Abstract Accurate cancer imaging is critical for early diagnosis, guiding therapy, and assessing clinical outcomes. Yet pancreatic ductal adenocarcinoma (PDAC) poses major imaging obstacles, mainly due to its complex microenvironment, extensive stromal composition, and rapid disease progression. Claudin-4 (CLDN4), a tight junction protein, is significantly overexpressed in PDAC, making it a promising diagnostic and therapeutic target. Our spatial transcriptomic and proteomic analyses confirmed a 16-fold increase in CLDN4 expression in PDAC compared with normal pancreas. This significant finding supports its accessibility on tumor cell surfaces and suitability for molecular imaging approaches such as positron emission tomography (PET).Methods:We designed selective CLDN4-targeted peptides using solid-phase peptide synthesis, followed by rational optimization through D-amino-acid substitutions to enhance metabolic stability and dimerization strategies to improve affinity and tumor retention. The peptide structures were conjugated to a DOTA chelator through pegylated linkers of varying lengths and evaluated for serum stability. Binding affinity was measured using biolayer interferometry (BLI). Peptides were radiolabeled with 68Ga and 64Cu and tested in subcutaneous and transgenic PDAC-KPTC mouse models using dynamic PET/CT imaging.Results:The synthesized peptides showed good binding affinity for CLDN4 and were successfully radiolabeled with 68Ga and 64Cu. Serum stability studies revealed that tracers with longer PEG linkers exhibited superior stability after 4 hours of incubation. We found a similar observation with D-amino-acid-modified sequences, which showed better stability than the parent peptide. For preclinical testing, we observed that tumor uptake of the tracers gradually increased during the first hour of the dynamic scan, surpassing 10% ID/g at 40 minutes post-injection. This uptake correlated with TdTomato fluorescence, which marks cells expressing CLDN-4 in our genetically engineered model. The in-vitro imaging in a negative control subsequent model confirms the specificity of our tracers to tumors expressing claudin4. Further studies are ongoing to evaluate preclinical imaging of dimeric peptides and D-amino acid-modified sequences. This peptide-based theragnostic strategy has strong potential to improve early detection and guide targeted therapy in PDAC. Citation Format: Marian N. Aziz, Nisi Zhang, Mallesh Pandrala, Jongmin An, Yutong Guo, Marina Raie, SPENCER TUMBALE, Basit Jan, Katherine W. Ferrara. Advancing pancreatic cancer theragnostic through claudin-4-selective radiolabeled peptides: Design, optimization, and preclinical validation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2614.
Aziz et al. (Fri,) studied this question.