First-generation high-affinity ST14 radiopharmaceutical: Design, synthesis, and preclinical PET imaging evaluation for pancreatic cancer detection.

The non-specificity of ¹⁸ F-FDG, coupled with high false-positive rates in pancreatitis, underscores an unmet clinical need for using specific positron emission tomography (PET) radiopharmaceuticals in noninvasive pancreatic cancer detection. ST14, a trypsin-like protease and a member of the type II transmembrane serine protease family, is overexpressed in various solid malignancies, including pancreatic cancer. This study aimed to develop a ⁶⁸ Ga-labeled PET radiopharmaceutical targeting ST14 for pancreatic cancer detection. A precursor ST14-06 was designed, and molecular docking was employed to preliminarily predict the binding mode. ST14-06 emerged as the preferred precursor with experimental inhibition assays confirming its high affinity for ST14 (IC ₅₀  = 1.06 ± 0.08 nM). ⁶⁸ Ga-ST14-06 was successfully synthesized with high radiochemical purity (RCP, >95 %) and molar activity (25-30 GBq/μmol) and was stable in saline and serum. In vitro studies demonstrated specific binding of the tracer to ST14-positive AsPC-1 cells compared to the blocking group (11.45 ± 0.12 % vs. 2.48 ± 0.34 %, P < 0.01). PET/CT imaging in AsPC-1 tumor-bearing mice confirmed ST14-specific uptake, which was reduced by co-administration of an excess blocking agent. Biodistribution studies revealed higher distribution in AsPC-1 tumors (0.99 ± 0.08 %ID/g) than in PANC-1 tumors (0.32 ± 0.02 %ID/g) and the blocking group (0.32 ± 0.04 %ID/g) at 1 h post-injection. Immunohistochemistry results showed that ST14 was highly positive in AsPC-1 tumors, but was negative in PANC-1 tumors. These preliminary findings suggest that ⁶⁸ Ga-ST14-06 has potential as a first-generation PET radiopharmaceutical for ST14-specific imaging, offering a promising tool for pancreatic cancer detection.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)