RADIOPHARMACEUTICAL COMPLEXES

• US 20110189088A1
• Filed: 12/23/2010
• Published: 08/04/2011
• Est. Priority Date: 12/24/2009
• Status: Abandoned Application

• Current Assignee: Lumiphore Inc.
• Original Assignee: Lumiphore Inc.
• Inventors: Butlin, Nathaniel G., Magda, Darren, Xu, Jide
• Application Number:
  US12/977,957
• Publication Number:
  US 20110189088A1
• Time in Patent Office: Days
• US Class Current: 424/1.73
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 213/89 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings

Abstract

The invention provides compounds such as chelating agents useful in chelating metal ions, particularly radionuclides, to provide metal ion complexes. The invention also provides methods of using the compounds and complexes of the invention, such as in therapeutic and diagnostic applications.

Claims

1. A complex comprising (a) a radionuclide and (b) a macrocycle comprising (i) a plurality of chelating moieties, (ii) a linker, (iii) a first scaffold moiety and (iv) a second scaffold moiety, wherein each of the chelating moieties is attached to the first scaffold moiety and the second scaffold moiety.

3. The complex of claim 1 wherein the plurality of chelating moieties comprises a plurality of oxygen donors and the radionuclide is chelated to the macrocycle via at least one of the oxygen donors.

4. The complex of claim 1 wherein the macrocycle comprises a plurality of oxygen donors and the radionuclide is chelated to the macrocycle via a plurality or all of the oxygen donors.

5. The complex of claim 1 wherein the chelating moieties are independently selected from

8. The complex of claim 5 wherein the chelating moieties all have the structure

11. The complex of claim 5 wherein the chelating moieties all have the structure

28. The complex of claim 1 wherein the second scaffold moiety is substituted heteroalkyl.

29. The complex of claim 1 wherein the second scaffold moiety has the structure

39. The complex of claim 29 wherein at least one of Z^1b, Z^2b, Z^3bZ^4b and Z^5b is substituted by a linker.

40. The complex of claim 1 wherein the first scaffold moiety is substituted heteroalkyl.

41. The complex of claim 1 wherein the first scaffold moiety has the structure

51. The complex of claim 41 wherein at least one of Z^1a, Z^2a, Z^3a, Z^4a and Z^5a is substituted by a linker.

52. The complex of claim 1 wherein the first scaffold moiety has the structure

59. The complex of claim 52 wherein at least one Z⁷ is substituted by a linker.

61. The complex of claim 1 wherein the linker has the structure -L¹¹-X, wherein L¹¹ is selected from a bond, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

and X is a reactive functional group or the targeting moiety.

63. The complex of claim 61 wherein X is selected from —

NH₂ and —

CO(O)H.

64. The complex of claim 61 wherein -L¹¹-X is selected from

65. The complex of claim 1 wherein the linker is a linker to a targeting moiety.

66. The complex of claim 65 wherein targeting moiety is selected from a peptide, a polypeptide, a nucleic acid, an oligonucleotide, a lipid, a polysaccharide, a small molecule, a cofactor and a hormone.

67. The complex of claim 66 wherein the targeting moiety is an antibody or antibody fragment.

71. The complex of claim 1 wherein the radionuclide is a metal ion.

72. The complex of claim 1 wherein the radionuclide is selected from an actinide and a lanthanide.

73. The complex of claim 1 wherein the radionuclide is an ion of an atom selected from U, Pu, Fe, Cu, Ce, Nd, Eu, Sm, Gd, Tb, Dy, Ho, Er, Yb, Lu, Y, Th, Zr, In, Ga, Bi, Ra and Ac.

74. The complex of claim 1 wherein the radionuclide is selected from Ra-223, Bi-213, Ac-225 and U-230.

75. The complex of claim 1 wherein the radionuclide is an isotope of Th.

76. The complex of claim 75 wherein the radionuclide is selected from Th-227 and Th-232.

77. The complex of claim 1 wherein the radionuclide is a 3⁺ or 4⁺ ion.

78. The complex of claim 1 wherein the radionuclide is a 3⁺ ion.

79. A method of treating a disease in an animal comprising administering the complex of claim 1 to the animal, whereby the disease is ameliorated or eliminated.

80. A method of diagnosing a disease in an animal comprising (a) administering the complex of claim 1 to the animal and (b) detecting the presence or absence of a signal emitted by the complex.

2. (canceled)

6-7. -7. (canceled)

9-10. -10. (canceled)

12-14. -14. (canceled)

15. A complex comprising (a) a radionuclide and (b) a chelator comprising (i) a plurality of chelating moieties and (ii) a first scaffold moiety, wherein each of the chelating moieties is attached to the first scaffold moiety and wherein each of the chelating moieties has a structure independently selected from

16. The complex of claim 15 wherein all the chelating moieties have the structure

21. The complex of any of claim 15 further comprising a linker.

17-20. -20. (canceled)

22. A complex comprising (a) a radionuclide and (b) a first chelator comprising (i) a plurality of chelating moieties, (ii) a linker and (iii) a first scaffold moiety, wherein each of the chelating moieties is attached to the first scaffold moiety and wherein each of the chelating moieties has a structure independently selected from:

23. The complex of claim 22 wherein the chelating moieties are selected from

24-27. -27. (canceled)

30-38. -38. (canceled)

42-50. -50. (canceled)

53-58. -58. (canceled)

60. (canceled)

62. (canceled)

68-70. -70. (canceled)

81-83. -83. (canceled)