Preclinical Evaluation and First-in-Human Study of [⁶⁸Ga]Ga-αvβ6–2: A Novel Dimeric Integrin αvβ6-Targeted PET Probe for Pancreatic Cancer Imaging

Integrin αvβ6 is highly expressed in pancreatic cancer, making it an ideal target for molecular imaging diagnosis. Multimerization is considered an effective strategy to increase the accumulation of molecular probes in tumors. Here, we synthesized monomeric and dimeric αvβ6-targeting molecular probes, labeled with ⁶⁸Ga, and designated them [⁶⁸Ga]Ga-αvβ6-1 and [⁶⁸Ga]Ga-αvβ6-2, respectively. Both in vitro and in vivo studies were conducted using human pancreatic cancer BxPC-3 cells and BxPC-3 tumor-bearing mice. Additionally, positron emission tomography/computed tomography (PET/CT) imaging with [⁶⁸Ga]Ga-αvβ6-2 was performed in three patients with pancreatic cancer. In vitro studies demonstrated that [⁶⁸Ga]Ga-αvβ6-2 exhibited greater binding affinity, cellular uptake, and internalization than did [⁶⁸Ga]Ga-αvβ6-1. Micro-PET/CT imaging and biodistribution studies revealed the superior imaging performance of [⁶⁸Ga]Ga-αvβ6-2. Furthermore, the first-in-human evaluation highlighted the favorable in vivo distribution and diagnostic efficacy of [⁶⁸Ga]Ga-αvβ6-2 in pancreatic cancer. These results underscore the effectiveness of the multimerization strategy in the application of αvβ6-targeted molecular probes, suggesting that [⁶⁸Ga]Ga-αvβ6-2 may possess favorable clinical translation potential.