutation also may be related to its reduced binding to vesicles. Interestingly, carboxyl- terminally truncated ⁇ -synuclein may be more prone to form filaments than the full-length protein.
  • the term "synucleionopathy” refers to neurological disorders that are characterized by a pathological accumulation of ⁇ -synuclein. This group of disorders includes PD, DLBD and MSA.
  • Parkinson's Disease is a neurological disorder characterized by bradykinesia, shuffling gait, postural instability, tremor, and a loss of automatic movement. It is due to the loss of dopamine-containing substantia nigra cells. It appears that about 50% of the cells need to be lost before symptoms appear. Associated symptoms often include rigidity, difficulty initiating movement (akinesia), small handwriting (micrographia), seborrhea, orthostatic hypertension, urinary difficulties, constipation, lymph pain, depression, dementia (up to a third of the patients), smelling disturbances (occurs early). Orthostatic hypertension might occur associated with the disease or as a complication of medication. Patients with Parkinsonism have greater mortality, about two times compared to general population without PD. This is attributed to greater frailty or reduced mobility.
  • nucleinopathic subject encompasses a subject that is affected by, or is at risk of developing PD. These subjects can be readily identified by persons of ordinary skill in the art by symptomatic diagnosis or by genetic screening, brain scans, SPEC, PET imaging, etc.
  • Diagnosis of PD is mainly clinical and is based on the clinical findings listed above. There are many conditions which may be mistaken for Parkinsonism. Among the most common are side effects of drugs, mainly the major tranquilizers, such as Haldol, strokes involving the basal ganglea, degenerative disorders, such as progressive supranuclear palsy (PSP), olivopontocerebellar degeneration (OPCD), MSA, and Huntington's Disease.
  • PSP progressive supranuclear palsy
  • OPCD olivopontocerebellar degeneration
  • MSA Huntington's Disease.
  • the pathological hallmark of PD are Lewy bodies, which are intracytoplasmatic inclusion bodies in effected neurons of the substantion nigra. Recently, ⁇ -synuclein has been identified as the main component of Lewy bodies in sporadic Parkinsonism.
  • Parkinson's can be clearly traced to genetic factors, viruses, stroke, or toxins in few individuals for the most part the cause of Parkinson's in any particular case is unknown (this is referred to as sporadic PD).
  • Environmental influences include drinking well water, farming and industrial exposure to heavy metals (iron, zinc, copper, mercury, magnesium and manganese), alkylated phosphates and orthonal chlorines.
  • Paraquat a herbicide
  • Parkinsonism may either be caused by an uncommon toxin combined with high genetic susceptibility or a common toxin combined with relatively low genetic susceptibility.
  • Subjects that are at risk of developing PD can be identified for example by genetic analysis. There is good evidence for genetic factors associated with PD. Large pedigrees of autosomal dominantly inherited PDs have been reported. A mutation in ⁇ -synuclein is responsible for one pedigree.
  • the term "synucleinopathic subject” also encompasses a subject that is affected by, or is at risk of developing DLBD. These subjects can be readily identified by persons of ordinary skill in the art by symptomatic diagnosis or by genetic screening, brain scans, SPEC, PET imaging, etc.
  • DLBD is the second commonest cause of neurodegenerative dementia in older people, it effects 7% of the general population older than 65 years and 30% of those aged over 80 years. It is part of a range of clinical presentations that share a neurotic pathology base of normal aggregation of the synaptic protein ⁇ -synuclein. DLBD has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's Disease. An "one year rule" can been used to separate DLBD from PD. According to this rule, onset of dementia within 12 months of Parkinsonism qualifies as DLBD, whereas more than 12 months of Parkinsonism before onset of dementia qualifies as PD.
  • DLBD central features of DLBD include progressive cognitive decline of sufficient magnitude to interfere with normal social and occupational function. Prominent or persistent memory impairment does not necessarily occur in the early stages, but it is evident with progression in most cases. Deficits on tests of attention and of frontal cortical skills and visual spatial ability can be especially prominent.
  • Core diagnostic features two of which are essential for diagnosis of probable and one for possible DLBD are fluctuating cognition with pronounced variations in attention and alertness, recurrent visual hallucinations that are typically well-formed and detailed, and spontaneous features of Parkinsonism.
