High-Affinity Probes for Androgen Receptor Imaging: From Cells and In Silico Modeling to Whole-Body Fluorescent...

Area of Science:

• Oncology
• Molecular Imaging
• Medicinal Chemistry

Background:

• Castrate-resistant prostate cancer (CRPC) progression is driven by androgen receptor (AR) signaling.
• Developing imaging tools to monitor AR signaling dynamics is crucial for CRPC management.

Purpose of the Study:

• To introduce ARi-FL, a novel series of fluorescent AR inhibitors for visualizing AR signaling.
• To evaluate the efficacy and specificity of ARi-FL probes in preclinical models.

Main Methods:

• Synthesis of ARi-FL probes based on an aryloxy cyclohexane scaffold with fluorophore conjugation.
• In vitro AR inhibition assays and IC50 determination.
• In vivo and ex vivo studies in human prostate cancer models.
• In silico modeling of AR binding affinities against wild-type and mutant AR.

Main Results:

• ARi-FL demonstrated potent AR inhibition (IC50 ~ 13 nM) and visualized cytoplasmic AR.
• Probes showed successful localization in AR-positive tumors in vivo and ex vivo.
• In silico analysis confirmed nanomolar binding affinities (Kd ~ 1-2 nM) for ARi-FL against various AR mutants.
• ARi-FL probes exhibited high selectivity, stability, and practical synthesis yields.

Conclusions:

• ARi-FL serves as a valuable chemical imaging platform for noninvasive AR tracking.
• These probes can aid in studying AR resistance mechanisms and informing treatment strategies for CRPC.