[⁶⁸Ga]Ga-CTR-FAPI versus [⁶⁸Ga]Ga-FAPI-04 PET/CT for patient evaluation in radioiodine-refractory differentiated thyroid cancer: A prospective comparative study.

OBJECTIVE: Incorporating a sulfur (VI)-fluoride exchange (SuFEx) chemistry-based linker, FAPI-based covalent targeted radioligand (CTR) showed better tumor binding affinity and longer retention time than FAPI-04 in animal studies. This study for the first time compared the lesion detection efficacy of [⁶⁸Ga]Ga-CTR-FAPI PET/CT and [⁶⁸Ga]Ga-FAPI-04 PET/CT in a radioiodine-refractory differentiated thyroid cancer clinical cohort. METHODS: A single-center prospective comparative study was conducted, enrolling 40 RAIR-DTC patients with distant metastases. All patients underwent sequential [⁶⁸Ga]Ga-FAPI-04 PET/CT and [⁶⁸Ga]Ga-CTR-FAPI PET/CT examinations at a 24-48 h interval. Two experienced nuclear medicine physicians performed blinded visual analysis of the images to assess lesion detection status. Semi-quantitative analysis included the measurement of maximum standardized uptake value (SUVmax) and tumor-to-background ratio (TBR) of lesions in different anatomical regions. The reference standard for lesion confirmation was a combination of conventional imaging, histopathological results (when feasible), and long-term clinico-radiological follow-up. The detection performances of the two imaging modalities were compared at the patient and lesion levels. RESULTS: Of the 40 enrolled patients, 37 had detectable metastatic lesions on both imaging modalities. Two patients had lesions exclusively detected by [⁶⁸Ga]Ga-CTR-FAPI PET/CT. [⁶⁸Ga]Ga-CTR-FAPI PET/CT achieved superior visual detection performance in 17.5% (7/40) of patients (p = 0.016) concerning lesion distribution areas. In total, 769 metastatic lesions were identified by the two tracers, with [⁶⁸Ga]Ga-CTR-FAPI PET/CT detecting 99.2% (763/769) and [⁶⁸Ga]Ga-FAPI-04 PET/CT detecting 62.4% (480/769) of lesions (p < 0.001). [⁶⁸Ga]Ga-CTR-FAPI PET/CT significantly improved detection rates in lung (99.4% vs. 37.5%, p < 0.001), pleural/peritoneal (99.0% vs. 76.4%, p < 0.001), lymph node (99.0% vs. 81.7%, p < 0.001) and bone (100% vs. 82.9%, p = 0.031) metastases. Semi-quantitative analysis showed that [⁶⁸Ga]Ga-CTR-FAPI PET/CT had significantly higher median SUVmax in lung (5.1 vs. 3.8, p < 0.001) and bone (8.3 vs. 3.4, p = 0.013) metastases, and significantly higher median TBR in local recurrence (11.2 vs. 8.6, p = 0.045) and lymph node metastases (6.0 vs. 5.1, p = 0.026) compared with [⁶⁸Ga]Ga-FAPI-04 PET/CT. Furthermore, [⁶⁸Ga]Ga-CTR-FAPI PET/CT exhibited additional cerebral and hepatic metastatic lesions as well as higher tracer uptake in shared lesions located at brain (n = 1), liver(n = 2) and kidney (n = 1), while the only mediastinal soft tissue metastasis showed an SUVmax slightly higher in [⁶⁸Ga]Ga-FAPI-04 PET/CT. CONCLUSION: [⁶⁸Ga]Ga-CTR-FAPI PET/CT exhibits superior lesion detection rate, higher tracer uptake and better tumor-to-background contrast compared with [⁶⁸Ga]Ga-FAPI-04 PET/CT in RAIR-DTC patients, thus enhances the comprehensive assessment of patients' tumor burden. These findings stimulate further research on the application of CTR-FAPI as a novel and promising theranostic agent. TRIAL REGISTRATION: ChiCTR ChiCTR2400091757. Registered 2 November 2024.