PET Imaging of Differentiated Thyroid Cancer with TSHR-Targeted [<sup>89</sup>Zr]Zr-TR1402
Grayson R. Gimblet, Hailey Houson, Jason Whitt, Pratheek Reddy, John Al Copland, Saad S. Kenderian, Mariusz W. Szkudlinski, Renata Jaskula‐Sztul, Suzanne E. Lapi
Abstract
Thyroid cancer is the most common endocrine cancer, with differentiated thyroid cancers (DTCs) accounting for 95% of diagnoses. While most DTC patients are diagnosed and treated with radioiodine (RAI), up to 20% of DTC patients become RAI refractory (RAI-R). RAI-R patients have significantly reduced survival rates compared to patients who remain RAI-avid. This study explores [ 89 Zr]Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [ 89 Zr]Zr-TR1402 was synthesized with a molar activity of 25.9 MBq/nmol by conjugating recombinant human TSH (rhTSH) analogue TR1402 to chelator p-SCN-Bn-deferoxamine (DFO) in a molar ratio of 3:1 (DFO/TR1402) and radiolabeling with 89 Zr ( t 1/2 = 78.4 h, β + = 22.7%). As TSHR is absent in commonly available DTC-derived cell lines, TSHR was reintroduced via stable transduction by delivering a lentivirus containing the full-length coding region of the human TSHR gene. Receptor-mediated uptake of [ 89 Zr]Zr-TR1402 was evaluated in vitro in stably transduced TSHR+ and wild-type TSHR– DTC cell lines. In vivo PET imaging was performed on Days 1–3 postinjection in male and female athymic nude mice bearing TSHR+ and TSHR– xenografts, along with ex vivo biodistribution on Day 3 postinjection. In vitro uptake of 1 nM [ 89 Zr]Zr-TR1402 was significantly higher in TSHR+ THJ529T ( P < 0.0001) and FTC133 ( P < 0.01) cells than in TSHR– THJ529T and FTC133 cells. This uptake was shown to be specific in both TSHR+ THJ529T ( P < 0.0001) and TSHR+ FTC133 ( P < 0.0001) cells by blocking uptake with 250 nm DFO-TR1402. In vivo PET imaging showed accumulation of [ 89 Zr]Zr-TR1402 in TSHR+ tumors, which was the highest on Day 1. In the male FTC133 xenograft model, ex vivo biodistribution confirmed a significant difference ( P < 0.001) in uptake between FTC133+ (1.3 ± 0.1%ID/g) and FTC133– (0.8 ± 0.1%ID/g) tumors. A significant difference ( P < 0.05) in uptake was also seen in the male THJ529T xenograft model between THJ529T+ (1.8 ± 0.6%ID/g) and THJ529T– (0.8 ± 0.4%ID/g) tumors. The in vitro and in vivo accumulation of [ 89 Zr]Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.