Translation of a novel EphA2-targeted PET tracer from preclinical models to first-in-human studies in pancreatic cancer.

PURPOSE: Ephrin type-A receptor 2 (EphA2) is a promising target in pancreatic ductal adenocarcinoma (PDAC). However, the clinical potential of targeting EphA2 requires further imaging evaluation. This study developed and preliminarily evaluated a novel 68Ga-labeled radiotracer for PET imaging of EphA2 expression in PDAC patients.

METHODS

68Ga-FZEAR-1, 68Ga-FZEAR-2, and 68Ga-FZEAR-3 were synthesized, and their stability, affinity, pharmacokinetics were evaluated in vitro and in vivo. Further biological evaluation was performed in EphA2-positive and EphA2-negative tumor xenografts. A pilot first-in-human PET/CT study of the lead candidate, 68Ga-FZEAR-2, was subsequently conducted in two PDAC patients.

RESULTS

The three 68Ga-radiotracers were synthesized with high radiochemical purity (> 99%) and demonstrated high stability and nanomolar affinity for EphA2. Cellular uptake was consistent with EphA2 expression and blocking assays confirmed specificity. In vivo, all tracers exhibited high tumor accumulation with low off-target uptake. 68Ga-FZEAR-2 showed favorable tumor-targeting ability, pharmacokinetics, and safety profile. In the pilot clinical study (n = 2), 68Ga-FZEAR-2 PET/CT visualized primary and metastatic lesions clearly without adverse effects. Immunohistochemical analysis confirmed EphA2 expression in lesions exhibiting high tracer uptake.

CONCLUSION

A series of 68Ga-labeled tracers for EphA2 imaging was successfully developed and evaluated. The lead candidate, 68Ga-FZEAR-2, showed promising targeting specificity and favorable pharmacokinetics. A pilot study indicated that 68Ga-FZEAR-2 provided preliminary evidence of noninvasive visualization of EphA2 expression in PDAC patients, thereby suggesting its potential as a tool for precision diagnosis in PDAC.