  • Patients with DLBD do better than those with Alzheimer's Disease in tests of verbal memory, but worse on visual performance tests. This profile can be maintained across the range of severity of the disease, but can be harder to recognize in the later stages owing to global difficulties.
  • DLBD typically presents with recurring episodes of confusion on a background of progressive deterioration. Patients with DLBD show a combination of cortical and subcortical neuropsychological impairments with substantial attention deficits and prominent frontal subcortical and visual special dysfunction. These help differentiate this disorder from Alzheimer's Disease.
  • Rapid eye movement (REM), sleep behavior and disorder is a parasomnia manifested by vivid and frightening dreams associated with simple or complex motor behavior during REM sleep.
  • This disorder is frequently associated with the synucleinopathies, DLBD, PD and MSA, but it rarely occurs in amyloidopathies and taupathies.
  • the neuropsychological pattern of impairment in REM sleep behavior disorder/dementia is similar to that reported in DLBD and qualitatively different from that reported in Alzheimer's Disease.
  • Neuropathological studies of REM sleep behavior disorder associated with neurodegenerative disorder have shown Lewy body disease or multiple system atrophy.
  • REM sleep wakefulness disassociations (REM sleep behavior disorder, daytime hypersomnolence, hallucinations, cataplexy) characteristic of narcolepsy can explain several feature of DLBD, as well as PD. Sleep disorders could not contribute to the fluctuations typical of DLBD and their treatment can improve fluctuations and quality of life. Subjects at risk of developing DLBD can be identified. Repeated falls, syncope, transient loss of consciousness, and depression are common in older people with cognitive impairment and can serve as (a red flag) to a possible diagnosis of DLBD. By contrast, narcoleptic sensitivity in REM sleep behavior disorder can be highly predictive of DLBD. Their detection depends on the clinicians having a high index of suspicion and asking appropriate screening questions.
  • Consensus criteria for diagnosing DLBD include ubiquitin immunohistochemistry for Lewy body identification and staging into three categories; brain stem predominant, limbic, or neocortical, depending on the numbers and distribution of Lewy bodies.
  • the recently-developed ⁇ -synuclein immunohistochemistry is a better marker that visualizes more Lewy bodies and also better source previously under recognized neurotic pathology, termed Lewy neurites.
  • Use of antibodies to ⁇ -synuclein moves the diagnostic rating for many DLBD cases from brain stem and limbic groups into the neocortical group.
  • Target symptoms for the accurate of DLBD can include extrapyramidal motor features, cognitive impairment, neuropsychiatric features (including hallucinations, depression, sleep disorder, and associated behavioral disturbances) or autonomic dysfunction.
  • Methods of the invention can be used in combination with one or more alternative treatments DLBD. For example, lowest acceptable doses of levodopa can be used for treating DLBD.
  • D2-receptor antagonists, particularly traditional neuroleptic agents can provoke severe sensitivity reactions in DLBD subjects with an increase in mortality of two to three times.
  • Cholinsterase inhibitors dicussed above are also used in the treatment of DLBD.
  • the term "synucleinopathic subject” also encompasses a subject that is affected by, or is at risk of developing MSA. These subjects can be readily identified by persons of ordinary skill in the art by symptomatic diagnosis or by genetic screening, brain scans, SPEC, PET imaging, etc.
  • MSA is a neurodegenerative disease marked by a combination of symptoms; affecting movement, blood pressure, and other body functions, hence the label "multiple system atrophy".
  • the cause of MSA is unknown.
  • Symptoms of MSA vary in distribution of onset and severity from person to person. Because of this, three different diseases were initially described to accomplish this range of symptoms; Shy-Drager syndrome, striatonigral degeneration (SD), and olivopontocerebellar atrophy (OPCA).
  • Shy-Drager syndrome the most prominent symptoms are those involving the autonomic system; blood pressure, urinary function, and other functions not involving conscious control. Striatonigral degeneration causes Parkinsonism symptoms, such as slowed movements and rigidity, while OPCA principally effects balance, coordination and speech.
  • the symptoms for MSA can also include orthostatic hypertension, male impotence, urinary difficulties, constipation, speech and swallowing difficulties, and blurred vision.
  • the initial diagnosis of MSA is usually made by carefully interviewing the patient and performing a physical examination.
  • Several types of brain imaging including computer histomography, scans, magnetic resonance imaging (MRI), and positron emission tomography (PET), are used.
