Integrin α6 has been considered a promising biomarker, is overexpressed in many tumors, and plays a vital role in tumor formation, recurrence, and metastasis. In this study, we identified a novel high-affinity integrin α6-targeted peptide named RD (Arg-Trp-Tyr-Asp-PEG4)-Lys-Lys and developed a F-radiolabeled peptide tracer ([F]-AlF-NOTA-RD) and evaluated its potential application in positron emission tomography (PET) imaging of pancreatic cancer. [F]-AlF-NOTA-RD was produced using GMP (Good Manufacturing Practice of Medical Products)-compliant automatic radiosynthesis on a single GE FASTLab2 cassette-type synthesis module. The stability of [F]-AlF-NOTA-RD was analyzed in phosphate-buffered saline (PBS) and fetal bovine serum (FBS). The cell uptake assay of the tracer was assessed using PANC-1 cells. In addition, small-animal PET imaging and biodistribution studies of [F]-AlF-NOTA-RD were performed in pancreatic cancer subcutaneous tumor-bearing mice. The PET tracer [F]-AlF-NOTA-RD was obtained with a radiochemical yield of 23.7 ± 4.7%, radiochemical purity of >99%, and molar activity of 165.7 ± 59.1 GBq/μmol. [F]-AlF-NOTA-RD exhibited good in vitro stability in PBS and FBS. LogP octanol water value for the tracer was -2.28 ± 0.05 ( = 3). The binding affinity of RD to the integrin α6 protein ( = 0.13 ± 3.65 μM, = 3) was significantly higher than that of the RWY (CRWYDENAC) ( = 6.97 ± 1.44 μM, = 3). Small-animal PET imaging and biodistribution also revealed that [F]-AlF-NOTA-RD displayed rapid and good tumor uptake and lower liver background uptake in PANC-1 tumor-bearing mice. [F]-AlF-NOTA-RD showed significant radioactivity accumulation in tumors and was successfully blocked by NOTA-RD. Compared with [F]-FDG, [F]-AlF-NOTA-RD PET imaging and biodistribution studies in PANC-1 xenograft tumor-bearing mice confirmed a good tumor-to-muscle ratio (8.69 ± 2.03 vs 1.41 ± 0.23, respectively) at 0.5 h and (2.99 ± 3.02 vs 1.43 ± 0.17, respectively) at 1 h post injection. Autoradiography of human pancreatic cancer tumor tissues further confirmed high accumulation of [F]-AlF-NOTA-RD. In summary, we developed an optimized integrin α6-targeted imaging tracer and obtained high radioactivity products with a cassette-type synthesis module; moreover, the tracer exhibited good binding affinity with integrin α6 and good target specificity for PANC-1 cells in xenograft pancreatic tumor-bearing mice, demonstrating its promising application as a noninvasive PET radiotracer of integrin α6 expression in pancreatic cancer.