Piperazine Derivatives for Binding and Imaging Amyloid Plaques and Their Use

1 . A diagnostic composition comprising a compound of formula I

or a pharmaceutically acceptable salt or a prodrug thereof,

wherein

Y is selected from the group consisting of:

F, Cl, Br, I, H, 18 F, 19 F, 76 Br, 123 I, 125 I, 11 C, 3 H, 13 F, 15 O;

a leaving group, tosyl, brosyl, nosy', triflate, sulfonate, substituted sulfonate, mesylate, and nonaflate; and if directly bound to an aromatic C-atom iodonium-aryl I + -aryl, trialkylammonium, preferred trimethylammonium, and NO 2 ;

Ar is selected from the group consisting of:

substituted or non-substituted mono-, bi- or tricyclic aromatic or heteroaromatic ring systems;

B is selected from the group consisting of:

direct bond, a branched or non-branched alkyl or alkylenchain comprised of 1-10 C-atoms;

A is selected from the group consisting of:

a direct bond, and CO—NH, CS—NH;

Ar′ is selected from the group consisting of:

substituted or non-substitued mono-, or bi-cyclic aromatic or heteroaromatic ring systems;

X is selected from the group consisting of:

a direct bond or a substituted or non-substituted C 1 -C 3 alkyl chain;

Ar″ is selected from the group consisting of:

substituted or non-substituted mono-, or bi-cyclic aromatic or heteroaromatic ring systems.

2 . The composition according to claim 1 , wherein Y is 18 F.

3 . A compound of formula I

or a pharmaceutically acceptable salt or a prodrug thereof,

wherein

Y is selected from the group consisting of:

F, Cl, Br, I, H, 18 F, 19 F, 76 Br, 123 I, 125 I, 11 C, 3 H, 13 N, 15 O;

a leaving group, tosyl, brosyl, nosyl, triflate, sulfonate, substituted sulfonate, mesylate, and nonaflate; and if directly bound to an aromatic C-atom iodonium-aryl I + -aryl, trialkylammonium, preferred trimethylammonium, and NO 2 ;

Ar is selected from the group consisting of:

substituted or non-substituted mono-, bi- or tricyclic aromatic or heteroaromatic ring systems;

B is selected from the group consisting of:

direct bond, a branched or non-branched alkyl or alkylenchain comprised of 1-10 C-atoms;

A is selected from the group consisting of:

a direct bond, and CO—NH, CS—NH;

Ar′ is selected from the group consisting of:

substituted or non-substitued mono-, or bicyclic aromatic or heteroaromatic ring systems;

X is selected from the group consisting of:

a direct bond or a substituted or non-substituted C 1 -C 3 alkyl chain;

Ar″ is selected from the group consisting of:

substituted or non-substituted mono-, or bi-cyclic aromatic or heteroaromatic ring systems,

with the provisio that if A and/or B are direct bonds the directly bound residue Ar or Ar′ is a six ring membered aromatic system.

4 . A compound of formula I

or a pharmaceutically acceptable salt or a prodrug thereof,

wherein

Y is selected from the group consisting of:

F, Cl, Br, I, H, 18 F, 19 F, 76 Br, 123 I, 125 I, 11 C, 3 H, 13 N, 15 O;

a leaving group, tosyl, brosyl, nosyl, triflate, sulfonate, substituted sulfonate, mesylate, and nonaflate; and if directly bound to an aromatic C-atom iodonium-aryl trialkylammonium, preferred trimethylammonium, and NO 2 ;

Ar is selected from the group consisting of:

mono-, bi- or tricyclic aromatic or heteroaromatic ring systems substituted by one or two alkyl, alkylen, alkynesubstituents and/or alkoxysubstituents,

B is selected from the group consisting of:

direct bond, a branched or non-branched alkyl or alkylenchain comprised of 1-10 C-atoms;

A is selected from the group consisting of:

a direct bond, and CO—NH, CS—NH;

Ar′ is selected from the group consisting of:

mono-, or bi-cyclic aromatic or heteroaromatic ring systems which are substituted by one or two alkyl, alkylen, alkynesubstituents and/or alkoxysubstituents and wherein the mono-, bi- or tricyclic aromatic or heteroaromatic ring systems are further substituted by electron withdrawing groups directly bound to an aromatic C-atom;

X is selected from the group consisting of:

a direct bond or a substituted or non-substituted C 1 -C 3 alkyl chain;

Ar″ is selected from the group consisting of:

substituted or non-substituted mono-, or bi-cyclic aromatic or heteroaromatic ring systems.