  • Pharmacological challenge tests may also be of help in those patients with typical Parkinsonism signs.
  • An incomplete and relatively poor response to dopamine replacement therapy, such as Sinemet may be a clue that MSA is present.
  • a characteristic involvement of multiple brain systems is a defining feature of MSA and one that an autopsy confirms the diagnosis.
  • Patients with MSA can have the presence of glial cytoplasmic inclusions in certain types of brain cells, as well. Lewy bodies are not present in MSA.
  • MSA MSA
  • any agent known to bind or interact with alpha-synuclein may be labeled and used in the inventive system.
  • the compound may be a small molecule, organic compound, protein, peptide, or polynucleotide.
  • the compound is a small molecule.
  • the agent is an organic compound.
  • the compound is a protein or peptide.
  • the unlabeled agent is a drug approved for use in humans by the U.S. Food and Drug Administration (FDA) or under consideration by the FDA (e.g., nortriptyline).
  • the agent has been discovered to prevent the aggregation of ⁇ -synuclein.
  • Agents may be screened for their ability to bind aggregations of ⁇ -synuclein using any techniques known in the art. For example, agent may be identified by isothermal chemistry, solution NMR spectroscopy, capillary gel electrophoresis, high-throughput screening,or cell culture screening. Several assays for identifying compounds that prevent the aggregation of ⁇ -synuclein are described in U.S. provisional patent application, USSN 60/915,828, filed May 3, 2007, which is incorporated herein by reference.
  • the assays involve testing for the aggregation of ⁇ -synuclein in hexafluoroisopropanol. In other embodiments, the assay involves testing for the aggregation of ⁇ -synuclein in an aqueous solution.
  • the agent is an antidepressant. In certain embodiments, the agent is a tricyclic antidepressant. In certain embodiments, the agent is selected from the group consisting of nortriptyline, maprotiline, protriptyline, nordoxepin, trimipramine, imipramine, desipramine, doxepin, amoxapine, amitriptyline, clomipramine, cyclobenzaprine, lofepramine, mirtazapine, cyproheptadine, and norclomipramine. In certain particular embodiments, the agent is nortriptyline. In certain embodiments, the agent is norclomipramine.
  • the agent is a monoamine reuptake inhibitor.
  • the reuptake inhibitor may block the re-uptake of neurotransmitters such as norepinephrine, dopamine, serotonin, or combinations thereof.
  • the reuptake inhibitor may be selective for a particular neurotransmitter, or it may be non-selective and block the reuptake of multiple neurotransmitters.
  • the agent is selective serotonin reuptake inhibitor (SSRI).
  • the agent is sertraline.
  • the agent is indatraline.
  • the agent is fluoxetine.
  • the agent is norfluoxetine.
  • the agent for use in the inventive system may be labeled with any radioisotope that emits detectable radiation.
  • the radioisotope is detectable by positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the radioisotope is detectable by scintillation counting.
  • the agent is labeled with a radioisotope of a halogen.
  • the agent is labeled with a radioisotope of fluorine.
  • the agent is labeled with F- 18.
  • the agent is labeled with a radioisotope of bromine.
  • the agent is labeled with Br-75. In certain embodiments, the agent is labeled with Br-76. In certain embodiments, the agent is labeled with a radioisotope of chlorine. In certain embodiments, the agent is labeled with Cl- 36. In certain embodiments, the agent is labeled with a radioisotope of iodine. In certain embodiments, the agent is labeled with 1-123. In certain embodiments, the agent is labeled with 1-131.
  • the inventive compound is of the formula: wherein each occurrence of a dashed line represent a bond or the absence of a bond; each occurrence of X is independently a halogen, wherein the halogen is a radioisotope of fluorine, chlorine, bromine, or iodine; each occurrence of n is independently an integer between 1 and 4;
  • V is N, C, or CH
  • X is F- 18. In certain embodiments, X is Br-75. In certain embodiments, X is Br-76. In certain embodiments, X is 1-123. In certain embodiments, X is 1-131.
  • At least one occurrence of n is 1. In certain embodiments, one occurrence of n is 1, and the other occurrence of n is 0. In certain embodiments, both occurrences of n are 1. In certain embodiments, at least one occurrence of n is 2. In certain embodiments, at least one occurrence of n is 3.
  • V is CH. In certain embodiments, V is C. In certain embodiments, V is N.
