Bicyclic compounds for diagnosis and therapy

Abstract

The present invention relates to novel compounds that can be employed in the diagnosis, monitoring of disease progression or monitoring of drug activity, of a group of disorders and abnormalities associated with alpha-synuclein (α-synuclein, A-synuclein, aSynuclein, A-syn, α-syn, aSyn) aggregates including, but not limited to, Lewy bodies and/or Lewy neurites, such as Parkinson's disease. The instant compounds are particularly useful in determining a predisposition to such a disorder, monitoring residual disorder, or predicting the responsiveness of a patient who is suffering from such a disorder to the treatment with a certain medicament. The present compounds can also be used to treat, alleviate or prevent a disorder or abnormality associated with alpha-synuclein aggregates.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         and all detectably labeled derivatives, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof; 
         wherein 
       
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and —CN, wherein 
       
         
           
           
               
               
           
         
       
       can be attached at any available position to the moiety U, and wherein 
       
         
           
           
               
               
           
         
       
       can be optionally substituted by one or more substituents R A ;
 wherein 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       can be attached at any available position, and wherein 
       
         
           
           
               
               
           
         
       
       can be optionally substituted by one or more substituents R B ;
 V is selected from the group consisting of S, NR a  and CR b R b , 
 Z is selected from the group consisting of N and CR c , 
 W is selected from the group consisting of N and CR c  or W is C if W is attached to U; 
 W 1  is selected from the group consisting of N and CR c  or W 1  is C if W 1  is attached to U; 
 X is selected from the group consisting of N and CR c  or X is C if X is attached to U; 
 Y is selected from the group consisting of N and CR c  or Y is C if Y is attached to U; 
 U is selected from the group consisting of —NR a —, —CH═CH—, —C≡C— and a bond; 
 for each occurrence, R a  is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl; 
 for each occurrence, R b  is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and halogen; 
 for each occurrence, R c  is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and halogen; 
 for each occurrence, R d  is independently selected from the group consisting of halogen, —OH, —O-alkyl and hydrogen; 
 for each occurrence, R e  is independently selected from the group consisting of hydrogen, —(CH 2 CH 2 —O) n —R f , —(CH 2 CH 2 —O) n —(CH 2 CH 2 )—R d , alkyl, carbocyclyl and heterocyclyl, wherein alkyl, carbocyclyl and heterocyclyl can be optionally substituted, 
 for each occurrence, R f  is independently selected from the group consisting of hydrogen, and alkyl, wherein alkyl can be optionally substituted; 
 for each occurrence, R A  is independently selected from the group consisting of halogen, CN, —O—R 10 , —NR 10 R 11 , —CONR 10 R 11 , —N(R 10 )—C(O)R 11 , —N(R 10 )—C(O)—R 11 , —(O—CH 2 CH 2 ) n —R d , ═O, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl, wherein alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl can be optionally substituted, or if more than one group R A  is present and two of the groups R A  are adjacent, they can optionally be taken together and can form a 5- to 8-membered ring containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatom (e.g., N, O and/or S)-containing moieties and wherein the 5- to 8-membered ring may be substituted; 
 for each occurrence, R B  is independently selected from the group consisting of halogen, CN, —O—R 10 , —NR 10 R 11 , —CONR 10 R 11 , —N(R 10 )—C(O)R 11 , —N(R 10 )—C(O)—R 11 , —(O—CH 2 CH 2 ) n —R d , ═O, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl, wherein alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl can be optionally substituted, or if more than one group R B  is present and two of the groups R B  are adjacent, they can optionally be taken together and can form a 5- to 8-membered ring containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatom (e.g., N, O and/or S)-containing moieties and wherein the 5- to 8-membered ring may be substituted; 
 for each occurrence, R 10  is independently selected from the group consisting of: hydrogen, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl can be optionally substituted; 
 for each occurrence, R 11  is independently selected from the group consisting of: hydrogen, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl can be optionally substituted; 
 for each occurrence, R 14  is independently selected from the group consisting of hydrogen, —(CH 2 CH 2 —O) n —R f , —(CH 2 CH 2 —O) n —(CH 2 CH 2 )—R d , alkyl, carbocyclyl and heterocyclyl, wherein alkyl, carbocyclyl and heterocyclyl can be optionally substituted; 
 for each occurrence, n is independently 1 to 4; and 
 for each occurrence, m is independently 1 to 4. 
 
     
     
         2 . The compound according to  claim 1 , which is a compound of the formula (Ia): 
       
         
           
           
               
               
           
         
         wherein A, U, B, X, Y, W, W 1  and Z are as defined in  claim 1 . 
       
