Sigma-2 receptors as biomarkers of tumor cell proliferation

Details Sigma-2 receptors as biomarkers of tumor cell proliferation Sigma-2 receptors as biomarkers of tumor cell proliferation

2000-03-20

2004-01-13

Jones, Dameron (Department: 1616)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

C424S001110, C424S001650, C424S001810, C424S001850, C514S212010, C546S124000, C546S184000, C546S125000, C546S001000, C540S001000

Reexamination Certificate

active

06676925

ABSTRACT:

BACKGROUND OF THE INVENTION
Breast cancer is characterized by a proliferative potential that can vary considerably from patient to patient. The rate of cell proliferation has been shown in breast tumors to predict the response to radiation therapy and chemotherapy. Presently, measures of cell proliferation are obtained by histological or flow-cytometric analysis. Both methods are limited by sampling procedures and only 60-70% of patient samples are suitable for flow cytometric analysis.
It was recently demonstrated that sigma-2 (&sgr;2) receptors are expressed in high density in a number of human and rodent breast cancer cell lines (
Cancer Research,
55, 408 (1995)). However, their expression is heterogenous, and their function is unknown.
A continuing need exists for noninvasive methods that can accurately assess the proliferative status of breast cancer. Such methods could have a significant impact on determining an optimal therapy for treating breast cancer patients.
SUMMARY OF THE INVENTION
The present invention provides a noninvasive method to detect cancer cells or to assess the proliferative status of cancer cells which express sigma-2 (&sgr;2) receptors, such as cells of solid tumors, in vitro or in vivo. The method preferably comprises (a) administering to a human patient afflicted with a solid tumor, such as breast cancer, an amount of a detectably labeled compound of formula (I):
wherein R is (C
1
-C
4
)alkyl, C
6
F
5
CH
2
, C
6
H
5
, or T—C
6
H
4
CH
2
wherein T is halo (Br, Cl, I, F),CH
3
S, CH
3
O, NH
2
or H; A is NH, O, or S; B is NH, O, or S; C is O or S; D is CH or N; E is CH or N; F is CH or N; Y and Z are individually H, halo, OH, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)C(O), (C
1
-C
4
)alkylS, NH
2
, SH, N(R)
2
or together are OCH
2
O; X is (CH
2
)
2
, (CH
2
)
3
or CH═CH; or a pharmaceutically acceptable salt thereof; and (b) determining the extent to which the compound of formula (I) binds to cells of said cancer, said extent providing a measure of the presence and/or proliferative status of said cells, which status correlates to the extent of sigma-2 receptor expression by said cells. The method is based on the ability of the compounds of formula (I) to selectively bind to sigma-2 (&sgr;2) receptors, versus &sgr;1 receptors.
Groups Z and Y can occupy any ring position, i.e., any one of E, D or F can be CY or CZ. Preferably, at least one of Y or Z is not H. Preferably A is O and B is NH. Preferably, R is CH
3
, benzyl or phenyl. Alkyl can be branched, unbranched, cycloalcyl or (cycloalkyl)alkyl.
Preferably, the label is a fluorescent label or radionuclide, such as a radioisotope of halogen (
125
I,
123
I,
18
F,
19
F) or
11
C. The compound is preferably administered parenterally, i.e., by intravenous, i.p., intrathecal or enteral administration.
Novel compounds of formula (I), labeled and unlabeled, are also within the scope of the invention, as are pharmaceutical compositions comprising one or more of said compounds. The unlabeled compounds can be used as intermediates to make labeled compounds or as sigma-2 specific ligands which can be used in competitive assays to assay for the presence of &sgr;2 receptors, as described below. The configuration at the 3-position can be exo- or endo-; of which endo- is referred.


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