Chiral dimethylamine flutamide derivatives—modeling, synthesis, androgen receptor affinities and carbon-11 labeling

Jacobson, Orit; Laky, Desideriu; Carlson, Kathryn E.; Elgavish, Sharona; Gozin, Michael; Even-Sapir, Einat; Leibovitc, Ilan; Gutman, Mordechai; Chisin, Roland; Katzenellenbogen, John A.; Mishani, Eyal

doi:10.1016/j.nucmedbio.2006.05.010

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 6 , Pages 695-704, August 2006

Chiral dimethylamine flutamide derivatives—modeling, synthesis, androgen receptor affinities and carbon-11 labeling

Orit Jacobson
- Department of Medical Biophysics and Nuclear Medicine, The Hebrew University of Jerusalem, Hadassah Hospital, Jerusalem 91120, Israel
Desideriu Laky
- Department of Medical Biophysics and Nuclear Medicine, The Hebrew University of Jerusalem, Hadassah Hospital, Jerusalem 91120, Israel
Kathryn E. Carlson
- Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
Sharona Elgavish
- Bioinformatics Unit, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
Michael Gozin
- School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel
Einat Even-Sapir
- Department of Nuclear Medicine, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv 64239, Israel
Ilan Leibovitc
- Department of Urology, Meir Medical Center, Sackler School of Medicine, Tel Aviv University, Kfar Sava 44281, Israel
Mordechai Gutman
- Department of Surgery A, Sapir Medical Center, Sackler School of Medicine, Tel Aviv University, Kfar Sava 44281, Israel
Roland Chisin
- Department of Medical Biophysics and Nuclear Medicine, The Hebrew University of Jerusalem, Hadassah Hospital, Jerusalem 91120, Israel
John A. Katzenellenbogen
- Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
Eyal Mishani
- Department of Medical Biophysics and Nuclear Medicine, The Hebrew University of Jerusalem, Hadassah Hospital, Jerusalem 91120, Israel
- Corresponding author. Tel.: +972 2 677931; fax: +972 2 6421203.

Received 16 April 2006; received in revised form 28 May 2006; accepted 28 May 2006.

Abstract

Most prostate cancers are androgen dependent upon initial diagnosis. On the other hand, some very aggressive forms of prostate cancer were shown to have lost the expression of the androgen receptor (AR). Although the AR is routinely targeted in endocrine treatment, the clinical outcome remains suboptimal. Therefore, it is crucial to demonstrate the presence and activity of the AR in each case of prostate cancer, before and after treatment. While noninvasive positron emission tomography (PET) has the potential to determine AR expression of tumor cells in vivo, fully optimized PET imaging agents are not yet available. Based on molecular modeling, three novel derivatives of hydroxyflutamide (Compounds 1–3) were designed and synthesized. They contain an electron-rich group (dimethylamine) located on the methyl moiety, which may confer a better stability to the molecule in vivo. Compounds 1–3 have AR binding that is similar or higher than that of the currently used commercial drugs. An automated carbon-11 radiolabeling route was developed, and the compounds were successfully labeled with a 10–15% decay-corrected radiochemical yield, 99% radiochemical purity and a specific activity of 4Ci/μmol end of bombardment (n=15). These labeled biomarkers may facilitate the future quantitative molecular imaging of AR-positive prostate cancer using PET and may also allow for image-guided treatment of prostate cancer.

Keywords: Androgen receptor, Prostate cancer, PET, Carbon-11