  • Ri is cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic. In certain embodiments, Ri is acyclic, unsubstituted, unbranched heteroaliphatic. In certain embodiments, Ri is acyclic, unsubstituted, branched heteroaliphatic. In certain embodiments, Ri is acyclic, substituted, unbranched heteroaliphatic. In certain embodiments, Ri is acyclic, substituted, branched heteroaliphatic. In certain embodiments, Ri is aminoalkyl. In certain embodiments, Ri is alkylaminoalkyl. In certain embodiments, Ri is dialkylaminoalkyl. In certain embodiments,
  • R I is In certain
  • Ri is
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula: wherein each occurrence of a dashed line represent a bond or the absence of a bond; each occurrence of X is independently a halogen, wherein the halogen is a radioisotope of fluorine, chlorine, bromine, or iodine; each occurrence of n is independently an integer between 1 and 4;
  • V is N, C, or CH
  • the inventive compound is of the formula:
  • the inventive compound is of the formula: wherein each occurrence of a dashed line represent a bond or the absence of a bond; each occurrence of X is independently a halogen, wherein the halogen is a radioisotope of fluorine, chlorine, bromine, or iodine; each occurrence of n is independently an integer between 1 and 4;
  • V is N, C, or CH
  • the inventive compound is of the formula: wherein each occurrence of a dashed line represent a bond or the absence of a bond; each occurrence of X is independently a halogen, wherein the halogen is a radioisotope of fluorine, chlorine, bromine, or iodine; each occurrence of n is independently an integer between 1 and 4;
  • V is N, C, or CH
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • each occurrence of X is independently a halogen, wherein the halogen is a radioisotope of fluorine, chlorine, bromine, or iodine; each occurrence of n is independently an integer between 1 and 4; and pharmaceutically acceptable salts thereof.
  • the present invention also includes methods of preparing the inventive radiolabeled ⁇ -synuclein binding agents.
  • a compound such as nortriptyline, protriptyline, imipramine, or desipramine may be radiolabeled with a radioisotope of fluorine, bromine, or iodine using methods known in the art.
  • the compound is labeled with F-18, Br-76, and 1-123.
  • a radioisotope of bromine or iodine is added to the ⁇ -synuclein binding agent (e.g., a tricyclic antidepressant) by halostannylation.
  • a radioisotope of fluorine is added to the ⁇ - synuclein binding agent (e.g., a tricyclic antidepressant) by nucleophilic substitution.
  • the substitution reaction involves substitution of a nitro group.
  • the ⁇ -synuclein binding agent is iodinated using a ICl reagent as described in Humphreys et al. MoI. Pharm. 36:620-26, 1989; Cassel et al. Analytical Chem. 170:63-67, 1988; Helmkamp et al. Appl. Radiat. Isotopes 18:747-754, 1967; Contreras et al.
  • the ICl reagent may be labeled with 1-123 or another radioisotope of iodine.
  • the radioisotope has a short half-life requiring that the labeling of the ⁇ -synuclein binding agent be done near the facility were the agent will be eventually used.
  • the ⁇ -synuclein binding compounds may be provided in any suitable stereoisomeric form, and/or pharmaceutically acceptable acid or base addition salt form.
  • pharmaceutically acceptable acid or base addition salts mentioned herein are meant to comprise the therapeutically active non-toxic acid and non-toxic base addition salt forms that the compounds are able to form.
  • the compounds that have basic properties can be converted into their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid.
  • Appropriate acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e., butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids
  • organic acids such as, for example, acetic, propanoi
  • the compounds that have acidic properties can be converted into their pharmaceutically acceptable base addition salts by treating the acid form with a suitable organic or inorganic base.
  • suitable organic or inorganic base include, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g., the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g., the benzathine, N- methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • acid or base addition salt also comprise the hydrates and the solvent addition forms which the compounds are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • stereochemically isomeric forms of compounds include all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemical ⁇ isomeric forms that the compound can take. The mixture can contain all diastereomers and/or enantiomers of the basic molecular structure of the compound. All stereochemically isomeric forms of the compounds both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
  • the labeled compounds are useful in detecting alpha-synuclein. They may be used in assays, autoradiographic experiments, or imaging studies to determine the presence of alpha-synuclein.
  • the binding of the labeled compound may be performed in vivo or in vitro.