     
     
         3 . The compound according to  claim 1 , which is a compound of the formula (Ib) or (Ic): 
       
         
           
           
               
               
           
         
         wherein A, U, B, X, Y, W, W 1  and Z are as defined in  claim 1 . 
       
     
     
         4 . The compound according to  claim 1 , which is a compound of the formula (Id), (Ie), (If), (Ig), (Ih) or (Ii): 
       
         
           
           
               
               
           
         
         wherein A and B are as defined in  claim 1 . 
       
     
     
         5 . The compound according to any one of  claims 1  to  4 , wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       can be attached at any available position,
 and wherein 
 
       
         
           
           
               
               
           
         
       
       can be optionally substituted by one or more substituents R B . 
     
     
         6 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         and all detectably labeled derivatives, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof; 
         wherein 
       
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       hydrogen and alkyl, wherein 
       
         
           
           
               
               
           
         
       
       and alkyl can be attached at any available position, and
 wherein 
 
       
         
           
           
               
               
           
         
       
       can be optionally substituted by one or more substituents R D ;
 wherein 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       can be attached at any available position, and wherein 
       
         
           
           
               
               
           
         
       
       can be optionally substituted by one or more substituents R E ;
 V 2  is selected from the group consisting of S, NR a  and CR b R b , 
 Z 2  is selected from the group consisting of N and CR c , 
 for each occurrence, R a  is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl; 
 for each occurrence, R b  is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and halogen; 
 for each occurrence, R c  is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and halogen; 
 for each occurrence, R d  is independently selected from the group consisting of halogen, —OH, —O-alkyl and hydrogen; 
 for each occurrence, R e  is independently selected from the group consisting of hydrogen, —(CH 2 CH 2 —O) n —R f , —(CH 2 CH 2 —O) n —(CH 2 CH 2 )—R d , alkyl, carbocyclyl and heterocyclyl, wherein alkyl, carbocyclyl and heterocyclyl can be optionally substituted, 
 for each occurrence, R f  is independently selected from the group consisting of hydrogen, and alkyl, wherein alkyl can be optionally substituted; 
 for each occurrence, R D  is independently selected from the group consisting of halogen, CN, —O—R 10 , —NR 10 R 11 , —CONR 10 R 11 , —N(R 10 )—C(O)R 11 , —N(R 10 )—C(O)—R 11 , —(O—CH 2 CH 2 ) n —R d , ═O, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl, wherein alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl can be optionally substituted, or if more than one group R D  is present and two of the groups R D  are adjacent, they can optionally be taken together and can form a 5- to 8-membered ring containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatom (e.g., N, O and/or S)-containing moieties and wherein the 5- to 8-membered ring may be substituted; 
 for each occurrence, R E  is independently selected from the group consisting of halogen, CN, —O—R 10 , —NR 10 R 11 , —CON R 10 R 11 , —N(R 10 )—C(O)R 11 , —N(R 10 )—C(O)—O—R 11 , —(O—CH 2 CH 2 ) n —R d , ═O, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl, wherein alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl can be optionally substituted, or if more than one group R E  is present and two of the groups R E  are adjacent, they can optionally be taken together and can form a 5- to 8-membered ring containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatom (e.g., N, O and/or S)-containing moieties and wherein the 5- to 8-membered ring may be substituted; 
 for each occurrence, R 10  is independently selected from the group consisting of: hydrogen, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl can be optionally substituted; 
 for each occurrence, R 11  is independently selected from the group consisting of: hydrogen, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl can be optionally substituted; 
 for each occurrence, R 14  is independently selected from the group consisting of hydrogen, —(CH 2 CH 2 —O) n —R f , —(CH 2 CH 2 —O) n —(CH 2 CH 2 )—R d , alkyl, carbocyclyl and heterocyclyl, wherein alkyl, carbocyclyl and heterocyclyl can be optionally substituted; 
 for each occurrence, n is independently 1 to 4; and 
 for each occurrence, m is independently 1 to 4. 
 
     
     
         7 . The compound according to  claim 6 , which is a compound of the formula (IIa): 
       
         
           
           
               
               
           
         
         wherein D and E are as defined in  claim 6 . 
       
     
     
         8 . The compound according to any one of  claims 1  to  7 , wherein the compound is detectably labeled, preferably with  2 H,  3 H,  18 F,  123 I,  124 I,  125 I,  131 I,  11 C,  13 N,  15 O, and  77 Br, more preferably with  18 F. 
     
     
         9 . A diagnostic composition comprising a compound according to any one of  claims 1  to  8  and a pharmaceutically acceptable carrier, diluent, adjuvant and/or excipient. 
     
