Synthesis and biological evaluation of a fluorine-18-labeled nonsteroidal androgen receptor antagonist, N-(3-[ 18 F]fluoro-4-nitronaphthyl)- cis -5-norbornene-endo-2,3-dicarboxylic imide Ephraim E. Parent a , Carmen S. Dence b , Terry L. Sharp b , Michael J. Welch b , John A. Katzenellenbogen a, 4 a Department of Chemistry, University of Illinois, Urbana, IL 61801, USA b Washington University School of Medicine, St. Louis, MO 63110, USA Received 20 March 2006; received in revised form 5 April 2006; accepted 15 April 2006 Abstract Introduction: Androgen receptor (AR), which is overexpressed in most prostate cancers, is the target of androgen ablation and antiandrogen therapies: it is also the target for the receptor-mediated imaging of AR-positive prostate cancer using radiolabeled ligands. Previous AR imaging agents were based on a steroidal core labeled with fluorine. To develop a novel class of nonsteroidal imaging agents, with binding and pharmacological characteristics that are more similar to those of clinically used AR antagonists, we synthesized N-(3-fluoro-4-nitronaphthyl)-cis -5-norbornene-endo-2,3-dicarboxylic imide (3-F-NNDI), an analog of recently reported AR antagonist ligands. Methods: 3-F-NNDI was synthesized in six steps starting with 1-nitronaphthalene, with fluorine incorporation as the final step. The labeling of 3-F-NNDI with fluorine-18 was achieved through a novel, extremely mild, S N Ar displacement reaction of an o -nitro- activated arene trimethylammonium salt, and 3-[ 18 F]F-NNDI was prepared in high specific activity. Results and Discussion: 3-F-NNDI was found to have an AR-binding affinity similar to that of its parent compound. In vitro assays demonstrated high stability of the labeled compound under physiological conditions in buffer and in the blood. Androgen target tissue uptake in diethylstilbestrol-pretreated male rats, however, was minimal, probably because of extensive metabolic defluorination 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 that are alternatives to steroidal AR agonist-based imaging agents. Although 3-[ 18 F]F-NNDI has significant affinity for AR, it showed limited promise as a PET imaging agent because of its poor target tissue distribution properties. D 2006 Elsevier Inc. All rights reserved. Keywords: Fluorine-18; Androgen receptor; Nonsteroidal androgen 1. Introduction Prostate cancer is the second leading cause of cancer death in men in the United States [1]. Androgen ablation monotherapy (medical or surgical castration to remove testosterone, which is produced by the testes) is the principal therapy for progressive prostate cancer and results in the regression of most androgen-dependent tumors [2]. Many men eventually fail androgen ablation therapy, however, and die of recurrent androgen-independent prostate cancer (AIPC). This term is applied because only a small fraction of these tumors responds to secondary hormonal therapies, including treatment with nonsteroidal antiandrogens fluta- mide and bicalutamide. Responses to these agents are generally modest and of short duration [3]. AIPC is a lethal form of prostate cancer that progresses and metastasizes; at present, there is no effective therapy for it. Androgen receptor (AR), which is the target of androgen ablation and antiandrogen therapies, is also the target for the receptor-mediated imaging of AR-positive prostate cancer using radiolabeled ligands [4]. Several 18 F-labeled androgens have been reported [5–9], and one of these, 16h-[ 18 F]fluoro- 5a-dihydrotestosterone (FDHT), has been used to image 0969-8051/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nucmedbio.2006.04.003 4 Corresponding author. Tel.: +1 217 333 6310. E-mail address: jkatzene@uiuc.edu (J.A. Katzenellenbogen). Nuclear Medicine and Biology 33 (2006) 615 – 624 www.elsevier.com/locate/nucmedbio