SIGMA-2 RECEPTOR RADIOTRACERS FOR IMAGING THE PROLIFERATIVE STATUS OF SOLID TUMORS

• US 20090041663A1
• Filed: 03/08/2008
• Published: 02/12/2009
• Est. Priority Date: 07/31/2003
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Mach, Robert
• Granted Patent: US 7,612,206 B2
• Time in Patent Office: Days
• US Class Current: 424/1.850
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 323/41 Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07D 217/04 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 257/02 not condensed with other rings
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain

Abstract

Novel benzamide compounds of Formula (I), Formula (II), and Formula (III), salts, water soluble salts, analogs and radiolabeled counterparts thereof as sigma-2 receptor radiotracers for imaging the proliferative status of solid tumors. A method for diagnosing a mammal for the presence of a mammalian tumor therein comprises administering to the mammal a diagnostic imaging detectable effective amount of a benzamide compound having a structure illustrated in Formula (I), Formula (II) and Formula (III) and detecting binding of the compound to a tumor in the mammal. A method for diagnostic imaging of a mammalian tissue having cell surface sigma-2 receptors comprising administering to a mammal a diagnostic imaging amount of a compound having a structure illustrated in Formula (I) Formula (II) and Formula (III) and detecting an image of a tissue having an ample cells with sigma-2 receptors.

Claims

1. A method of detecting a cancer in a mammal in vivo, the method comprising:

a) administering to a mammal a radiolabeled compound or salt thereof of Formula

2. A method of detecting a cancer in accordance with claim 1, wherein the radioisotope is a ³H.

3. A method of detecting a cancer in accordance with claim 1, wherein the radioisotope is a ¹¹C.

4. A method of detecting a cancer in accordance with claim 1, wherein the compound is selected from the group consisting of:

5. A method of detecting a cancer in accordance with claim 1, wherein each of A and A₁ is a methoxyl.

6. A method of detecting a cancer in accordance with claim 1, wherein the compound is Compound 6

7. A method of detecting a cancer in accordance with claim 1, wherein the compound is Compound 10

8. A method of detecting a cancer in accordance with claim 1, wherein the radioisotope is selected from the group consisting of an ¹²³I, an ¹²⁴I and an ¹²⁵I.

9. A method of detecting a cancer in accordance with claim 8, wherein the radioisotope is an ¹²³I.

10. A method of detecting a cancer in accordance with claim 8, wherein the radioisotope is an ¹²⁵I.

11. A method of detecting a cancer in accordance with claim 8, wherein the compound has the structure

12. A method of detecting a cancer in accordance with claim 8, wherein the compound is selected from the group consisting of

13. A method of detecting a cancer in accordance with claim 1, wherein the administering to a mammal a radiolabeled compound or salt thereof comprises administering to the mammal a pharmaceutical composition comprising the radiolabeled compound or salt thereof and a pharmaceutically acceptable carrier.

14. A method of detecting a cancer in accordance with claim 1, wherein the detecting the distribution of the radioisotope comprises imaging the distribution of the radioisotope.

15. A method of detecting a cancer in accordance with claim 1, wherein the mammal is a human.

16. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo, the method comprising:

a) administering to a mammal comprising a tumor, a radiolabeled compound or salt thereof of Formula

17. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 16, wherein the radioisotope is selected from the group consisting of a ³H and a ¹¹C.

18. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 16, wherein the compound is selected from the group consisting of:

19. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 16, wherein each of A and A₁ is a methoxyl.

20. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 16, wherein the compound is Compound 6

21. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 16, wherein the compound is Compound 10

22. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 16, wherein the radioisotope is selected from the group consisting of an ¹²³I, an ¹²⁴I and an ¹²⁵I.

23. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 22, wherein the radioisotope is selected from the group consisting of an ¹²³I and an ¹²¹I.

24. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 22, wherein the compound has the structure

25. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 22, wherein the compound is selected from the group consisting of

26. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 16, wherein the administering to a mammal a radiolabeled compound or salt thereof comprises administering to the mammal a pharmaceutical composition comprising the radiolabeled compound or salt thereof and a pharmaceutically acceptable carrier.

27. A method of determining the proliferative status of cells comprised by a mammalian tumor in vivo in accordance with claim 16, wherein the mammal is a human.

28. A method of determining progression of a cancerous tumor in a mammal, the method comprising:

a) administering to a mammal a radiolabeled compound or salt thereof of Formula

29. A method of determining progression of a cancerous tumor in accordance with claim 28, wherein the radioisotope is selected from the group consisting of a ³H and a ¹¹C.

30. A method of determining progression of a cancerous tumor in accordance with claim 28, wherein the compound is selected from the group consisting of:

31. A method of determining progression of a cancerous tumor in accordance with claim 28, wherein each of A and A₁ is a methoxyl.

32. A method of determining progression of a cancerous tumor in accordance with claim 28, wherein the compound is Compound 6

33. A method of determining progression of a cancerous tumor in accordance with claim 28, wherein the compound is Compound 10

34. A method of determining progression of a cancerous tumor in accordance with claim 28, wherein the radioisotope is selected from the group consisting of an ¹²³I, an ¹²⁴I and an ¹²⁵I.

35. A method of determining progression of a cancerous tumor in accordance with claim 34, wherein the radioisotope is selected from the group consisting of an ¹²³I and an ¹²⁵I.

36. A method of determining progression of a cancerous tumor in accordance with claim 34, wherein the compound has the structure

37. A method of determining progression of a cancerous tumor in accordance with claim 34, wherein the compound is selected from the group consisting of

38. A method of determining progression of a cancerous tumor in accordance with claim 28, wherein the administering to a mammal a radiolabeled compound or salt thereof comprises administering to the mammal a pharmaceutical composition comprising the radiolabeled compound or salt thereof and a pharmaceutically acceptable carrier.

39. A method of determining progression of a cancerous tumor in accordance with claim 28, wherein the mammal is a human.