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<p>Thyrotropin-alfa is an FDA approved recombinant human TSH agonist. This study represents a preclinical evaluation of thyrotropin-alfa as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical, [<sup>89</sup>Zr]Zr-thyrotropin-alfa. [<sup>89</sup>Zr]Zr-thyrotropin-alfa was synthesized by conjugating p-SCN-Bn-deferoxamine (DFO) to thyrotropin-alfa in a molar ratio of 3:1 (DFO:thyrotropin-alfa) and radiolabeling with <sup>89</sup>Zr (t<sub>1/2</sub> = 78.4&#xa0;h, β<sup>+</sup> = 22.7%) at a molar activity of 25.9 MBq/nmol. [<sup>89</sup>Zr]Zr-thyrotropin-alfa uptake was assessed in THJ529T and FTC133 cells stably transduced with the TSHR and compared to their low-expressing wild-type. Studies included a combination of <i>in vitro</i> cell uptake, <i>in vivo</i> PET imaging, and <i>ex vivo</i> biodistribution on Days 1–3 post-injection in male and female mice. <i>In vitro</i> uptake was significantly higher (<i>P</i> &lt; 0.0001) in TSHR + THJ529T (6.6 ± 1.3% bound/mg) and FTC133 (3.5 ± 0.5% bound/mg) cells over low-expressing wild-type counterparts (2.9 ± 1.3% bound/mg and 2.0 ± 0.4% bound/mg, respectively). Blocking uptake with excess DFO-thyrotropin-alfa showed specificity for TSHR (<i>P</i> &lt; 0.0001). <i>In vivo</i> PET imaging showed the highest uptake in TSHR + xenografts on Day 1 post-injection. <i>Ex vivo</i> biodistribution demonstrated significantly higher uptake in the TSHR + female FTC133 xenograft model (<i>P</i> &lt; 0.0001) and TSHR + male FTC133 xenograft model (<i>P</i> &lt; 0.0001) compared to TSHR- xenografts. Uptake of [<sup>89</sup>Zr]Zr-thyrotropin-alfa supports continued preclinical optimization and potential studies in clinical trials.</p>

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PET imaging of differentiated thyroid cancer with thyrotropin-alfa

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月3日

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  • Grayson R. Gimblet,
  • Pratheek Reddy,
  • Michelle M. Holland,
  • Hailey A. Houson,
  • Jason Whitt,
  • John A. Copland,
  • Saad S. Kenderian,
  • Renata Jaskula-Sztul,
  • Suzanne E. Lapi

摘要

Thyrotropin-alfa is an FDA approved recombinant human TSH agonist. This study represents a preclinical evaluation of thyrotropin-alfa as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical, [89Zr]Zr-thyrotropin-alfa. [89Zr]Zr-thyrotropin-alfa was synthesized by conjugating p-SCN-Bn-deferoxamine (DFO) to thyrotropin-alfa in a molar ratio of 3:1 (DFO:thyrotropin-alfa) and radiolabeling with 89Zr (t1/2 = 78.4 h, β+ = 22.7%) at a molar activity of 25.9 MBq/nmol. [89Zr]Zr-thyrotropin-alfa uptake was assessed in THJ529T and FTC133 cells stably transduced with the TSHR and compared to their low-expressing wild-type. Studies included a combination of in vitro cell uptake, in vivo PET imaging, and ex vivo biodistribution on Days 1–3 post-injection in male and female mice. In vitro uptake was significantly higher (P < 0.0001) in TSHR + THJ529T (6.6 ± 1.3% bound/mg) and FTC133 (3.5 ± 0.5% bound/mg) cells over low-expressing wild-type counterparts (2.9 ± 1.3% bound/mg and 2.0 ± 0.4% bound/mg, respectively). Blocking uptake with excess DFO-thyrotropin-alfa showed specificity for TSHR (P < 0.0001). In vivo PET imaging showed the highest uptake in TSHR + xenografts on Day 1 post-injection. Ex vivo biodistribution demonstrated significantly higher uptake in the TSHR + female FTC133 xenograft model (P < 0.0001) and TSHR + male FTC133 xenograft model (P < 0.0001) compared to TSHR- xenografts. Uptake of [89Zr]Zr-thyrotropin-alfa supports continued preclinical optimization and potential studies in clinical trials.