Synthesis and biological evaluation of a nonsteroidal bromine-76-labeled androgen receptor ligand 3-[⁷⁶Br]bromo-hydroxyflutamide

Abstract 

Introduction

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-[⁷⁶Br]bromo-hydroxyflutamide (⁷⁶Br-3), an analog of hydroxyflutamide, the active metabolite of the AR antagonist ligand flutamide.

Materials and Methods

⁷⁶Br-3 was synthesized in three steps, starting with commercially available compounds. Labeling of ⁷⁶Br-3 was achieved through the nucleophilic opening of an epoxide intermediate, and a labeled compound was obtained in high specific activity and good radiochemical yield.

Results and Discussion

(±)-3-Bromo-hydroxyflutamide has a significantly higher affinity for ARs compared to hydroxyflutamide, its parent compound. The androgen target-tissue uptake of ⁷⁶Br-3 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 ⁷⁶Br-3 has a significant affinity for ARs, it showed limited promise as a PET imaging agent because of its poor target-tissue distribution properties.

Keywords: Bromine-76, Androgen receptor, Nonsteroidal androgen, Flutamide