     
         10 . The compound according to any one of  claims 1  to  8  for use in diagnostics. 
     
     
         11 . The compound according to any one of  claims 1  to  8  for use in the imaging of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites. 
     
     
         12 . The compound for use according to  claim 11 , wherein the compound is for use in the positron emission tomography imaging of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites. 
     
     
         13 . The compound according to any one of  claims 1  to  8  for use in the diagnostics of a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites or a predisposition therefor. 
     
     
         14 . The compound for use according to  claim 13 , wherein the disorder is selected from Parkinson's disease (including sporadic, familial with alpha-synuclein mutations, familial with mutations other than alpha-synuclein, pure autonomic failure or Lewy body dysphagia), dementia with Lewy bodies (including “pure” Lewy body dementia), sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease, normal aging (including Down syndrome), multiple system atrophy (including Shy-Drager syndrome, striatonigral degeneration or olivopontocerebellar atrophy), traumatic brain injury, chronic traumatic encephalopathy, tauopathies (including Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration or Niemann-Pick type C1 disease), motor neuron disease, amyotrophic lateral sclerosis (including sporadic, familial or ALS-dementia complex of Guam), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (including Hallervorden-Spatz syndrome), prion diseases, ataxia telangiectatica, Meige's syndrome, subacute sclerosing panencephalitis, Gaucher disease, lysosomal storage disorders (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder, preferably Parkinson's disease. 
     
     
         15 . A method of imaging of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites, wherein an effective amount of a compound according to any one of  claims 1  to  8  is administered to a patient in need thereof. 
     
     
         16 . The method according to  claim 15 , wherein the method is positron emission tomography imaging of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites. 
     
     
         17 . A method of diagnosing a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites or a predisposition therefor in a subject, wherein a diagnostically effective amount of a compound according to any one of  claims 1  to  8  is administered to a patient in need thereof. 
     
     
         18 . The method according to  claim 17 , wherein the disorder is selected from Parkinson's disease (including sporadic, familial with alpha-synuclein mutations, familial with mutations other than alpha-synuclein, pure autonomic failure or Lewy body dysphagia), dementia with Lewy bodies (including “pure” Lewy body dementia), sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease, normal aging (including Down syndrome), multiple system atrophy (including Shy-Drager syndrome, striatonigral degeneration or olivopontocerebellar atrophy), traumatic brain injury, chronic traumatic encephalopathy, tauopathies (including Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration or Niemann-Pick type C1 disease), motor neuron disease, amyotrophic lateral sclerosis (including sporadic, familial or ALS-dementia complex of Guam), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (including Hallervorden-Spatz syndrome), prion diseases, ataxia telangiectatica, Meige's syndrome, subacute sclerosing panencephalitis, Gaucher disease, lysosomal storage disorders (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder, preferably Parkinson's disease. 
     
     
         19 . A method of collecting data for the diagnosis of a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in a patient comprising:
 (a) bringing a sample or specific body part or body area of the patient suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with a compound as defined in any one of  claims 1  to  8 ;   (b) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (c) detecting the compound bound to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites; and   (d) optionally correlating the presence or absence of compound binding with the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area.   
     
     
         20 . A method of collecting data for determining a predisposition to a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in a patient comprising detecting the specific binding of a compound as defined in any one of  claims 1  to  8  to alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in a sample or specific body part or body area of the patient which comprises the steps of:
 (a) bringing the sample or specific body part or body area suspected to contain the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with the compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites; 
 (b) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex; 
 (c) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex; 
 (d) optionally correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area; and 
 (e) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value. 
 
     
     
         21 . A method of collecting data for monitoring residual disorder in a patient suffering from a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites who has been treated with a medicament, wherein the method comprises:
 (a) bringing a sample or specific body part or body area suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with a compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (b) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (c) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (d) optionally correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area; and   (e) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value.   
     
     
         22 . The method according to  claim 21 , wherein step (d) is present and wherein the method further comprises steps (i) to (vi) before step (a):
 (i) bringing a sample or specific body part or body area suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with the compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (ii) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (iii) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (iv) correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area;   (v) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value; and   (vi) treating the patient with the medicament;   and wherein the method further comprises step (A) after step (d) or step (e):   (A) comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex determined in step (iv) to the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex determined in step (d).   
     
     
         23 . The method according to  claim 21  or  22 , wherein steps (a) to (c) and optionally steps (d) and (e) are repeated one or more times. 
     
     
         24 . A method of collecting data for predicting responsiveness of a patient suffering from a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites and being treated with a medicament comprising:
 (a) bringing a sample or specific body part or body area suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with a compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (b) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (c) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (d) optionally correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area; and   (e) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value.   
     
