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

  • Eur J Nucl Med Mol Imaging. 2025 Sep 23. doi: 10.1007/s00259-025-07577-5.
Shuyi Lin  #  1  2  3  4 ,  Xiangwei Wang  #  1  2  3  4 ,  Fangning Wan  #  5 ,  Jianping Zhang  1  2  3  4 ,  Xiaoping Xu  1  2  3  4 ,  Bingxin Gu  6  7  8  9 ,  Zhongyi Yang  10  11  12  13 ,  Shaoli Song  14  15  16  17
Affiliations
  • 1. Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3. Center for Biomedical Imaging, Fudan University, Shanghai, China.
  • 4. Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China.
  • 5. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 6. Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China. [email protected].
  • 7. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 8. Center for Biomedical Imaging, Fudan University, Shanghai, China. [email protected].
  • 9. Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China. [email protected].
  • 10. Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China. [email protected].
  • 11. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 12. Center for Biomedical Imaging, Fudan University, Shanghai, China. [email protected].
  • 13. Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China. [email protected].
  • 14. Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China. [email protected].
  • 15. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 16. Center for Biomedical Imaging, Fudan University, Shanghai, China. [email protected].
  • 17. Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 40986091 DOI: 10.1007/s00259-025-07577-5
Abstract

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 68Ga-labeled Enzalutamide-based positron emission tomography (PET) tracers for AR imaging.

Methods: [68Ga]Ga-DOTA-FZAR-1, [68Ga]Ga-DOTA-FZAR-2, and [68Ga]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 [68Ga]Ga-DOTA-FZAR-2 was conducted in eight patients with prostate Cancer.

Results: [68Ga]Ga-DOTA-FZAR-1, [68Ga]Ga-DOTA-FZAR-2, and [68Ga]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 [68Ga]Ga-DOTA-FZAR-2 in AR-associated prostate Cancer patients.

Conclusion: We developed and validated a series of 68Ga-labeled Enzalutamide-based PET tracers for AR imaging. Initial preclinical and clinical evidence indicate that [68Ga]Ga-DOTA-FZAR-2 enables noninvasive, whole-body, and dynamic monitoring of AR expression in prostate Cancer patients throughout therapy.

Keywords
Androgen receptor; First-in-human; Gallium-68; PET; Prostate cancer.
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