[⁶⁸Ga]Ga-CTR-FAPI versus [⁶⁸Ga]Ga-FAPI-04 PET/CT for patient evaluation in radioiodine-refractory differentiated...

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.

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 (SUV_max) 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.

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 SUV_max 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 SUV_max slightly higher in [⁶⁸Ga]Ga-FAPI-04 PET/CT.

[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.

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