Synthesis and biological evaluation of a nonsteroidal bromine-76-labeled androgen receptor ligand 3-[76Br]bromo-hydroxyflutamide.
BACKGROUND
Androgen receptors (ARs) are overexpressed in normal tissues and in most primary and metastatic prostate cancers. In our efforts to develop a nonsteroidal AR-specific imaging agent, we synthesized (+/-)-3-[(76)Br]bromo-hydroxyflutamide ((76)Br-), an analog of hydroxyflutamide, the active metabolite of the AR antagonist ligand flutamide.


METHODS
(76)Br- was synthesized in three steps, starting with commercially available compounds. Labeling of (76)Br- was achieved through the nucleophilic opening of an epoxide intermediate, and a labeled compound was obtained in high specific activity and good radiochemical yield.


CONCLUSIONS
(+/-)-3-Bromo-hydroxyflutamide has a significantly higher affinity for ARs compared to hydroxyflutamide, its parent compound. The androgen target-tissue uptake of (76)Br- in diethylstilbestrol-treated male rats was examined; however, AR-mediated uptake was minimal due most likely to the rapid metabolic debromination of the radiolabeled ligand.


CONCLUSIONS
This study is part of our first look at a novel class of nonsteroidal AR antagonists as positron emission tomography (PET) imaging agents, which are alternatives to steroidal AR agonist-based imaging agents. Although (76)Br- has a significant affinity for ARs, it showed limited promise as a PET imaging agent because of its poor target-tissue distribution properties.
Parent
Ephraim E
EE
Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
Jenks
Carl
C
Sharp
Terry
T
Welch
Michael J
MJ
Katzenellenbogen
John A
JA
D000818:Animals; D001967:Bromine Radioisotopes; D005485:Flutamide / Q000031:analogs & derivatives* / Q000378:metabolism; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D014018:Tissue Distribution
D001967:Bromine Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D011944:Receptors, Androgen; C014290:hydroxyflutamide; D005485:Flutamide