Development of a 18F-Radiolabeled CD38 Probe for Targeted PET Imaging of NSCLC Xenografts with Different EGFR-Mutant Status

Abstract Non-invasive identification of epidermal growth factor receptor (EGFR) mutation status remains a critical unmet clinical need for personalized therapy of non-small-cell lung cancer (NSCLC). Given that CD38 is markedly downregulated in EGFR-mutant NSCLC while remaining highly expressed in EGFR-wild-type tumors, CD38 can serve as a surrogate imaging biomarker for the indirect stratification of EGFR molecular phenotypes. Herein, we report the preclinical development and comprehensive characterization of 18F-NOTA-78c, a novel 18F-radiolabeled small-molecule PET imaging probe targeting CD38. 18F-NOTA-78c was synthesized under mild aqueous conditions with high radiochemical purity (>95%). The tracer exhibited favorable in vitro and in vivo stability, high hydrophilicity (logD7.4 = −1.76 ± 0.02), and specific CD38-mediated cellular binding, with the cold precursor showing an IC50 value of 38.27 nM. In vivo micro-PET/CT and biodistribution studies in NSCLC xenograft-bearing mice demonstrated higher tracer accumulation in EGFR wild-type A549 tumors (SUVmax = 1.28, T/M = 4.74), whereas low uptake was observed in EGFR-mutant HCC827 and H1975 tumors. Our findings validate the proof-of-concept application of CD38-targeted PET for indirect EGFR status differentiation in NSCLC.