The integrin α_vβ₆, an epithelium-specific cell surface receptor, is overexpressed on numerous malignancies, including the highly lethal pancreatic ductal adenocarcinomas. Here, we developed and tested a novel α_vβ₆-targeting peptide, DOTA-5G (1) radiolabeled with ⁶⁸Ga, for PET/CT imaging and ¹⁷⁷Lu for treatment. With the goal to develop a radiotheranostic, further modifications were made for increased circulation time, renal recycling, and tumor uptake, yielding DOTA-albumin-binding moiety-5G (2). Methods: Peptides 1 and 2 were synthesized on solid phase, and their affinity for α_vβ₆ was assessed by enzyme-linked immunosorbent assay. The peptides were radiolabeled with ⁶⁸Ga and ¹⁷⁷Lu. In vitro cell binding, internalization, and efflux of ⁶⁸Ga-1 and ¹⁷⁷Lu-2 were evaluated in α_vβ₆-positive BxPC-3 human pancreatic cancer cells. PET/CT imaging of ⁶⁸Ga-1 and ⁶⁸Ga-2 was performed on female nu/nu mice bearing subcutaneous BxPC-3 tumors. Biodistribution was performed for ⁶⁸Ga-1 (1 and 2 h after injection), ⁶⁸Ga-2 (2 and 4 h after injection), and ¹⁷⁷Lu-1 and ¹⁷⁷Lu-2 (1, 24, 48, and 72 h after injection). The ¹⁷⁷Lu-2 biodistribution data were extrapolated for human dosimetry data estimates using OLINDA/EXM 1.1. Therapeutic efficacy of ¹⁷⁷Lu-2 was evaluated in mice bearing BxPC-3 tumors. Results: Peptides 1 and 2 demonstrated high affinity (<55 nM) for α_vβ₆ by enzyme-linked immunosorbent assay. ⁶⁸Ga-1, ⁶⁸Ga-2, ¹⁷⁷Lu-1, and ¹⁷⁷Lu-2 were synthesized in high radiochemical purity. Rapid in vitro binding and internalization of ⁶⁸Ga-1 and ¹⁷⁷Lu-2 were observed in BxPC-3 cells. PET/CT imaging and biodistribution studies demonstrated uptake in BxPC-3 tumors. Introduction of the albumin-binding moiety in ¹⁷⁷Lu-2 resulted in a 5-fold increase in tumor uptake and retention over time. Based on the extended dosimetry data, the dose-limiting organ for ¹⁷⁷Lu-2 is the kidney. Treatment with ¹⁷⁷Lu-2 prolonged median survival by 1.5- to 2-fold versus controls. Conclusion: ⁶⁸Ga-1 and ¹⁷⁷Lu-2 demonstrated high affinity for the integrin α_vβ₆ both in vitro and in vivo, were rapidly internalized into BxPC-3 cells, and were stable in mouse and human serum. Both radiotracers showed favorable pharmacokinetics in preclinical studies, with predominantly renal excretion and good tumor-to-normal-tissue ratios. Favorable human dosimetry data suggest the potential of ¹⁷⁷Lu-2 as a treatment for pancreatic ductal adenocarcinoma.

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