Chiral dimethylamine flutamide derivatives--modeling, synthesis, androgen receptor affinities and carbon-11 labeling

Area of Science:

• Oncology
• Radiochemistry
• Molecular Imaging

Background:

• Androgen receptor (AR) is crucial in most prostate cancers, but its expression and activity are not routinely assessed noninvasively.
• Current endocrine treatments targeting AR have suboptimal clinical outcomes.
• Optimized positron emission tomography (PET) imaging agents are needed to evaluate AR status in vivo.

Purpose of the Study:

• To design, synthesize, and radiolabel novel hydroxyflutamide derivatives as potential PET imaging agents for AR-positive prostate cancer.
• To evaluate the in vitro AR binding affinity and in vivo stability of these novel compounds.

Main Methods:

• Molecular modeling was used to design three novel hydroxyflutamide derivatives (Compounds 1-3) with an electron-rich dimethylamine group.
• Automated carbon-11 radiolabeling was performed.
• AR binding affinity was compared to commercial drugs.
• Radiochemical yield, purity, and specific activity were determined.

Main Results:

• Compounds 1-3 exhibited AR binding affinity comparable or superior to existing drugs.
• Successful carbon-11 radiolabeling was achieved with 10-15% decay-corrected radiochemical yield, 99% purity, and high specific activity.
• The novel derivatives demonstrated potential for in vivo stability.

Conclusions:

• The novel radiolabeled hydroxyflutamide derivatives show promise as PET imaging agents for AR-positive prostate cancer.
• These agents could enable quantitative molecular imaging and image-guided treatment strategies.
• Further studies are warranted to validate their clinical utility.