99mTc-FAPI-YQ3 SPECT/CT for characterizing FAPI uptake phenotypes and metabolic-stromal heterogeneity in advanced...

Advanced and metastatic differentiated thyroid carcinoma (DTC), particularly radioactive iodine (RAI)-refractory disease, is characterized by spatially heterogeneous tumor biology and limited therapeutic options. Fibroblast activation protein inhibitor (FAPI)-targeted imaging may provide noninvasive imaging correlates of stromal-related tumor phenotypes; however, tracer uptake should not be interpreted as direct tissue proof of FAP expression without immunohistochemical or multi-omics validation. This exploratory study evaluated 99mTc-FAPI-YQ3 SPECT/CT for characterizing FAPI uptake phenotypes and metabolic-stromal imaging heterogeneity in advanced DTC.

A quinolone-derived FAPI pharmacophore was designed using scaffold-hopping and conformational-constraint strategies and radiolabeled with 99mTc. From June 2024 to February 2025, patients with pathologically confirmed DTC and locally advanced, recurrent, nodal metastatic, or distant metastatic disease were prospectively enrolled in this single-center observational study. No formal sample-size calculation was performed because the study was designed as an exploratory first clinical imaging-radiomics analysis. All patients underwent whole-body 99mTc-FAPI-YQ3 SPECT/CT and 18F-FDG PET/CT within 1 week. Lesion detection, biodistribution, tumor-to-background ratio (TBR), dual-tracer concordance, and exploratory radiomics classification of FAPI uptake phenotypes were analyzed.

Seventeen patients with 103 lesions were included. The mean TBR of 99mTc-FAPI-YQ3 was 6.8 +/- 2.3, and the mean lesion diameter was 2.69 +/- 1.35 cm. Dual-tracer phenotypes included concordant FDG-positive/FAPI-positive lesions (54/103, 52.4%), FDG-positive/FAPI-negative lesions (44/103, 42.7%), and FDG-negative/FAPI-positive lesions (5/103, 4.9%); no FDG-negative/FAPI-negative lesion was observed. Overall crude concordance was 52.4%, Cohen kappa was -0.0955 (P = 0.0477), and the positive-class Jaccard index was 0.524. 99mTc-FAPI-YQ3 showed high detection rates for thyroid-bed lesions (19/21) and bone lesions (7/8), moderate detection of lymph-node lesions (18/29), and limited detection of pulmonary lesions (10/40). In the exploratory lesion-level radiomics analysis, the logistic-regression model showed AUC values of 0.951 in the training set, 0.927 in the validation set, and 0.874 in five-fold cross-validation.

99mTc-FAPI-YQ3 SPECT/CT appears to be a feasible and accessible approach for evaluating FAPI uptake phenotypes in advanced DTC. Dual FDG-FAPI imaging provides preliminary evidence of metabolic-stromal imaging heterogeneity, but the findings should be interpreted as imaging phenotypes rather than validated tissue-based FAP expression. Further prospective studies with histopathologic, immunohistochemical, multi-omics, and patient-level validation are required.