  • the compound bound to alpha-synuclein is then detected by the radiation that is emitted from the radioactive label (e.g., 1-123, 1-131, F-18, Br-76, or Br-75).
  • the invention provides methods of detecting and/or quantifying alpha-synuclein deposits in a biological sample.
  • the method includes contacting a biological sample with an effective amount of a labeled, alpha-synuclein binding agent and then assessing the quantity of alpha-synuclein binding agent bound to the biological sample based on detection of radiation emitted from the label.
  • the radiation is detected by scintillation counting.
  • the radiation is detected by autoradiogram.
  • the biological sample is a biological fluid such as plasma, serum, blood, sweat, cerebral spinal fluid, lymph, etc.
  • the biological sample is a tissue sample (e.g., a brain section).
  • the biological sample is a biopsy sample.
  • the biological sample is derived from the nervous system of an animal.
  • the biolgical sample is derived from a mammal.
  • the biological sample is derived from a primate.
  • the biological sample is derived from a human.
  • the biological sample is derived from an experimental animal such as a pig, dog, rat, or mouse. [00122]
  • the invention provides methods of detecting and/or quantifying alpha-synuclein deposits in a subject.
  • Such methods may be useful in diagnosing a patient suspected of having a synucleinopathy, in following the progression of disease in a subject, and/or in following treatment of a subject.
  • the method includes administering an effective amount of a labeled, alpha-synuclein binding agent to a subject followed by imaging of the subject or a portion thereof.
  • the binding agent is administered as part of a pharmaceutical composition.
  • the binding agent may be administered using any technique known in the art.
  • the agent is administered parenterally (e.g., intravenously).
  • the agent is administered orally.
  • the agent is administered intrathecally.
  • the effective amount of the labeled agent may be from about lOng/kg of body weight to about 1000mg/kg of body weight.
  • a certain amount of time may be allowed to pass between the time when the labeled agent is administered and the time the imaging is performed.
  • the delay between administration and imaging may range from minutes to days. In certain embodiments, the delay ranges from 5 minutes to 30 minutes. In certain embodiments, the delay ranges from 30 minutes to 6 hours. In certain embodiments, the delay ranges from 6 hours to 12 hours. In certain embodiments, the delay ranges from 12 hours to 24 hours. In certain embodiments, the delay ranges from 24 hours to 36 hours. In certain embodiments, the delay ranges from 36 hours to 48 hours. In certain embodiments, the delay is approximately 1 week.
  • the subject is imaged to determine the extent of labeled alpha-synuclein binding agent present in the subject.
  • the subject may be imaged using any technique known in the art to detect radiation from a radioisotope.
  • PET imaging is used.
  • SPECT imaging is used.
  • the whole subject may be imaged or only a portion of the subject may be imaged.
  • the head and neck of the subject are imaged.
  • the brain of the subject is imaged.
  • the central nervous system of the subject is imaged.
  • the subject may be any animal.
  • the subject is a mammal.
  • the subject is a primate.
  • the subject is a rodent. In certain embodiments, the subject is a mouse. In certain embodiments, the subject is a rat. In certain embodiments, the subject is a transgenic animal that expresses alpha-synuclein. In certain embodiments, the subject is a human.
  • the subject being imaged using the inventive method may be susceptible to developing a synucleinopathy such as Parkinson's disease.
  • the subject may be starting to exhibit some of the symptoms associated with Parkinson's disease such as rigidity, tremor, or bradykinesia. Therefore, imaging the patient may assist the attending physician in diagnosing and treating the subject.
  • the patient is already diagnosed with a synucleinopathy and is being treated for the disease.
  • Periodic imaging of the subject using the inventive ystem may be used to assess the success of the treatment or to assess disease progression.
  • the subject may be being treated with an RNAi, a vaccine, or a small molecule based therapy.
  • the subject may be imaged every month, 6 months, 12 months, 24 months, or 36 months, for example.
  • kits for performing the inventive methods include the necessary quantity of a labeled alpha-synuclein binding agent to detect alpha-synuclein in a biological sample or in a subject.
  • the labeled agent may be provided in a convenient composition for use in the inventive methods.
  • the labeled agent is provided in a pharmaceutical composition for administration to a subject for the imaging of synuclein.
  • the kit may also include labeling and/or instructions for use of the labeled alpha-synuclein binding agent.
