# US 7,612,206 B2 · Sigma-2 receptor radiotracers for imaging the proliferative status of solid tumors

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- Number: US 7,612,206 B2
- Document ID: US7612206B2
- Status: Granted
- Kind: B2
- Application number: 12/044,952
- Filed: 2008-03-08
- Published: 2009-02-12
- Granted: 2009-11-03
- Earliest claimed: 2003-07-31
- Assignees: Washington University
- Inventors: Robert Mach; Michael J. Welch; Douglas J. Rowland; Zhude Tu
- Web page: https://patentgrep.com/patent/US7612206B2

## CPC

- C07D 295/13: to an acyclic saturated chain
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 51/04: Organic compounds
- A61K 51/0497: {conjugates with a carrier being an organic compounds}
- A61P 35/00: Antineoplastic agents
- C07C 323/41: Y being a hydrogen or an acyclic carbon atom
- C07D 217/04: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 257/02: not condensed with other rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## 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

### Claim 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 C1-C4 alkoxyl, a C1-C4 alkyl, a C1-C4 fluoroalkyl, a C1-C4 fluoroalkoxyl, a CF3, and an OCF3, 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 A1 is independently selected from the group consisting of a C1-C4 alkoxyl, a C1-C4 fluoroalkyl and a C1-C4 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

A method of detecting a cancer in accordance with claim 1, wherein the compound is Compound 6
and wherein the Br is a 76Br.

### Claim 7 (depends on 1)

A method of detecting a cancer in accordance with claim 1, wherein the compound is Compound 10
and wherein the 2-methoxyl comprises a 11C.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 8)

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

### Claim 10 (depends on 8)

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

### Claim 11 (depends on 8)

A method of detecting a cancer in accordance with claim 8, wherein the compound has the structure
wherein X is H or OCH3 and n=2 or 4.

### Claim 12 (depends on 8)

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

### Claim 13 (depends on 1)

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.

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 1)

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

### Claim 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 C1-C4 alkoxyl, a C1-C4 alkyl, a C1-C4 fluoroalkyl, a C1-C4 fluoroalkoxyl, a CF3, and an OCF3, 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 A1 is independently selected from the group consisting of a C1-C4 alkoxyl, a C1-C4 fluoroalkyl and a C1-C4 fluoroalkoxyl; and
b) determining, for cells comprised by the tumor, a ratio of proliferating cells to quiescent cells.

### Claim 17 (depends on 16)

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.

### Claim 18 (depends on 16)

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:

### Claim 19 (depends on 16)

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.

### Claim 20 (depends on 16)

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 76Br.

### Claim 21 (depends on 16)

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 11C.

### Claim 22 (depends on 16)

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.

### Claim 23 (depends on 22)

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.

### Claim 24 (depends on 22)

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 OCH3 and n=2 or 4.

### Claim 25 (depends on 22)

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

### Claim 26 (depends on 16)

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.

### Claim 27 (depends on 16)

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.

### Claim 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 C1-C4 alkoxyl, a C1-C4 alkyl, a C1-C4 fluoroalkyl, a C1-C4 fluoroalkoxyl, a CF3, and an OCF3, 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 A1 is independently selected from the group consisting of a C1-C4 alkoxyl, a C1-C4 fluoroalkyl and a C1-C4 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.

### Claim 29 (depends on 28)

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.

### Claim 30 (depends on 28)

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

### Claim 31 (depends on 28)

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

### Claim 32 (depends on 28)

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 76Br.

### Claim 33 (depends on 28)

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 11C.

### Claim 34 (depends on 28)

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.

### Claim 35 (depends on 34)

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.

### Claim 36 (depends on 34)

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 OCH3 and n=2 or 4.

### Claim 37 (depends on 34)

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

### Claim 38 (depends on 28)

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.

### Claim 39 (depends on 28)

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