Radiolabeled selective androgen receptor modulators and their use in prostate cancer imaging and therapy

Abstract

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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This Application is a Divisional Application of U.S. patent application Ser. No. 10 / 371,210, filed Feb. 24, 2003, which claims priority of U.S. Ser. No. 60 / 360,108 filed Feb. 28, 2002, U.S. Ser. No. 60 / 420,287 filed Oct. 23, 2002, and U.S. Ser. No. 60 / 420,247 filed Oct. 23, 2002, the contents of which are hereby incorporated by reference.FIELD OF INVENTION[0002]The present invention relates to radiolabeled selective androgen receptor modulator (SARM) compounds and their use in imaging and prevention / therapy of prostate cancer. The present invention further relates to methods for 1) imaging of cancer in a subject, 2) imaging an androgen receptor-containing tissue in a subject, 3) in-vivo imaging in a subject, 4) treating a subject suffering from prostate cancer, 5) delaying the progression of prostate cancer in a subject suffering from prostate cancer, 6) preventing the recurrence of prostate cancer in a subject suffering from prostate can...

AI Technical Summary

Problems solved by technology

However, no curative therapies exist for advanced disease.

Existing diagnostic tests such as magnetic resonance imaging (“MRI”), computed tomographic scans (“CT”), and ultrasound (“US”) lack both the specificity and sensitivity to substitute for exploratory surgery in staging malignant disease.

However, these methods are not selective.

However, a major concern is that patients may develop human antimurine antibody (“HAMA”) responses as a result of the murine origin of the antibody, resulting in adverse reactions and precluding the use of subsequent antibody imaging (Babaian et al., “Radioimmunological Imaging of Metastatic Prostate Cancer With 111-Indium-Labeled Monoclonal Antibody PAY276,” J.

However, the majority of these compounds were not useful for AR-mediated imaging due to rapid metabolic cleavage of the radiolabel, low AR binding affinity, or inadequate specific activity.

Binding of steroidal AR-imaging agents to progesterone and / or glucocorticoid receptors in the body contributes to their poor target site specificity for imaging.

However, it was recently found that this relationship did not hold for a series of androgen analogs (Choe).

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