  • the invention provides diagnostic kits for performing in vivo imaging.
  • the invention also provides kits for research purposes.
  • the kit is designed for labeling an alpha-synuclein binding agent with a radioisotope.
  • an agent such as a tricyclic antidepressant known to bind alpha-synuclein may be provided in the kit with the necessary reagents for labeling the agent.
  • the radioisotope has such a short half-life that it is preferable to label the agent soon before its use.
  • the isotope for labeling may be provided by the user and used with the kit.
  • the radioisotope may be roduced by a cyclotron on site.
  • the present invention provides "pharmaceutically acceptable" compositions, which comprise a therapeutically effective amount of one or more of the compounds described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydrox
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically-acceptable salts in this respect refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. ScL 66: 1-19.
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from nontoxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et ah, supra).
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, g
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made in a suitable machine in which a mixture of the powdered compound is moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Dissolving or dispersing the compound in the proper medium can make such dosage forms. Absorption enhancers can also be used to increase the flux of the compound across the skin. Either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel can control the rate of such flux.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue. [00154] In certain embodiments, a compound or pharmaceutical preparation is administered orally. In other embodiments, the compound or pharmaceutical preparation is administered intravenously. Alternative routs of administration include sublingual, intramuscular, and transdermal administrations.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and then gradually increasing the dosage until the desired effect is achieved.
  • doses of the compounds of this invention for a patient when used for the indicated effects, will range from about 0.0001 mg to about 100 mg per kg of body weight.
  • the daily dosage will range from 0.001 mg to 50 mg of compound per kg of body weight, and even more preferably from 0.01 mg to 10 mg of compound per kg of body weight.
  • the dose administered to a subject for imaging may be modified as the physiology of the subject changes due to age, disease progression, weight, or other factors.
  • a compound of the present invention While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition) as described above.
  • the compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
  • compounds for treating neurological conditions or diseases can be formulated or administered using methods that help the compounds cross the blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • the vertebrate brain (and CNS) has a unique capillary system unlike that in any other organ in the body.
  • the unique capillary system has morphologic characteristics which make up the blood-brain barrier (BBB).
  • the blood-brain barrier acts as a system-wide cellular membrane that separates the brain interstitial space from the blood.
  • the unique morphologic characteristics of the brain capillaries that make up the BBB are: (a) epithelial-like high resistance tight junctions which literally cement all endothelia of brain capillaries together, and (b) scanty pinocytosis or trans endothelial channels, which are abundant in endothelia of peripheral organs. Due to the unique characteristics of the blood-brain barrier, hydrophilic drugs and peptides that readily gain access to other tissues in the body are barred from entry into the brain or their rates of entry and/or accumulation in the brain are very low.
  • alpha-synuclein binding compounds that cross the BBB are particularly useful for imaging in the present invention.
  • alpha-synuclein binding compounds that are non-charged (e.g., not positively charged) and/or non-lipophilic may cross the BBB with higher efficiency than charged (e.g., positively charged) and/or lipophilic compounds. Therefore, it will be appreciated by a person of ordinary skill in the art that some of the compounds of the invention might readily cross the BBB.
  • the compounds of the invention can be modified, for example, by the addition of various substitutuents that would make them less hydrophilic and allow them to more readily cross the BBB.
  • the permeability of the blood brain barrier can be increased by administering a blood brain barrier agonist, for example bradykinin (US 5,112,596 incorporated herein in its entirety by reference), or polypeptides called receptor mediated permeabilizers (RMP) (US 5,268,164 incorporated herein in its entirety by reference).
  • a blood brain barrier agonist for example bradykinin (US 5,112,596 incorporated herein in its entirety by reference), or polypeptides called receptor mediated permeabilizers (RMP) (US 5,268,164 incorporated herein in its entirety by reference).
  • Exogenous molecules can be administered to the host's bloodstream parenterally by subcutaneous, intravenous or intramuscular injection or by absorption through a bodily tissue, such as the digestive tract, the respiratory system or the skin.
  • the form in which the molecule is administered depends, at least in part, on the route by which it is administered.
  • the administration of the exogenous molecule to the host's bloodstream and the intravenous injection of the agonist of blood-brain barrier permeability can occur simultaneously or sequentially in time.
