Glycogen synthase kinase-3 (GSK-3) contributes to tumorigenesis in pancreatic cancer by modulating cell proliferation and survival. This study evaluated the lead GSK-3 targeted PET radiotracers for neuro-PET imaging, [11C]PF-367 and [11C]OCM-44, in pancreatic cancer xenograft mice. Immunohistochemistry showed that GSK-3α and GSK-3β were overexpressed in PANC-1 xenografts. In autoradiography studies, higher specific binding was observed for [3H]PF-367 compared to [3H]OCM-44 when co-incubated with unlabeled PF-367 (59.2±1.8% vs 22.6±3.75%, respectively). Co-incubation of [11C]OCM-44 with OCM-44 did not improve the specific binding (25.5±30.2%). In dynamic PET imaging of PANC-1 xenograft mouse models, tumors were not visualized with [11C]PF-367 but were well visualized with [11C]OCM-44. Time-activity curves revealed no difference in accumulation in PANC-1 tumor tissue compared to muscle tissue in [11C]PF-367 baseline studies, while a significant difference was observed for [11C]OCM-44 with a tumor-to-muscle ratio of 1.6. Tumor radioactivity accumulation following injection with [11C]OCM-44 was not displaced by pre-treatment with unlabeled PF-367. Radiometabolite analysis showed that intact [11C]PF-367 accounted for 7.5% of tumor radioactivity, with >30% in plasma, at 40 min post-injection of the radiotracer, and that intact [11C]OCM-44 accounted for 20% of tumor radioactivity, with >60% in plasma. [11C]OCM-44 is superior to [11C]PF-367 for detecting lesions in preclinical mouse models of pancreatic cancer, however, both radiotracers undergo rapid metabolism in vivo. GSK-3 PET radiotracers with improved in vivo stability are needed for clinical translation. To our knowledge this work represents the first PET imaging study of GSK-3 in oncology.
Keywords: GSK-3; Glycogen synthase kinase-3; PET; carbon-11; oncology; pancreatic cancer.
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