title: Chiral dimethylamine flutamide derivatives--modeling, synthesis, androgen receptor affinities and carbon-11 labeling.
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/mumol 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.
authors.affiliation: Department of Medical Biophysics and Nuclear Medicine, The Hebrew University of Jerusalem, Hadassah Hospital, Jerusalem 91120, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.forename: Desideriu
authors.initials: D
authors.lastname: Laky
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: Sharona
authors.initials: S
authors.lastname: Elgavish
authors.forename: Michael
authors.initials: M
authors.lastname: Gozin
authors.forename: Einat
authors.initials: E
authors.lastname: Even-Sapir
authors.forename: Ilan
authors.initials: I
authors.lastname: Leibovitc
authors.forename: Mordechai
authors.initials: M
authors.lastname: Gutman
authors.forename: Roland
authors.initials: R
authors.lastname: Chisin
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Eyal
authors.initials: E
authors.lastname: Mishani
mesh_terms: D002250:Carbon Radioisotopes; D005485:Flutamide / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008958:Models, Molecular; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011944:Receptors, Androgen / Q000032:analysis / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D011944:Receptors, Androgen; C014290:hydroxyflutamide; D005485:Flutamide