  • a therapeutic drug can be administered orally in tablet form while the intravenous administration of an agonist of blood-brain barrier permeability is given later (e.g. between 30 minutes later and several hours later). This allows time for the drug to be absorbed in the gastrointestinal tract and taken up by the bloodstream before the agonist is given to increase the permeability of the blood-brain barrier to the drug.
  • an agonist of blood-brain barrier permeability e.g. bradykinin
  • compounds of the invention can be formulated as a prodrug with a fatty acid carrier (and optionally with another neuroactive drug).
  • the prodrug is stable in the environment of both the stomach and the bloodstream and may be delivered by ingestion.
  • the prodrug passes readily through the blood brain barrier.
  • the prodrug preferably has a brain penetration index of at least two times the brain penetration index of the drug alone.
  • the prodrug is hydro lyzed into the fatty acid carrier and the alpha-synuclein binding agent.
  • the carrier preferably is a normal component of the central nervous system and is inactive and harmless.
  • the compound and/or drug, once released from the fatty acid carrier, is capable of binding alpha-synuclein.
  • the fatty acid carrier is a partially-saturated straight chain molecule having between about 16 and 26 carbon atoms, and more preferably 20 and 24 carbon atoms. Examples of fatty acid carriers are provided in U.S. Patents 4,939,174; 4,933,324; 5,994,932; 6,107,499; 6,258,836; and 6,407,137; the disclosures of which are incorporated herein by reference in their entirety.
  • Thioflavin T fluorescence can be used to measures aggregation of amyloidogenic proteins, including ⁇ -synuclein (exctiation, 440 nm; emission, 495 nm) (Naiki et al. (1989). "Fluorometric determination of amyloid fibrils in vitro using the fluorescent dye, thioflavin TV Anal. Biochem. 177(2):244- 9; Conway et al. (2000).
  • Nortriptyline ( Figure 2) causes a dose-dependent increase in the rate of structure formation of ⁇ -synuclein in the presence of HFIP as determined by Thioflavin T fluorescence and fluorescence polarization. Dose-dependent effects on ⁇ - synuclein aggregation were also observed by Thioflavin T fluorescence measurements for protriptyline, maprotiline ( Figure 3), norclomipramine, nordoxepin ( Figure 4) , amoxapine, doxepin ( Figure 5), desipramine, trimipramine ( Figure 6) clomipramine, and imipramine ( Figure T).
  • Nortriptyline also binds to ⁇ -synuclein in a buffer system relevant to physiological conditions as monitored by effects on aggregation.
  • the rate of the ⁇ -synuclein aggregation was determined by monitoring the amount of ⁇ -synuclein monomer in solution and by fluorescence polarization.
  • Recombinant ⁇ -synuclein 70 ⁇ M, 20 mM Bis-tris propane, 100 mM LiCl, pH 7.4, 700 ⁇ l total volume was incubated at 37 0 C with gentle agitation.
  • Nortriptyline decreased ⁇ -synuclein neurotoxicity toward dopaminergic neurons.
  • Midbrain cultures will be prepared from E17 rat ventral mesencephalon as described in a published protocol (Xu et al. (2002). "Dopamine-dependent neurotoxicity of alpha - synuclein: a mechanism for selective neurodegeneration in Parkinson disease” Nat. Med. 8(6):600-6; incorporated herein by reference).
  • Cultured cells were infected with a recombinant lentivirus encoding human A53T ⁇ -synuclein (A53T) or a control virus (none). Cells were treated with various concentrations of nortriptyline (white bars) for 3 days.
  • Nortriptyline was administered to mice of the ⁇ -synuclein transgenic line described in Masliah et al. ((2000). "Dopaminergic loss and inclusion body formation in alph ⁇ -synuclein mice: implications for neurodegenerative disorders” Science 287(5456): 1265-9; which is incorporated herein by reference). Animals from this line have ⁇ -synuclein neuronal inclusions in the cortex, hippocampus, and the olfactory bulb (Masliah et al. (2000). "Dopaminergic loss and inclusion body formation in ⁇ -synuclein mice: implications for neurodegenerative disorders” Science 287(5456): 1265-9).
  • mice were administered nortriptyline in saline (0.9%) or the same volume of vehicle alone once a day intraperitoneally for 30 days. At the end of treatment, mice were sacrificed and the brains removed and hemisected. One hemisphere of each was fixed in 4% paraformaldehyde/PBS (pH 7.4), cryoperserved, then sectioned for histology. From the other hemisphere, the cortex and hippocampus were dissected, homogenized, and processed into cytoplasmic and membrane fractions.
