Detection of cancer cells in vitro using sigma-2 receptor ligands as radiotracers

• US 7,893,266 B2
• Filed: 08/28/2009
• Issued: 02/22/2011
• Est. Priority Date: 07/31/2003
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Tu, Zhude, Rowland, Douglas J., Welch, Michael J., Mach, Robert H.
• Primary Examiner(s): Chandrakumar; Nizal S
• Application Number:
  US12/550,220
• Publication Number:
  US 20100028936A1
• Time in Patent Office: 543 Days
• Field of Search: 546/86, 546/87, 424/1.85, 424/1.81
• US Class Current: 546/86
• 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

Methods for detection of cancer cells and for determining the proliferative status of cells in a tissue sample in vitro are disclosed. These methods comprise contacting a tissue sample with a radiolabeled compound or salt thereof of Formula

wherein at least one of X, Y, and Z comprises a radioisotope, n is an integer from 2 to about 10; and each of A and A₁ is a C₁-C₄ alkoxyl, a C₁-C₄ fluoroalkyl or a C₁-C₄ fluoroalkoxyl. The methods further comprise detecting the distribution of the radioisotope in the tissue sample, whereby a cell having a high density of the radioisotope compared to quiescent cells is diagnostic for a cancer cell.

Claims

1. A method for detecting a cancer cell in a mammalian tissue sample in vitro, the method comprising:

a) contacting a mammalian tissue sample with a radiolabeled compound or salt thereof of Formula

2. A method for detecting a cancer cell in vitro in accordance with claim 1, wherein the radioisotope is selected from the group consisting of an ³H and a ¹¹C.

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

4. A method for detecting a cancer cell in vitro in accordance with claim 1, wherein each of A and A₁ is a methoxyl.

5. A method for detecting a cancer cell in vitro in accordance with claim 1, wherein the compound is Compound 6

6. A method for detecting a cancer cell in vitro in accordance with claim 1, wherein the compound is Compound 10

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

8. A method for detecting a cancer cell in vitro in accordance with claim 7, wherein the radioisotope is selected from the group consisting of an ¹²³I and an ¹²⁵I.

9. A method for detecting a cancer cell in vitro in accordance with claim 7, wherein the compound has the structure

10. A method for detecting a cancer cell in vitro in accordance with claim 1, wherein the mammalian tissue sample is a human tissue sample.

11. A method for detecting a cancer cell in vitro in accordance with claim 1, wherein the detecting the distribution of the radioisotope comprises imaging the distribution of the radioisotope.

12. A method of determining the proliferative status of cells comprised by a mammalian tissue sample in vitro, the method comprising:

a) contacting a mammalian tissue sample in vitro with a radiolabeled compound or salt thereof of Formula

13. A method of determining the proliferative status of cells comprised by a mammalian tissue sample in vitro in accordance with claim 12, wherein the radioisotope is selected from the group consisting of a ³H and a ¹¹C.

14. A method of determining the proliferative status of cells comprised by a mammalian tissue sample in vitro in accordance with claim 12, wherein the compound is selected from the group consisting of:

15. A method of determining the proliferative status of cells comprised by a mammalian tissue sample in vitro in accordance with claim 12, wherein each of A and A₁ is a methoxyl.

16. A method of determining the proliferative status of cells comprised by a mammalian tissue sample in vitro in accordance with claim 12, wherein the compound is Compound 6

17. A method of determining the proliferative status of cells comprised by a mammalian tissue sample in vitro in accordance with claim 12, wherein the compound is Compound 10

18. A method of determining the proliferative status of cells comprised by a mammalian tissue sample in vitro in accordance with claim 12, wherein the compound has the structure

19. A method of determining the proliferative status of cells comprised by a mammalian tissue sample in vitro in accordance with claim 12, wherein the mammal is a human.

20. A method of determining the proliferative status of cells comprised by a mammalian tissue sample in vitro in accordance with claim 12, wherein the determining a ratio of proliferating cells to quiescent cells comprises imaging the distribution of the radioisotope.