Amyloid targeting imaging agents and uses thereof
View Patent ↗Amyloid-targeting imaging agents such as radiolabeled amyloid targeting molecules and amyloid targeting molecule-chelator conjugates for imaging, e.g., amyloid plaques in vivo, and/or for the treatment of amyloidosis disorders. The invention provides amyloid-targeting imaging agents that are useful for imaging sites of amyloid disease. Imaging agents of the invention are capable of binding specifically to amyloid plaques, as an aid in diagnosis and/or early treatment of amyloidosis disorders.
1. An amyloid-targeting imaging agent of the formula
where z is 0 or 1; A t is an amyloid targeting moiety selected from the group consisting of
NaO 3 SCH 2 (CH 2 ) 4 CH 2 SO 3 Na, NaO 3 SNHCH 2 CH 2 CH 2 OSO 3 Na,
and pharmaceutically acceptable salts thereof;
A lnk is a linker moiety; and A lab is a labeling moiety.
2. The amyloid-targeting imaging agent of claim 1 , wherein A lab includes a radionuclide selected from 99m Tc, 99 Tc, 64 Cu, 67 Cu, 97 Ru, 109 Pd, 186 Re, 188 Re 111 In, 113m In, 153 Gd, 90 Y, 153 Sm, 166 Ho, 198 Au, 199 Au, 90 Sr, 89 Sr, 105 Rh, 201 Tl, 51 Cr, 67 Ga, 57 co, 60 Co, 123 I, 125 I, 131 I or 18 F.
3. The amyloid-targeting imaging agent of claim 1 , wherein A lab includes a radionuclide selected from the group consisting of Tc and Re.
4. The amyloid-targeting imaging agent of claim 1 , wherein A lab is a metal chelate of a radioactive or paramagnetic metal ion.
5. The amyloid-targeting imaging agent of claim 1 , wherein A lab comprises a chelating ligand of the formula
where R 10 is a linear or branched, saturated or unsaturated C 1-4 alkylene group interrupted by one or two heteroatoms; R 11 is H or R 10 , or R 10 and R 11 taken together, form a 5- to 8-membered saturated or unsaturated heterocyclic ring optionally substituted with one or more of halogen, hydroxyl, amino, carboxyl, oxo, C 1-4 alkyl, aryl, or C(O)R groups; R 3 , R 4 , R 5 and R 6 are independently H, carboxyl, C 1-4 alkyl, an alpha carbon side chain of a D- or L-amino acid other than proline, or C(O)R; R 7 and R 8 are independently H, carboxyl, amino, C 1-4 alkyl, C 1-4 alkyl; R 9 is H or a sulfur protecting group; and L is hydroxyl, alkoxy, an amino acid residue, or a linking group.
6. A kit for preparing a radiopharmaceutical preparation, said kit comprising:
an amyloid-targeting imaging agent of claim 1 ;
a reducing agent;
a buffering agent;
a transchelating agent, and
instructions for the preparation and use of the radiopharmaceutical in the imaging of amyloid or an amyloid-related condition.
7. A method of diagnostic medical imaging of an amyloid-associated disease comprising the steps of administering to a patient a pharmaceutical composition according to claim 1 and then imaging said patient.
8. The method of diagnostic medical imaging according to claim 7 wherein A lab of said pharmaceutical composition is a radiopharmaceutical.
9. The method of diagnostic medical imaging according to claim 7 wherein A lab of said pharmaceutical composition is a metal chelate.
10. The method of diagnostic medical imaging according to claim 9 wherein said metal chelate is gadolinium-DTPA, gadolinium-DOTA, or gadolinium-DO3A.
11. The method of diagnostic medical imaging according to claim 9 wherein said metal chelate is a chelate of 99m Tc or 111 In.
12. The method of diagnostic medical imaging according to claim 7 wherein said imaging step is ultrasound imaging.
13. A method for imaging amyloid deposition in a patient, comprising administering an amyloid-targeting imaging agent according to claim 1 to a patient, and imaging said amyloid-targeting imaging agent in said patient to determine the presence of amyloid in said patient.
14. The method of claim 13 , wherein said imaging step is radionuclide imaging.
15. The method of claim 14 , wherein said imaging step is SPECT imaging.
16. The method of claim 13 , wherein said imaging step is magnetic resonance imaging.
17. The method of claim 13 , wherein said imaging step is ultrasound imaging.
18. The method of claim 13 , wherein said imaging step is X-ray imaging.
19. The method of claim 13 , wherein said imaging step is fluorescence imaging.
20. A method for diagnostic medical imaging of an amyloid-associated disease in a patient, comprising administering to a patient a pharmaceutical composition comprising an amyloid-targeting imaging agent of claim 1 , and imaging the amyloid-targeting imaging agent in said patient.
21. The method of claim 20 , wherein A lab of said pharmaceutical composition is a radiopharmaceutical.
22. The method of claim 20 , wherein A lab of said pharmaceutical composition is a metal chelate.
23. The method of claim 20 , wherein A lab of said pharmaceutical composition is a metal chelate and said imaging step is magnetic resonance imaging or radionuclide imaging.
24. The method of claim 22 , wherein said metal chelate is gadolinium DTPA, gadolinium-DOTA, or gadolinium-DO3A.
25. The method of claim 22 , wherein said metal chelate is a chelate of 99m Tc or 111 In.
26. The method of claim 20 , wherein said imaging step is ultrasound imaging.
27. A method for diagnosing an amyloid-related condition in a patient, comprising administering an amyloid-targeting imaging agent according to claim 1 to a patient, and imaging said amyloid-targeting imaging agent in said patient to determine the presence of amyloid in said patient, such that the presence or absence of an amyloid-related condition in sad patient is determined.
28. The method of claim 27 , wherein said amyloid-related condition is selected from the group consisting of Creutzfeld-Jakob Disease (CJD), Kuru, transmissible cerebral amyloidosis, transmissible virus dementias, familial CJD, scrapie, transmissible mink encephalopathy, bovine spongiform encephalopathy (BSE), inflammation-associated amyloid, type II diabetes, primary amyloidosis, feline spongiform encephalopathy, non-transmissible cerebral amyloidosis, prion-mediated diseases, dialysis-related amyloidosis, light chain-related amyloidosis, cerebral amyloid angiopathy, and Alzheimer's disease.
29. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
NaO 3 SCH 2 (CH 2 ) 4 CH 2 SO 3 Na
or a pharmaceutically acceptable salt thereof.
30. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
NaO 3 SNHCH 2 CH 2 CH 2 OSO 3 Na
or a pharmaceutically acceptable salt thereof.
31. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
or a pharmaceutically acceptable salt thereof.
32. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
or a pharmaceutically acceptable salt thereof.
33. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
or a pharmaceutically acceptable salt thereof.
34. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
or a pharmaceutically acceptable salt thereof.
35. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
or a pharmaceutically acceptable salt thereof.
36. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
or a pharmaceutically acceptable salt thereof.
37. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
or a pharmaceutically acceptable salt thereof.
38. The amyloid-targeting imaging agent of claim 1 , wherein the amyloid targeting moiety is of the formula
or a pharmaceutically acceptable salt thereof.