Radiolabeled selective androgen receptor modulators and their use in prostate cancer imaging and therapy
View Patent ↗Provided is a class of radiolabeled androgen receptor targeting agents (ARTA), useful for prostate cancer imaging and in treating or preventing prostate cancer. The agents define a new-subclass of radiolabeled compounds, which are selective androgen receptor modulators (SARM), which demonstrate antiandrogenic activity of a nonsteroidal ligand for the androgen receptor, and/or which bind irreversibly to the androgen receptor. The present invention further provides methods for a) imaging of cancer in a subject, b) imaging an androgen receptor-containing tissue in a subject, c) in-vivo imaging in a subject, d) treating a subject suffering from prostate cancer, e) delaying the progression of prostate cancer in a subject suffering from prostate cancer, f) preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, and g) treating the recurrence of prostate cancer in a subject suffering from prostate cancer, which comprise using the radiolabeled compounds of the present invention. The present invention further provides a method of producing the radiolabeled SARM compounds, and precursor compounds useful in the preparation of the radiolabeled SARM compounds.
1. A radiolabeled selective androgen receptor modulator compound (SARM) represented by the structure of formula I:
wherein
X is a radioactive or nonradioactive O
G is a radioactive O;
T is a radioactive or nonradioactive OH;
Z is a radioactive or a nonradioactive NO 2 or CN;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is a radioactive or a nonradioactive halogen, CN, NHCOCH 3 ;
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is a radioactive or nonradioactive CH 3 ;
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; and
R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 ;
wherein at least one of X, T, Z, Y, Q, R, R 1 , R 2 or R 3 is radioactive and Y, or R 2 or R 3 is a radioactive halogen.
2. A radiolabeled selective androgen receptor modulator (SARM) compound represented by the structure of formula I:
wherein
X is a radioactive or nonradioactive, O;
G is a radioactive or nonradioactive O;
T is a radioactive or nonradioactive OH;
Z is a radioactive or a nonradioactive NO 2 or CN;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is a radioactive or a nonradioactive halogen, CN, NHCOCH 3 ;
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is a radioactive or nonradioactive CH 3 ;
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; and
R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 ;
or its isomer, pharmaceutically acceptable salt, N-oxide, hydrate or any combination thereof,
wherein at least one of X, T, Z, Y, Q, R, R 1 , R 2 or R 3 is radioactive and Y, or R 2 or R 3 is a radioactive halogen.
3. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein Z is NO 2 .
4. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein Z is CN.
5. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein Y is CF 3 .
6. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein Q is NHCOCH 3 .
7. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein Q is F.
8. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein Q is NCS.
9. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein R 2 is a radioactive halogen.
10. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein R 3 is a radioactive halogen.
11. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein said compound is an androgen receptor antagonist.
12. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein said compound is an androgen receptor agonist.
13. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein said compound binds irreversibly to an androgen receptor.
14. The radiolabeled selective androgen receptor modulator compound of claim 1 , wherein said compound is an alkylating agent.
15. A composition comprising the radiolabeled compound of claim 1 , and a pharmaceutically acceptable carrier.