  • the means are not intended to be limited to the means disclosed herein for performing the recited function, but are intended to cover in scope any means, known now or later developed, for performing the recited function.
  • Use of ordinal terms such as “first”, “second”, “third”, etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des agents de liaison d'alpha-synucléine radiomarqués qui sont utiles dans l'imagerie de dépôts d'alpha-synucléine dans le cerveau de sujets présentant une synucléinopathie ou susceptibles de présenter une synucléinopathie. Les agents sont particulièrement utiles pour l'imagerie via l'imagerie en médecine nucléaire PET et SPECT. Les techniques d'imagerie peuvent être utilisées pour diagnostiquer un patient, suivre la progression de la maladie, ou suivre le traitement de la maladie.
PCT/US2008/071017 2007-08-01 2008-07-24 Imagerie d'alpha-synucléine WO2009018088A2 (fr)

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US8629135B2 (en) 2008-07-14 2014-01-14 Queen's University At Kingston Pharmaceutical compositions comprising RET inhibitors and methods for the treatment of cancer
WO2014152024A2 (fr) * 2013-03-15 2014-09-25 Millikelvin Technologies Llc Techniques, systèmes et programmes lisibles par machine améliorés pour résonance magnétique
US9014785B2 (en) 2011-03-23 2015-04-21 Millikelvin Technologies Llc Techniques, systems and machine readable programs for magnetic resonance
US9176208B2 (en) 2011-03-23 2015-11-03 Millikelvin Technologies Llc Techniques, systems and machine readable programs for magnetic resonance
CN105277632A (zh) * 2014-07-24 2016-01-27 江苏维赛科技生物发展有限公司 高效液相－串联质谱法检测猪尿中赛庚啶残留量的方法
WO2017053834A1 (fr) * 2015-09-25 2017-03-30 Board Of Regents Of The University Of Nebraska Analogues de mibg et leurs utilisations
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats
CN111803473A (zh) * 2019-04-10 2020-10-23 云南帕精生物科技有限公司 去甲替林应用于治疗帕金森病

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Cited By (14)

* Cited by examiner, † Cited by third party
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US8629135B2 (en) 2008-07-14 2014-01-14 Queen's University At Kingston Pharmaceutical compositions comprising RET inhibitors and methods for the treatment of cancer
US20130291131A1 (en) * 2008-08-08 2013-10-31 Absolute Software Corporation Approaches for a location aware client
US9117092B2 (en) * 2008-08-08 2015-08-25 Absolute Software Corporation Approaches for a location aware client
US9207298B2 (en) 2011-03-23 2015-12-08 Millikelvin Technologies Llc Techniques, systems and machine readable programs for magnetic resonance
US9714995B2 (en) 2011-03-23 2017-07-25 Millikelvin Technologies Llc Techniques, systems and machine readable programs for magnetic resonance
US9014785B2 (en) 2011-03-23 2015-04-21 Millikelvin Technologies Llc Techniques, systems and machine readable programs for magnetic resonance
US9176208B2 (en) 2011-03-23 2015-11-03 Millikelvin Technologies Llc Techniques, systems and machine readable programs for magnetic resonance
WO2014152024A3 (fr) * 2013-03-15 2014-11-13 Millikelvin Technologies Llc Techniques, systèmes et programmes lisibles par machine améliorés pour résonance magnétique
WO2014152024A2 (fr) * 2013-03-15 2014-09-25 Millikelvin Technologies Llc Techniques, systèmes et programmes lisibles par machine améliorés pour résonance magnétique
CN105277632A (zh) * 2014-07-24 2016-01-27 江苏维赛科技生物发展有限公司 高效液相－串联质谱法检测猪尿中赛庚啶残留量的方法
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats
WO2017053834A1 (fr) * 2015-09-25 2017-03-30 Board Of Regents Of The University Of Nebraska Analogues de mibg et leurs utilisations
US10874752B2 (en) 2015-09-25 2020-12-29 Board Of Regents Of The University Of Nebraska MIBG analogs and uses thereof
CN111803473A (zh) * 2019-04-10 2020-10-23 云南帕精生物科技有限公司 去甲替林应用于治疗帕金森病

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