Radiohalide-labeled targeted diagnostics and therapeutics
Disclosed are chemical entities of formula (I) wherein R 1 , R 2 and n are defined herein, and methods of use thereof. These chemical entities are radiative emitters and are useful, e.g., as therapeutic agents for the treatment of, or as diagnostic (e.g., imaging) agents for cancers, e.g., cancers in which PARP1 is overexpressed.
1. A chemical entity, which is a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
one of R 1 and R 2 is 123 I, 124 I, 125 I, 131 I, 211 At or 18 F,
and the other is H, 123 I, 124 I, 125 I, 131 I, 211 At or 18 F; and
n is 0, 1 or 2.
2. The chemical entity of claim 1 , wherein:
one of R 1 and R 2 is 123 I, 124 I, 125 I, 131 I, or 211 At,
and the other is H, 123 I, 124 I, 125 I, 131 I, or 211 At.
3. The chemical entity of claim 1 , wherein n is 0.
4. The chemical entity of claim 1 , wherein n is 1.
5. The chemical entity of claim 1 , wherein n is 2.
6. The chemical entity of claim 2 , wherein n is 0.
7. The chemical entity of claim 2 , wherein n is 1.
8. The chemical entity of claim 2 , wherein n is 2.
9. The chemical entity of any of claims 1 - 8 , wherein:
one of R 1 and R 2 is 123 I or 125 I, and
the other is H.
10. The chemical entity of any of claims 1 - 8 , wherein:
one of R 1 and R 2 is 123 I, and
the other is H.
11. The chemical entity of any of claims 1 - 8 , wherein:
one of R 1 and R 2 is 131 I, and
the other is H.
12. The chemical entity of any of claims 1 - 8 , wherein:
one of R 1 and R 2 is 211 At, and
the other is H.
13. The chemical entity of any of claims 1 - 8 , wherein:
one of R 1 and R 2 is 124 I, and
the other is H.
14. The chemical entity of any of claim 1 or 3 - 5 , wherein:
one of R 1 and R 2 is 18 F, and
the other is H.
15. The chemical entity of claim 1 , which is the compound
or a pharmaceutically acceptable salt thereof, wherein I* is 123 I.
16. The chemical entity of claim 1 , which is the compound
or a pharmaceutically acceptable salt thereof, wherein I* is 131 I.
17. The chemical entity of claim 1 , which is the compound
or a pharmaceutically acceptable salt thereof, wherein I* is 124 I.
18. The chemical entity of claim 1 , which is the compound
or a pharmaceutically acceptable salt thereof, wherein F* is 18 F.
19. A composition comprising the chemical entity of any of claim 1 - 8 or 15 - 18 and a pharmaceutically acceptable carrier, adjuvant or vehicle.
20. A method of treating a disease or disorder characterized by overexpression of PARP1 in a patient in need of such treatment comprising administering an effective amount of the chemical entity of any of claim 1 - 8 or 15 - 18 .
21. The method of claim 20 , wherein the disease or disorder is cancer.
22. The method of claim 21 , wherein the cancer comprises a brain malignancy.
23. The method of claim 21 , wherein the cancer comprises glioma.
24. The method of claim 21 , wherein the cancer comprises glioblastoma multiforme.
25. The method of claim 20 , wherein said administering comprises parenteral administration.
26. The method of claim 20 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
27. The method of claim 26 , wherein said therapy comprises radiotherapy.
28. The method of claim 26 , wherein said therapy comprises administration of a DNA-damaging agent.
29. A method for imaging a tumor in a subject, comprising:
administering to the subject an image-generating amount of the chemical entity of any of claim 1 - 8 or 15 - 18 ; and
measuring the distribution of the compound.
30. The method of claim 29 , wherein the chemical entity is the chemical entity of claim 15 or claim 16 .
31. The method of claim 30 , wherein said measuring comprises single-photon emission computed tomography (SPECT).
32. The method of claim 29 , wherein the chemical entity is the chemical entity of claim 17 or claim 18 .
33. The method of claim 32 , wherein said measuring comprises positron emission tomography (PET).
34. The method of claim 21 , wherein said administering comprises parenteral administration.
35. The method of claim 22 , wherein said administering comprises parenteral administration.
36. The method of claim 23 , wherein said administering comprises parenteral administration.
37. The method of claim 24 , wherein said administering comprises parenteral administration.
38. The method of claim 21 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
39. The method of claim 22 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
40. The method of claim 23 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
41. The method of claim 24 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
42. The method of claim 25 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
43. The method of claim 34 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
44. The method of claim 35 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
45. The method of claim 36 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
46. The method of claim 37 , wherein the patient has received or is receiving therapy that induces PARP1 expression or localization of PARP1 to DNA.
47. A composition comprising the chemical entity of claim 9 and a pharmaceutically acceptable carrier, adjuvant or vehicle.
48. A composition comprising the chemical entity of claim 10 and a pharmaceutically acceptable carrier, adjuvant or vehicle.
49. A composition comprising the chemical entity of claim 11 and a pharmaceutically acceptable carrier, adjuvant or vehicle.
50. A composition comprising the chemical entity of claim 12 and a pharmaceutically acceptable carrier, adjuvant or vehicle.
51. A composition comprising the chemical entity of claim 13 and a pharmaceutically acceptable carrier, adjuvant or vehicle.
52. A composition comprising the chemical entity of claim 14 and a pharmaceutically acceptable carrier, adjuvant or vehicle.