     
         25 . The method according to  claim 24 , wherein step (d) is present and wherein the method further comprises steps (i) to (vi) before step (a):
 (i) bringing a sample or specific body part or body area suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with the compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (ii) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (iii) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (iv) correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area;   (v) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value; and   (vi) treating the patient with the medicament;   and wherein the method further comprises step (A) after step (d) or step (e):   (A) comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex determined in step (iv) to the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex determined in step (d).   
     
     
         26 . The method according to  claim 24  or  25 , wherein steps (a) to (c) and optionally steps (d) and (e) are repeated one or more times. 
     
     
         27 . A method of diagnosing a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in a patient comprising:
 (a) bringing a sample or specific body part or body area of the patient suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with a compound as defined in any one of  claims 1  to  8 ;   (b) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (c) detecting the compound bound to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites; and   (d) optionally correlating the presence or absence of compound binding with the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area.   
     
     
         28 . A method of determining a predisposition to a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in a patient comprising detecting the specific binding of a compound as defined in any one of  claims 1  to  8  to alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in a sample or specific body part or body area of the patient which comprises the steps of:
 (a) bringing the sample or specific body part or body area suspected to contain the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with the compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites; 
 (b) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex; 
 (c) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex; 
 (d) optionally correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area; and 
 (e) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value. 
 
     
     
         29 . A method of monitoring residual disorder in a patient suffering from a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites who has been treated with a medicament, wherein the method comprises:
 (a) bringing a sample or specific body part or body area suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with a compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (b) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (c) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (d) optionally correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area; and   (e) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value.   
     
     
         30 . The method according to  claim 29 , wherein step (d) is present and wherein the method further comprises steps (i) to (vi) before step (a):
 (i) bringing a sample or specific body part or body area suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with the compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (ii) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (iii) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (iv) correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area;   (v) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value; and   (vi) treating the patient with the medicament;   and wherein the method further comprises step (A) after step (d) or step (e):   (A) comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex determined in step (iv) to the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex determined in step (d).   
     
     
         31 . The method according to  claim 29  or  30 , wherein steps (a) to (c) and optionally steps (d) and (e) are repeated one or more times. 
     
     
         32 . A method of predicting responsiveness of a patient suffering from a disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites and being treated with a medicament comprising:
 (a) bringing a sample or specific body part or body area suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with a compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (b) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (c) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (d) optionally correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area; and   (e) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value.   
     
     
         33 . The method according to  claim 32 , wherein step (d) is present and wherein the method further comprises steps (i) to (vi) before step (a):
 (i) bringing a sample or specific body part or body area suspected to contain alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites into contact with the compound as defined in any one of  claims 1  to  8 , which compound specifically binds to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites;   (ii) allowing the compound to bind to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites to form a compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (iii) detecting the formation of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex;   (iv) correlating the presence or absence of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area;   (v) optionally comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex to a normal control value; and   (vi) treating the patient with the medicament;   and wherein the method further comprises step (A) after step (d) or step (e):   (A) comparing the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex determined in step (iv) to the amount of the compound/(alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites) complex determined in step (d).   
     
     
         34 . The method according to  claim 32  or  33 , wherein steps (a) to (c) and optionally steps (d) and (e) are repeated one or more times. 
     
     
         35 . The method according to any one of  claims 19  to  34 , wherein the disorder is selected from Parkinson's disease (including sporadic, familial with alpha-synuclein mutations, familial with mutations other than alpha-synuclein, pure autonomic failure or Lewy body dysphagia), dementia with Lewy bodies (including “pure” Lewy body dementia), sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease, normal aging (including Down syndrome), multiple system atrophy (including Shy-Drager syndrome, striatonigral degeneration or olivopontocerebellar atrophy), traumatic brain injury, chronic traumatic encephalopathy, tauopathies (including Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration or Niemann-Pick type C1 disease), motor neuron disease, amyotrophic lateral sclerosis (including sporadic, familial or ALS-dementia complex of Guam), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (including Hallervorden-Spatz syndrome), prion diseases, ataxia telangiectatica, Meige's syndrome, subacute sclerosing panencephalitis, Gaucher disease, lysosomal storage disorders (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder, preferably Parkinson's disease. 
     
