Estrogen receptor imaging agents
Compounds useful for molecular imaging of cells expressing estrogen receptors are provided. Also provided are intermediates for making the compounds and methods of making the compounds using a modular convergent strategy. Further, methods of making the intermediates are described, as well as methods of diagnosing disease in a subject by using the compounds as imaging agents.
1. A compound according to formula (I)
wherein n is a number in the range of 1-10; m is a number in the range of 4-10; R 1 is H or a C 1-3 alkyl group; and R 2 is either absent, or selected from the group consisting of H and a C 1-3 alkyl group.
2. A compound according to formula (II)
wherein m is a number in the range of 4-10; and R 1 is H or a C 1-3 alkyl group; and R 2 is either absent, or selected from the group consisting of H and a C 1-3 alkyl group.
3. A compound according to formula (III)
wherein m is a number in the range of 4-10; R 1 is H or a C 1-3 alkyl group; and R 2 is either absent, or selected from the group consisting of H and a C, 1-3 alkyl group.
4. A process for the preparation of a compound according to formula (I) comprising the step of reacting a compound according to formula (II) with a compound according to formula (IV) using a Huisgen [3+2] cycloaddition reaction,
wherein n is a number in the range of 1-10; m is a number in the range of 4-10; R 1 is H or a C 1-3 alkyl group; and R 2 is either absent, or selected from the group consisting of H and a C 1-3 alkyl group, and wherein x is a number in the range of 1-10.
5. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically effective carrier or diluent.
6. A method of diagnosing a disease characterized by overexpression of estrogen receptors in a subject, the method comprising detecting a cell of the subject expressing estrogen receptors by contacting the compound according to claim 1 with the cell, imaging the cell with positron emission tomography (PET) or single photon emission computed tomography (SPECT), and determining from the imaging whether estrogen receptors are overexpressed in the cell compared to a normal cell, wherein the subject is diagnosed as having the disease if overexpression of estrogen receptors is detected in the cell, wherein the disease is breast cancer or endometrial cancer.
7. A method of determining effectiveness of an anticancer treatment of a subject with breast cancer or endometrial cancer, the method comprising providing an anti-cancer treatment to the subject followed by detecting cells of the subject expressing estrogen receptors by contacting the compound according to claim 1 with the cells, imaging the cells by positron emission tomography (PET) or single photon emission computed tomography (SPECT), and determining from the imaging whether estrogen receptors are overexpressed in the cells compared to normal cells, wherein the treatment is considered effective if overexpression of estrogen receptors is decreased in the cells compared to before the treatment.
8. A process for the preparation of a compound according to formula (XVIII)
comprising the steps of transforming estra-5(10),9(11)-diene-3,17-dione 3-ethylenedioxy ketal (1) into 11β-(4-Hydroxy-phenyl)-estra-4,9-diene-3,17-dione (3) by reacting (1) initially with a peroxide reagent to give an epoxide, treating the product obtained with the Grignard reagent derived from trimethylsilyloxyphenyl bromide to obtain compound (3), alkylating (3) with dimethylaminoethyl chloride to obtain compound (4), aromatizing (4) with acetyl bromide and acetic anhydride to obtain compound (5), reducing and saponifying (5) to obtain compound (6), demethylating (6) with alpha chloroethyl chloroformate to obtain compound (7), and reacting (7) with reagent (8a),
thereby obtaining the compound according to formula (XVIII).
9. A process for the preparation of a compound according to formula (XIX)
comprising the steps of transforming estra-5(10),9(11)-diene-3,17-dione 3-ethylenedioxy ketal (1) into 11β-(4-Hydroxy-phenyl)-estra-4,9-diene-3,17-dione (3), by reacting (1) initially with a peroxide reagent to give an epoxide, treating the product obtained with the Grignard reagent derived from trimethylsilyloxyphenyl bromide to obtain compound (3), alkylating (3) with dimethylaminoethyl chloride to obtain compound (4), aromatizing (4) with acetyl bromide and acetic anhydride to obtain compound (5), reducing and saponifying (5) to obtain compound (6), demethylating (6) with alpha chloroethyl chloroformate to obtain compound (7), and reacting (7) with reagent (8b)
thereby obtaining the compound according to formula (XIX).
10. A process for the preparation of a compound according to formula (XX)
comprising the steps of: preparing 2-(4-bromophenoxy)-N,N-dimethylethanamine (1) by reacting 4-bromophenol with 2-dimethylaminoethyl chloride, converting (1) to (4-(2-(dimethylamino)ethoxy)phenyl)magnesium bromide (2) by treating with reagents comprising Mg, and iodine, and reacting (2) with 3,3-Ethylenedioxy-5(10)-α-epoxy-estr-9-ene-17-one (3) in the presence of CuI and acetic acid
thereby obtaining the compound according to formula (XX).
11. A kit comprising a compound according to Formula (II)
wherein m is a number in the range of 4-10; and R 1 is H or a C 1-3 alkyl group; and R 2 is either absent, or selected from the group consisting of H and a C 1-3 alkyl group, a labeling moiety, and instructions for reacting the compound and the labeling moiety to provide a compound according to claim 1 , wherein the labeling moiety is a compound of formula (IV)
wherein, n is a number in the range of 1-10.
12. A kit comprising a compound according to Formula (III)
wherein m is a number in the range of 4-10; R 1 is H or a C 1-3 alkyl group; and R 2 is either absent, or selected from the group consisting of H and a C 1-3 alkyl group, a labeling moiety, and instructions for reacting the compound and the labeling moiety to provide a compound according to claim 1 , wherein the labeling moiety is a compound of formula (XXI)
wherein n is a number in the range of 1-10.