Imaging agents for detecting neurological disorders

• US 20100239496A1
• Filed: 03/23/2010
• Published: 09/23/2010
• Est. Priority Date: 03/23/2009
• Status: Active Grant

• Current Assignee: Eli Lilly and Company
• Original Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Inventors: Kolb, Hartmuth C., Cashion, Daniel Kurt, Mocharia, Vani P., Chen, Gang, Zhang, Wei, Gangadharmath, Umesh B., Szardenings, Anna Katrin, Scott, Peter J.H., Sinha, Anjana, Walsh, Joseph C., Wang, Eric, Kasi, Dhanalakshmi, Yu, Chul, Liu, Changhui
• Granted Patent: US 8,491,869 B2
• Time in Patent Office: Days
• US Class Current: 424/1.650
• CPC Class Codes: A61K 51/0453 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 51/0455 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 51/0459 having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
• CPC Class Codes: A61K 51/0463 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07B 59/002 Heterocyclic compounds
• CPC Class Codes: C07D 215/06 having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
• CPC Class Codes: C07D 235/14 Radicals substituted by nitrogen atoms by nitro radicals C07D235/10
• CPC Class Codes: C07D 277/62 Benzothiazoles
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Imaging agents of formula (I) and methods for detecting neurological disorders comprising administering to a patient in need compounds of formula (I) capable of binding to tau proteins and β-amyloid peptides are presented herein. The invention also relates to methods of imaging Aβ and tau aggregates comprising introducing a detectable quantity of pharmaceutical formulation comprising a radiolabeled compound of formula (I) and detecting the labeled compound associated with amyloid deposits and/or tau proteins in a patient. These methods and compositions enable preclinical diagnosis and monitoring progression of AD and other neurological disorders.

Claims

1. A compound of Formula (I) having binding affinity to amyloid peptides of senile plaques and/or tau proteins of neurofibrillary tangles, which can be associated with neurological disorders, wherein the compound of Formula (I) is:

formula (I)

2. The compound of claim 1, wherein at least one of R₁-R₉ comprises a radiolabel selected from the group consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ⁷⁶Br and ⁷⁷Br.

3. The compound of claim 2, wherein the radiolabel is ¹⁸F.

4. The compound of claim 1, wherein A is a bond.

5. The compound of claim 1, wherein A is C₂ alkyne or acetylene.

6. The compound of claim 5, wherein Z is

7. The compound of claim 6, wherein at least one of R₁-R₆ is —

(O—

CH₂—

CH₂)₂—

or —

(OCH₂—

CH₂)₃—

.

8. The compound of claim 4, wherein Z is

9. The compound of claim 8, wherein at least one of R₁-R₉ is —

(O—

CH₂—

CH₂)₂—

.

10. The compound of claim 9, wherein Z is quinoline.

11. The compound of claim 4, wherein Z is

12. The compound of claim 5, wherein Z is

13. The compound of claim 5, wherein Z is

14. The compound of claim 10, wherein R₁ is saturated heterocycle.

15. The compound of claim 1, wherein at least one of R₁-R₉ is a heterocycle.

16. The compound of claim 15, wherein at least one of R₁-R₉ is —

(O—

CH₂—

CH₂)₂—

.

18. The formulation diagnostic formulation of claim 16 for detection of amyloid peptides.

19. The formulation diagnostic formulation of claim 16 for detection of tau proteins of neurofibrillary tangles.

20. The formulation diagnostic formulation of claim 16 wherein the neurological disorder is Alzheimer'"'"'s disease.

22. A method according to claim 20 wherein the neurological disorder is detected by measuring the affinity of compounds of formula (I) for senile plaques.

23. A method according to claim 20 wherein the neurological disorder is detected by measuring the affinity of compounds of formula (I) for tau aggregates.

24. A method for ex vivo or in vitro detection of amyloid deposit in a brain tissue, the method comprising treating the tissue with a compound of claim 1 for detection of the amyloid deposit.

25. A method for in vivo detection of amyloid deposits in a patient, the method comprising administering an effective amount of the radiolabeled compound of claim 1 to the patient, and detecting the binding level of the compound to the amyloid deposit to the patient.

26. A method for ex vivo or in vitro detection of tau proteins in a brain tissue, the method comprising treating the tissue with a compound of any one of claim 11, 12 or 14 for detecting of the neurofibrillary tangles.

27. A method for in vivo detection of neurofibrillary tangles in a patient, the method comprising administering an effective amount of the radiolabeled compound of any one of claim 11, 12 or 14 to the patient, and detecting the binding level of the compound to tau proteins.

17. A pharmaceutical diagnostic formulation comprising a radiolabeled compound of formula (I) or a pharmaceutically acceptable salt thereof in a suitable vehicle or diluent for imaging and detection of neurological disorders.

21. A method for imaging and detection of senile plaques and/or neurofibrillary tangles in a brain tissue, the method comprising treating the tissue with a compound of formula (I) for detection of neurological disorders.

28. The method of claim 21, wherein the disorder is Alzheimer'"'"'s disease (AD).

29. The method of claims 21, wherein the detection is performed using gamma imaging, magnetic resonance imaging, magnetic resonance spectroscopy or fluorescence spectroscopy.

30. The method of any of the claims 28, wherein the detection by gamma imaging is PET or SPECT.