Gimblet Grayson R, Reddy Pratheek, Holland Michelle M, Houson Hailey A, Whitt Jason, Copland John A, Kenderian Saad S, Jaskula-Sztul Renata, Lapi Suzanne E
Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Sci Rep. 2025 Apr 3;15(1):11375. doi: 10.1038/s41598-025-94923-0.
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, [Zr]Zr-thyrotropin-alfa. [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 Zr (t = 78.4 h, β = 22.7%) at a molar activity of 25.9 MBq/nmol. [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 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 [Zr]Zr-thyrotropin-alfa supports continued preclinical optimization and potential studies in clinical trials.
促甲状腺素α是一种经美国食品药品监督管理局（FDA）批准的重组人促甲状腺激素激动剂。本研究是对促甲状腺素α作为一种靶向甲状腺刺激激素受体（TSHR）的正电子发射断层扫描（PET）放射性药物[锆]锆 - 促甲状腺素α的临床前评估。[锆]锆 - 促甲状腺素α是通过将对 - 硫氰基苄基 - 去铁胺（DFO）与促甲状腺素α以3:1的摩尔比（DFO:促甲状腺素α）偶联，并以25.9 MBq/nmol的摩尔活度用锆（半衰期t = 78.4小时，β = 22.7%）进行放射性标记而合成的。在稳定转导了TSHR的THJ529T和FTC133细胞中评估[锆]锆 - 促甲状腺素α的摄取，并与低表达野生型细胞进行比较。研究包括在雄性和雌性小鼠注射后第1 - 3天进行体外细胞摄取、体内PET成像和离体生物分布的综合研究。与低表达野生型对应物（分别为2.9±1.3%结合/毫克和2.0±0.4%结合/毫克）相比，TSHR + THJ529T细胞（6.6±1.3%结合/毫克）和FTC133细胞（3.5±0.5%结合/毫克）中的体外摄取显著更高（P < 0.0001）。用过量的DFO - 促甲状腺素α阻断摄取显示出对TSHR的特异性（P < 0.0001）。体内PET成像显示注射后第1天TSHR + 异种移植瘤中的摄取最高。离体生物分布表明，与TSHR - 异种移植瘤相比，TSHR + 雌性FTC133异种移植瘤模型（P < 0.0001）和TSHR + 雄性FTC133异种移植瘤模型（P < 0.0001）中的摄取显著更高。[锆]锆 - 促甲状腺素α的摄取支持在临床试验中继续进行临床前优化和潜在研究。
