Automated Radiosynthesis and Biodistribution of [18F]Fluoroflutamide

Background The androgen receptor (AR) is upregulated in multiple cancers, such as salivary gland cancer, glioblastoma, triple-negative breast cancer, and, most commonly, prostate cancer. Imaging expression of the AR via radiolabeling an AR antagonist would enable non-invasive clinical staging and assessment of tumor heterogeneity, complementing the findings of a [ ⁶⁸ Ga]PSMA-11 scan. Previous efforts described the radiolabeling of enzalutamide with fluorine-18 but were limited by low specific activity. In this study, we developed a high-yielding automated synthesis of [ ¹⁸ F]fluoroflutamide using zinc-mediated radiofluorination and assessed its biodistribution in preclinical models of prostate cancer. Results From 1.87 Ci (69.19 GBq) of [ ¹⁸ F]fluoride, [ ¹⁸ F]fluoroflutamide was isolated with a radiochemical yield of 3.46 ± 1.30% (n = 4) and a radiochemical purity of > 99% in an average 79 min from end-of-beam (EOB) using a bromoamide precursor. The average non-decay corrected A _m was found to be 1,573.89 Ci/mmol (or 58,233.93 GBq/mmol), and the radiochemical purity after 4 h was > 97%, indicating no detectable radiolysis. A biodistribution and imaging study was performed using nude athymic mice with 22Rv1 human prostate cancer xenografts. From the results of this study, we observed a ‘mass effect’ in which carrier-added mice displayed an increased uptake of the tracer across most organs. Conclusions Herein, we report the optimized automated radiosynthesis of [ ¹⁸ F]fluoroflutamide with high purity and yield sufficient for imaging AR expression in mouse models of prostate cancer. The lack of uptake to androgen receptor-rich organs and xenografts suggests that CYP1A2 metabolism to the more potent metabolite, 2-hydroxyflutamide, was blocked by the addition of the α-3°-fluorine. The automated production of a fluoroamide via zinc-mediated radiofluorination, in high specific activity, was demonstrated to evaluate a potential radioligand for the detection of androgen receptor-positive prostate cancer tumors.