     
         36 . A method of determining the amount of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in a sample or specific body part or body area of a patient comprising:
 (a) providing the sample or specific body part or body area;   (b) testing the sample or specific body part or body area for the presence of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites with a compound as defined in any one of  claims 1  to  8 ;   (c) determining the amount of compound bound to the alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites; and   (d) calculating the amount of alpha-synuclein aggregates including, but not limited to, Lewy bodies and/or Lewy neurites in the sample or specific body part or body area.   
     
     
         37 . The method according to any one of  claims 19  to  36 , wherein the sample is a tissue and/or a body fluid representative of the specific body part or body area under investigation. 
     
     
         38 . A mixture comprising a compound as defined in any one of  claims 1  to  8  and at least one compound selected from an imaging agent different from the compound as defined in any one of  claims 1  to  8 , preferably an abeta or tau imaging agent, a pharmaceutically acceptable carrier, a diluent and an excipient. 
     
     
         39 . A mixture comprising a compound as defined in any one of  claims 1  to  8  and at least one compound selected from a therapeutic agent different from the compound as defined in any one of  claims 1  to  8 , a pharmaceutically acceptable carrier, a diluent and an excipient. 
     
     
         40 . A pharmaceutical composition comprising a compound according to any one of  claims 1  to  8  and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient. 
     
     
         41 . The compound as defined in any one of  claims 1  to  8  for use in the treatment, alleviation or prevention of a disorder or abnormality associated with alpha-synuclein aggregates, wherein the disorder is optionally selected from Parkinson's disease (including sporadic, familial with alpha-synuclein mutations, familial with mutations other than alpha-synuclein, pure autonomic failure or Lewy body dysphagia), dementia with Lewy bodies (including “pure” Lewy body dementia), sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease, normal aging (including Down syndrome), multiple system atrophy (including Shy-Drager syndrome, striatonigral degeneration or olivopontocerebellar atrophy), traumatic brain injury, chronic traumatic encephalopathy, tauopathies (including Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration or Niemann-Pick type C1 disease), motor neuron disease, amyotrophic lateral sclerosis (including sporadic, familial or ALS-dementia complex of Guam), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (including Hallervorden-Spatz syndrome), prion diseases, ataxia telangiectatica, Meige's syndrome, subacute sclerosing panencephalitis, Gaucher disease, lysosomal storage disorders (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder, preferably Parkinson's disease. 
     
     
         42 . A compound of formula (IIIa) or (IIIb) 
       
         
           
           
               
               
           
         
         wherein R e , R 14 , R A , m, B, U, Y, W, W 1 , X, Z and V are as defined in  claim 1 , 
       
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       can be attached at any available position to the moiety U, and wherein 
       
         
           
           
               
               
           
         
       
       can be optionally substituted by one or more substituents R A ; and
 LG is a leaving group. 
 
     
     
         43 . A compound of formula (IVa) or (IVb) 
       
         
           
           
               
               
           
         
         wherein R e , R D , E, V 2  and Z 2  are as defined in  claim 6 ; 
       
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and alkyl, wherein 
       
         
           
           
               
               
           
         
       
       and alkyl can be attached at any available position, and wherein 
       
         
           
           
               
               
           
         
       
       can be optionally substituted by one or more substituents R D ; and
 LG is a leaving group. 
 
     
     
         44 . The compound according to  claim 42  or  43 , wherein LG is selected from nitro, halogen, trimethylammonium, C 1-4  alkyl sulfonate or C 6-10  aryl sulfonate. 
     
     
         45 . A method for preparing the compound according to  claim 8 , wherein the compound is labelled by  18 F, comprising reacting the compound according to  claim 42  or  43  with a  18 F-fluorinating agent, so that LG is replaced by  18 F. 
     
     
         46 . The method according to  claim 45 , wherein the  18 F-fluorinating agent is selected from K 18 F, H 18 F, Cs 18 F, Na 18 F and tetrabuylammonium [ 18 F]fluoride. 
     
     
         47 . Use of the compound according to any one of  claims 1  to  8  as an in vitro analytical reference or an in vitro screening tool. 
     
     
         48 . A test kit for detection and/or diagnosis of a disorder or abnormality associated with alpha-synuclein aggregates, wherein the test kit comprises at least one compound as defined in any one of  claims 1  to  8 . 
     
     
         49 . The test kit according to  claim 48  comprising a container containing at least one compound as defined in any one of  claims 1  to  8  and instructions for using the at least one compound for the purpose of binding to alpha-synuclein aggregates to form a compound/protein complex and detecting the formation of the compound/protein complex such that presence or absence of the compound/protein complex correlates with the presence or absence of the alpha-synuclein aggregates. 
     
     
         50 . A kit for preparing a radiopharmaceutical preparation, wherein the kit comprises a sealed vial containing at least one compound as defined in  claim 42  or  43 .