5 . A compound according to claim 3 , wherein

the alkyl, alkylen, alkynesubstituents and/or alkoxysubstituents of Ar, Ar′ and Ar″ are selected from the group consisting of oxo or hydroxyl,

and wherein the alkyl, alkylen, alkynesubstituents and/or alkoxysubstituents of Ar, Ar′and Ar″ are interrupted by 1-5 oxygen atoms, preferably the subtituents are polyethylenglycol-moieties,

and wherein further the alkyl, alkylen, alkynesubstituents and/or alkoxysubstituents of Ar, Ar′ and Ar″ comprise C 3 -C 6 cycloalkyl moieties, and wherein the optional electron withdrawing groups of Ar, Ar′ and Ar″ are selected from the group consisting of —CN or CF 3 ,

and wherein

B is selected from the group consisting of direct bond, CONH—CH 2 CO, CO—(CH 2 ) 2 CO, (CH 2 ) n CO, O(CH 2 ) n CO with n=1 to 10, (CH═CH)CO,

and wherein

X is selected from the group consisting of direct bond, OCH 2 , NHCO, CH2O, CONH, NHCS, or CSNH.

6 . A compound according to claim 3 , wherein

Ar is selected from the group consisting of

propylpyrimidin-2-yl, ethoxyphenyl, (CH 2 CH 2 O) 3 phenyl, alkylphenyl, alkoxyphenyl, N-alkylindolyl, and alkylpyridyl,

and wherein

Ar′ is selected from the group consisting of

propylpyrimidin-2-yl, ethoxyphenyl, (CH 2 CH 2 O) 3 phenyl, allylphenyl, alkoxyphenyl, N-alkylindolyl, phenyl, benzofuranyl, indolyl and alkylpyridyl;

and wherein

Ar″ is selected from the group consisting of

phenyl, 1-phenyl, 1-naphthyl, 2-naphthyl, and all respective heterocycles thereof.

7 . A compound, selected from the group consisting of

8 . A compound according to claim 7 , wherein F has the meaning of 18 F.

9 . A compound according to claim 3 containing a detectable label, such as a radioactive nuclide or a fluorescent label.

10 . A compound according to claim 9 , wherein the detectable label is 18 F.

11 . A compound according to claim 3 as a diagnostic compound.

12 . A compound according to claim 3 as a medicament.

13 . A compound according to claim 8 as a diagnostic compound for a disease selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis.

14 . A compound according to claim 12 as a medicament for treating a disease selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis.

15 . A method for the preparation of a fluorinated compound according to claim 3 , the method comprising reacting a suitable precursor molecule with a fluorinating agent.

16 . A method for treating or preventing a disorder selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis in a mammal, this method comprising administering a therapeutically effective amount of a compound according to claim 3 to said mammal.

17 . A method for treating a disease selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis in a mammal, said method comprises administering a therapeutically effective amount of a compound of claim 3 to said mammal.

18 . A method for diagnosing a disease in a mammal selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis, this method comprising administering to said mammal a composition according to claim 1 .

19 . The method of claim 18 , this method comprising imaging of said mammal and detecting the imaging signal.

20 . The method of claim 19 , where said imaging is performed using an imaging method selected from the group consisting of PET, SPECT, MR-spectroscopy, and MR-tomography.

21 . A method according to claim 18 , wherein the effect of a therapy is monitored.

22 . A method for diagnosing or therapy monitoring of a disease selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis in a mammal, said method comprising analyzing in vitro a sample of said mammal, wherein said mammal or sample has been treated with a compound according to claim 3 .

23 . The method of claim 22 , wherein the sample is cerebrospinal fluid.

24 . A kit comprising a compound according to claim 7 in a sealed vial.

25 . A compound according claim 7 , wherein F is replaced by a leaving group.

26 . A compound according to claim 25 , wherein the leaving group is selected from the group consisting of tosyl, brosyl, nosyl, triflate, sulfonate, substituted sulfonate, mesylate, nonaflate; and if directly bound to an aromatic C-atom iodonium-aryl I + -aryl trialkylammonium, trimethylammonium, and NO 2 .

27 . A method of preparing a compound according to claim 7 , comprising reacting the corresponding compound where F is replaced by a leaving group, with a fluorinating agent.