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Background <p>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 using a radiolabeled AR antagonist would enable non-invasive clinical staging and assessment of tumor heterogeneity via positron emission tomography (PET), complementing the findings of a [<sup>68</sup>Ga]PSMA-11 scan. Previous efforts described the radiolabeling of enzalutamide with fluorine-18 but were limited by low molar activity. In this study, we showcase an efficient, reproducible automated synthesis of [<sup>18</sup>F]fluoroflutamide via zinc-mediated radiofluorination and assess its biodistribution in preclinical models of prostate cancer.</p> Results <p>From 1.87 Ci (69.19 GBq) of [<sup>18</sup>F]fluoride, [<sup>18</sup>F]fluoroflutamide was isolated with a non-decay-corrected radiochemical yield of 3.46 ± 1.30% (<i>n</i> = 4) and a radiochemical purity of &gt; 99% in an average 79&#xa0;min from end-of-beam using a bromoamide precursor. The average A<sub>m</sub> was 1.57 Ci/µmol (or 58.23 GBq/µmol) at the end of synthesis, and the radiochemical purity after 4&#xa0;h was &gt; 97%, indicating negligible 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.</p> Conclusions <p>Herein, we report the optimized automated radiosynthesis of [<sup>18</sup>F]fluoroflutamide with high purity and sufficient yield for preclinical evaluation of AR-targeted imaging in mouse models of prostate cancer. The lack of uptake in androgen receptor-rich tissues and xenografts suggests impaired in vivo target engagement. While α-tertiary fluorination may attenuate CYP1A2-mediated oxidation to the higher-affinity 2-hydroxyflutamide metabolite, the observed signal is also consistent with reduced intrinsic AR affinity and/or altered pharmacokinetics of the fluorinated analog.</p>

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Automated radiosynthesis and biodistribution of [18F]fluoroflutamide

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • Gina Kaup,
  • Jason Anthony Witek,
  • Shelbie Jaylene Cingoranelli,
  • Jenelle Stauff,
  • David Raffel,
  • Allen Frederick Brooks,
  • Peter James Henry Scott,
  • Jay Samuel Wright

摘要

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 using a radiolabeled AR antagonist would enable non-invasive clinical staging and assessment of tumor heterogeneity via positron emission tomography (PET), complementing the findings of a [68Ga]PSMA-11 scan. Previous efforts described the radiolabeling of enzalutamide with fluorine-18 but were limited by low molar activity. In this study, we showcase an efficient, reproducible automated synthesis of [18F]fluoroflutamide via zinc-mediated radiofluorination and assess its biodistribution in preclinical models of prostate cancer.

Results

From 1.87 Ci (69.19 GBq) of [18F]fluoride, [18F]fluoroflutamide was isolated with a non-decay-corrected radiochemical yield of 3.46 ± 1.30% (n = 4) and a radiochemical purity of > 99% in an average 79 min from end-of-beam using a bromoamide precursor. The average Am was 1.57 Ci/µmol (or 58.23 GBq/µmol) at the end of synthesis, and the radiochemical purity after 4 h was > 97%, indicating negligible 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 [18F]fluoroflutamide with high purity and sufficient yield for preclinical evaluation of AR-targeted imaging in mouse models of prostate cancer. The lack of uptake in androgen receptor-rich tissues and xenografts suggests impaired in vivo target engagement. While α-tertiary fluorination may attenuate CYP1A2-mediated oxidation to the higher-affinity 2-hydroxyflutamide metabolite, the observed signal is also consistent with reduced intrinsic AR affinity and/or altered pharmacokinetics of the fluorinated analog.