Preclinical and first-in-human evaluation of novel androgen receptor-targeted PET imaging in prostate cancer.

[PURPOSE] Activation of androgen receptor (AR) signaling is a hallmark of prostate cancer. Dynamic changes in AR expression exacerbate AR heterogeneity throughout prostate cancer therapy. This study aims to develop a series of Ga-labeled Enzalutamide-based positron emission tomography (PET) tracers for AR imaging.

[METHODS] [Ga]Ga-DOTA-FZAR-1, [Ga]Ga-DOTA-FZAR-2, and [Ga]Ga-DOTAGA-FZAR-3 were synthesized and the stability was analyzed in vitro. The AR specificity of the three radiotracers was assessed in vitro using AR-negative and AR-positive prostate cancer cell lines and in vivo using tumor xenograft-bearing mice. Moreover, the first-in-human evaluation of [Ga]Ga-DOTA-FZAR-2 was conducted in eight patients with prostate cancer.

[RESULTS] [Ga]Ga-DOTA-FZAR-1, [Ga]Ga-DOTA-FZAR-2, and [Ga]Ga-DOTAGA-FZAR-3 were successfully synthesized with a radiochemical purity of more than 99%, and had good stability in vitro. Cellular uptake assays revealed that the radiotracers had the highest, intermediate, and lowest uptake in LNCaP, 22Rv1, and PC-3 cells, respectively, strongly correlating with AR expression levels (P < 0.001). Consistent with cellular uptake, the radiotracers also exhibited a hierarchical uptake pattern (highest to lowest) in tumors of mice bearing LNCaP, 22Rv1 and PC-3 xenografts, respectively. In addition, all three radiotracers were primarily eliminated through the urinary system, as confirmed by ex vivo biodistribution studies. More importantly, first-in-human investigation showed safety and diagnostic value of [Ga]Ga-DOTA-FZAR-2 in AR-associated prostate cancer patients.

[CONCLUSION] We developed and validated a series of Ga-labeled Enzalutamide-based PET tracers for AR imaging. Initial preclinical and clinical evidence indicate that [Ga]Ga-DOTA-FZAR-2 enables noninvasive, whole-body, and dynamic monitoring of AR expression in prostate cancer patients throughout therapy.