[18F]AlF-NOTA-PCP2 PET/CT to Assess PD-L1 Status in Head and Neck Cancer

Purpose: While PD-L1 expression heterogeneity limits the predictive value of localized biopsies, molecular imaging offers a dynamic alternative. We developed [ 18 F]AlF-NOTA-PCP2, a hydrophilic PD-L1–targeted peptide tracer, and first evaluated its clinical utility in head and neck (HNC) cancer through a head-to-head comparison with [ 18 F]FDG PET/CT. Methods: Preclinical validation included competitive binding assays and micro-PET/CT in PD-L1–positive HNC xenografts. A prospective trial (NCT04304066) enrolled 24 HNC patients for [ 18 F]AlF-NOTA-PCP2 PET/CT, with paired [ 18 F]FDG scans in 17 patients. PD-L1 expression was quantified via 22C3 immunohistochemistry (IHC). Safety, biodistribution, and tracer correlations were analyzed, with dynamic PD-L1 changes monitored in 5 pembrolizumab-treated patients. Results: [ 18 F]AlF-NOTA-PCP2 exhibited high PD-L1 affinity (IC 50 = 24.7 nM) and selectively targeted PD-L1–positive tumors in preclinical models. In 24 HNC patients, tracer uptake strongly correlated with PD-L1 TPS ( r s = 0.890, P < 0.001). Favorable biodistribution and minimal off-target uptake were observed, with the highest accumulation in the spleen and PD-L1–positive lesions. Head-to-head analysis (58 lesions, n = 17) revealed limited concordance between [ 18 F]AlF-NOTA-PCP2 and [ 18 F]FDG SUVmax ( rs = 0.323, P = 0.042). Tracer uptake varied by HPV status (HPV+ vs. HPV−: 5.93 ± 2.61 vs. 2.25 ± 0.57, P = 0.007) and anatomic site. Dynamic monitoring in immunotherapy responders showed early [ 18 F]AlF-NOTA-PCP2 uptake reduction (ΔSUVmax = −37.7%) preceding metabolic changes on FDG, reflecting PD-L1 downregulation. Conclusions: [ 18 F]AlF-NOTA-PCP2 PET/CT provides a superior, noninvasive approach for evaluating PD-L1 expression in HNC. Its high specificity for PD-L1 and favorable biodistribution position it as a promising tool for monitoring immunotherapy responses and informing treatment decisions.