Sigma-2 receptor radiotracers for imaging the proliferative status of solid tumors
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.
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
wherein:
each of X, Y, and Z is a substituent selected from the group consisting of a hydrogen, a halogen, a C 1 -C 4 alkoxyl, a C 1 -C 4 alkyl, a C 1 -C 4 fluoroalkyl, a C 1 -C 4 fluoroalkoxyl, a CF 3 , and an OCF 3 , wherein at least one of X, Y and Z comprises a radioisotope selected from the group consisting of a bromine, an iodine, a carbon of a 2-methoxyl and a tritium of a 2-methoxyl;
n is an integer from 2 to about 10; and
each of A and A 1 is independently selected from the group consisting of a C 1 -C 4 alkoxyl, a C 1 -C 4 fluoroalkyl and a C 1 -C 4 fluoroalkoxyl; and
b) detecting the distribution of the radioisotope in the mammal, whereby a cell having a high density of the radioisotope compared to quiescent cells is diagnostic for a cancerous tumor cell.
2. A method of detecting a cancer in accordance with claim 1 , wherein the radioisotope is a 3 H.
3. A method of detecting a cancer in accordance with claim 1 , wherein the radioisotope is a 11 C.
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 A 1 is a methoxyl.
6. A method of detecting a cancer in accordance with claim 1 , wherein the compound is Compound 6
and wherein the Br is a 76 Br.
7. A method of detecting a cancer in accordance with claim 1 , wherein the compound is Compound 10
and wherein the 2-methoxyl comprises a 11 C.
8. A method of detecting a cancer in accordance with claim 1 , wherein the radioisotope is selected from the group consisting of an 123 I, an 124 I and an 125 I.
9. A method of detecting a cancer in accordance with claim 8 , wherein the radioisotope is an 123 I.
10. A method of detecting a cancer in accordance with claim 8 , wherein the radioisotope is an 125 I.
11. A method of detecting a cancer in accordance with claim 8 , wherein the compound has the structure
wherein X is H or OCH 3 and n=2 or 4.
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
wherein:
each of X, Y, and Z is a substituent selected from the group consisting of a hydrogen, a halogen, a C 1 -C 4 alkoxyl, a C 1 -C 4 alkyl, a C 1 -C 4 fluoroalkyl, a C 1 -C 4 fluoroalkoxyl, a CF 3 , and an OCF 3 , wherein at least one of X, Y and Z comprises a radioisotope selected from the group consisting of a bromine, an iodine, a carbon of a 2-methoxyl and a tritium of a 2-methoxyl;
n is an integer from 2 to about 10;
each of A and A 1 is independently selected from the group consisting of a C 1 -C 4 alkoxyl, a C 1 -C 4 fluoroalkyl and a C 1 -C 4 fluoroalkoxyl; and
b) determining, for cells comprised by the tumor, a ratio of proliferating cells to quiescent cells.
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 3 H and a 11 C.
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 A 1 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
and wherein the Br is a 76 Br.
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
and wherein the 2-methoxyl comprises a 11 C.
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 123 I, an 124 I and an 125 I.
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 123 I and an 121 I.
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
wherein X is H or OCH 3 and n=2 or 4.
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
wherein:
each of X, Y, and Z is a substituent selected from the group consisting of a hydrogen, a halogen, a C 1 -C 4 alkoxyl, a C 1 -C 4 alkyl, a C 1 -C 4 fluoroalkyl, a C 1 -C 4 fluoroalkoxyl, a CF 3 , and an OCF 3 , wherein at least one of X, Y and Z comprises a radioisotope selected from the group consisting of a bromine, an iodine, a carbon of a 2-methoxyl and a tritium of a 2-methoxyl;
n is an integer from 2 to about 10; and
each of A and A 1 is independently selected from the group consisting of a C 1 -C 4 alkoxyl, a C 1 -C 4 fluoroalkyl and a C 1 -C 4 fluoroalkoxyl; and
b) acquiring, at a first selected time, a first image of the distribution of the radioisotope in the mammal;
c) acquiring, at a second selected time, a second image of the distribution of the radioisotope in the mammal,
whereby the radioisotope accumulates at a tumor, and a change in intensity of the radioisotope at the tumor from the first selected time to the second selected time indicates a change in tumor size.
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 3 H and a 11 C.
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 A 1 is a methoxyl.
32. A method of determining progression of a cancerous tumor in accordance with claim 28 , wherein the compound is Compound 6
and wherein the Br is a 76 Br.
33. A method of determining progression of a cancerous tumor in accordance with claim 28 , wherein the compound is Compound 10
and wherein the 2-methoxyl comprises a 11 C.
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 123 I, an 124 I and an 125 I.
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 123 I and an 125 I.
36. A method of determining progression of a cancerous tumor in accordance with claim 34 , wherein the compound has the structure
wherein X is H or OCH 3 and n=2 or 4.
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.