Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors
This invention relates to novel compounds suitable for labeling or already labeled by 18 F, methods of preparing such a compound, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by positron emission tomography (PET).
1. A compound of formula Ia
wherein
W is —CH 2 —C≡CH;
A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, G 4 -(C 2 -C 4 )alkynyl-, G 4 -(C 1 -C 4 )alkoxy-, (G 4 -(C 1 -C 4 )alkyl)aryl-, or G 4 -(C 1 -C 4 )alkoxy)aryl-,
G 1 , G 2 , G 3 and G 4 are, independently and individually, at each occurrence, hydrogen, (C 1 -C 4 )alkyl, L, or —(C 1 -C 6 )alkyl-L,
with the proviso that exactly one of G 1 -G 4 is L or —(C 1 -C 6 )alkyl-L,
L is a leaving group, or L is F,
n is an integer from 0 to 6, and
m is an integer from 1 to 4,
or a pharmaceutically acceptable salt, ester, amide, or complex thereof.
2. The compound according to claim 1 , wherein A is substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, G 4 -(C 3 -C 4 )alkynyl-, G 4 -(C 1 -C 3 )alkoxy-, (G 4 -(C 1 -C 3 )alkyl)phenyl-, or (G 4 -(C 1 -C 3 )alkoxy)phenyl-.
3. The compound according to claim 2 , wherein A is substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, (G 4 -(C 1 -C 3 )alkyl)phenyl-, (G 4 -(C 1 -C 3 )alkoxy)phenyl-, hydroxy-phenyl, halo-phenyl, methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl, or ((C 1 -C 4 )alkyl)-phenyl.
4. The compound according to claim 3 , wherein A is substituted or unsubstituted phenyl, (G 4 -(C 1 -C 3 )alkoxy)phenyl-, hydroxyl-phenyl, fluorophenyl, methoxyphenyl, or methylphenyl.
5. The compound according to claim 1 , wherein G 1 , G 2 , G 3 and G 4 are independently and individually, at each occurrence, hydrogen, (C 1 -C 4 )alkyl, L, or —(C 1 -C 4 )alkyl-L, with the proviso that exactly one of G 1 -G 4 is L or —(C 1 -C 4 )alkyl-L.
6. The compound according to claim 5 , wherein G 1 , G 2 , G 3 and G 4 are independently and individually, at each occurrence, hydrogen, methyl, L, or —(C 1 -C 2 )alkyl-L, with the proviso that exactly one of G 1 -G 4 is L or —(C 1 -C 2 )alkyl-L.
7. The compound according to claim 6 , wherein G 1 , G 2 , G 3 and G 4 are independently and individually, at each occurrence, hydrogen, methyl, L, or -methyl-L, with the proviso that exactly one of G 1 -G 4 is L or -methyl-L.
8. The compound according to claim 1 , wherein L is halo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, or (4-methoxy-phenyl)sulfonyloxy.
9. The compound according to claim 8 , wherein L is chloro, bromo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, or (2,4,6-tri-isopropyl-phenyl) sulfonyloxy.
10. The compound according to claim 1 which is
11. The compound according to claim 1 , wherein L is not F.
12. The compound according to claim 1 , wherein L is 18 F.
13. The compound according to claim 1 , wherein L is 19 F.
14. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
15. A composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier or diluent.
16. A composition comprising a compound according to claim 13 and a pharmaceutically acceptable carrier or diluent.
17. A composition comprising a compound according to claim 11 and a pharmaceutically acceptable carrier or diluent.
18. A kit comprising a sealed vial containing a predetermined quantity of a compound according to claim 11 .
19. A method for detecting the presence of monoamine oxidase in a patient's body, comprising: introducing into said patient's body a detectable amount of a compound according to claim 12 and detecting said compound by positron emission tomography (PET).
20. A method of treatment of a disease of the central nervous system comprising the step of introducing into a patient a suitable quantity of a compound according to claim 1 .
21. A method of treatment of a disease of the central nervous system comprising the step of introducing into a patient a suitable quantity of a compound according to claim 12 .
22. A method of treatment of a disease of the central nervous system comprising the step of introducing into a patient a suitable quantity of a compound according to claim 13 .
23. The compound according to claim 13 , wherein said compound contains exactly one 19 F-atom and the 19 F-atom is attached to an sp 3 -hybridized carbon atom.
24. The compound according to claim 1 , wherein n is 1-3.
25. The compound according to claim 1 , wherein n is 1-2.
26. The compound according to claim 1 , wherein m is 1 to 2.
27. The method according to claim 19 , wherein said method is for imaging a disease of the central nervous system in said patient.
28. The compound according to claim 12 , wherein said compound is selected from the following compounds:
29. The compound according to claim 13 , wherein said compound is selected from the following compounds:
30. A method of synthesizing a compound according to claim 12 , comprising reacting one or more compounds of formula Ia wherein L is a leaving group with an F-fluorinating agent in which F is 18 F.
31. The method according to claim 30 , wherein L is halo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl) sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, or (4-methoxy-phenyl)sulfonyloxy.
32. The method according to claim 30 , wherein L is chloro, bromo, or iodo.
33. The method according to claim 30 , wherein said one or more compounds of formula Ia is or includes a compound wherein G 2 is L, and L is chloro, bromo, or iodo.
34. The method according to claim 33 , wherein the compound synthesized is one wherein G 1 is —(C 1 -C 6 )alkyl-L.
35. The method according to claim 33 , wherein the compound synthesized is one wherein G 1 is -methyl-L.
36. The method according to claim 30 , wherein said F-fluorinating agent is 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, KF, HF, KH F 2 , CsF, NaF or a tetraalkylammonium salt, wherein F is 18 F.
37. A method of synthesizing a compound according to claim 13 , comprising reacting one or more compounds of formula Ia wherein L is a leaving group with an F-fluorinating agent in which F is 19 F.
38. The method according to claim 37 , wherein L is halo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, or (4-methoxy-phenyl)sulfonyloxy.
39. The method according to claim 37 , wherein L is chloro, bromo, or iodo.
40. The method according to claim 37 , wherein said one or more compounds of formula Ia is or includes a compound wherein G 2 is L, and L is chloro, bromo, or iodo.
41. The method according to claim 40 , wherein the compound synthesized is one wherein G 1 is —(C 1 -C 6 )alkyl-L.
42. The method according to claim 40 , wherein the compound synthesized is one wherein G 1 is -methyl-L.
43. The method according to claim 37 , wherein said F-fluorinating agent is 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, KF, HF, KH F 2 , CsF, NaF or a tetraalkylammonium salt, wherein F is 19 F.
44. The method according to claim 30 , wherein a mixture of the following compounds 42 and 43
is reacted with a 18 F-fluorinating agent to obtain a mixture of the following compounds 13 and 39