PET Imaging of Differentiated Thyroid Cancer with TSHR-Targeted [89Zr]Zr-TR1402

• Published in: Molecular pharmaceutics 2024-08, Vol.21 (8), p.3889-3896
• Main Authors: Gimblet, Grayson R., Houson, Hailey A., Whitt, Jason, Reddy, Pratheek, Copland, John Al, Kenderian, Saad S., Szkudlinski, Mariusz W., Jaskula-Sztul, Renata, Lapi, Suzanne E.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Female; Humans; Male; Mice; Mice, Nude; Positron-Emission Tomography - methods; Radioisotopes - chemistry; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Receptors, Thyrotropin - genetics; Receptors, Thyrotropin - metabolism; Thyroid Neoplasms - diagnostic imaging; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Tissue Distribution; Zirconium - chemistry
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.4c00224

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 [89Zr]­Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [89Zr]­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 89Zr (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 [89Zr]­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 [89Zr]­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 [89Zr]­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 [89Zr]­Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.