68Ga-FZEAR-2 PET Tracer Non-Invasively Visualizes EphA2 Expression in Pancreatic Cancer Patients

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis, largely due to its metastatic potential and lack of effective therapeutic targets. Ephrin type-A receptor 2 (EphA2) is significantly upregulated in many cancers, including PDAC, making it a promising target for both therapy and diagnostic imaging. However, the clinical utility of targeting EphA2, particularly for non-invasive evaluation, remains underexplored. Developing a reliable imaging tool for EphA2 expression could enable precision diagnosis and guide targeted treatment strategies for PDAC patients.

Researchers synthesized three novel 68Ga-labeled radiotracers: 68Ga-FZEAR-1, 68Ga-FZEAR-2, and 68Ga-FZEAR-3. Their stability, affinity, and pharmacokinetics were evaluated in vitro and in vivo using EphA2-positive and EphA2-negative tumor xenografts. The lead candidate, 68Ga-FZEAR-2, was then advanced to a pilot first-in-human PET/CT study involving n=2 PDAC patients. The study assessed its ability to visualize lesions and its safety profile, with immunohistochemical analysis confirming EphA2 expression in visualized tumors.

All three 68Ga-radiotracers were synthesized with high radiochemical purity (>99%) and exhibited high stability, demonstrating nanomolar affinity for EphA2. In vitro cellular uptake was consistent with EphA2 expression levels, and blocking assays confirmed their specificity. In vivo, all tracers showed high tumor accumulation with low off-target uptake in xenograft models. 68Ga-FZEAR-2 emerged as the lead candidate due to its favorable tumor-targeting ability, pharmacokinetics, and safety profile in preclinical models. In the pilot clinical study with n=2 PDAC patients:

68Ga-FZEAR-2 PET/CT clearly visualized primary and metastatic lesions without any reported adverse effects. Immunohistochemical analysis of patient lesions confirmed EphA2 expression, correlating directly with areas of high tracer uptake, providing preliminary evidence for noninvasive EphA2 visualization.