Purpose <p>Nectin-4 is highly expressed in pancreatic cancer. Accurate and quantitative measurements of Nectin-4 is useful for tumor diagnosis, treatment selection, and prognostic assessment. This study aimed to evaluate the diagnostic efficacy of a Nectin-4-targeted radioligand [⁶⁸Ga]Ga-FZNR-1 for pancreatic ductal adenocarcinoma.</p> Methods <p>Thirty-three patients with PDAC were recruited and underwent head-to-head [⁶⁸Ga]Ga-FZNR-1 and [¹⁸F]-FDG PET/CT for initial staging or to detect recurrence and metastases. PET/CT findings were confirmed by histopathology or follow-up imaging. Thirteen primary and metastatic lesions from the 33 patients were evaluated for Nectin-4 immunohistochemical expression.</p> Results <p>[¹⁸F]-FDG and [⁶⁸Ga]Ga-FZNR-1 PET/CT were comparable in detecting primary tumors, lymph node metastases, and distant metastases (96.00% [24/25] vs. 92.00% [23/25], 88.24% [15/17] vs. 82.35% [14/17], 95.24% [20/21] vs. 95.24% [20/21]). [⁶⁸Ga]Ga-FZNR-1 PET/CT demonstrated slightly higher specificity and accuracy than [¹⁸F]-FDG PET/CT for distant metastases (100.00% vs. 93.75%, 100.00% vs. 96.97%). The receiver operating characteristic (ROC) curve revealed that [⁶⁸Ga]Ga-FZNR-1 had high sensitivity and specificity in detecting Nectin-4-expressing lesions. Both SUV_max and TBR on [⁶⁸Ga]Ga-FZNR-1 PET/CT were significantly and positively correlated with the expression of Nectin-4 (both <i>r</i> = 0.89, both <i>p</i> &lt; 0.001).</p> Conclusion <p>[⁶⁸Ga]Ga-FZNR-1 is excellent in diagnosing primary, metastatic, and recurrent lesions of PDAC. In particular, it may be a useful complement in patients with distant metastases that cannot be detected by [¹⁸F]-FDG PET/CT. [⁶⁸Ga]Ga-FZNR-1 PET/CT could quantify the Nectin-4 expression. Moreover, [⁶⁸Ga]Ga-FZNR-1 PET/CT may have potential predictive value in the prognostic assessment of patients with PDAC.</p>