Synthesis and assessment of ZD2-(⁶⁸Ga-NOTA) specific to extradomain B fibronectin in tumor microenvironment for PET imaging of pancreatic cancer

Patients diagnosed with pancreatic cancer at a late stage have a dismal survival rate. Accurate early detection of pancreatic cancer with a size of 10 mm or less could dramatically improve patient survival after timely treatments. We have developed a new PET probe ZD2-(⁶⁸Ga-NOTA) specific to extradomain-B fibronectin (EDB-FN), an oncoprotein in tumor microenvironment, for sensitive molecular imaging and early diagnosis of pancreatic cancer. A targeted ligand ZD2-NOTA is synthesized by conjugation of a macrocyclic ligand NOTA via a 6-aminohexanoic acid spacer to a linear ZD2 peptide (Thr-Val-Arg-Thr-Ser-Ala-Asp). ZD2-(⁶⁸Ga-NOTA) is synthesized by relabeling of ZD2-NOTA with ⁶⁸GaCl₃ in a high purity under GMP conditions. The expression of EDB-FN is demonstrated in BxPC3 and Capan-1 human pancreatic cancer cells and tumor xenografts in mice. ZD2-(⁶⁸Ga-NOTA) results in significantly higher uptake in the both BxPC3 and Capan-1 tumor xenografts than normal organs and tissues, including the brain, heart, liver and muscle, at 1 hr postinjection in mice. The tumor to muscle uptake ratio is at least 5 folds for the tracer in both tumors. ZD2-(⁶⁸Ga-NOTA) is able to clearly delineate the PaCa tumors with a size of 10 mm or less with minimal background noise in normal tissues, including the liver. Substantial tumor uptake is still visible at 2 hr post-injection. The results suggest that the ZD2 peptide targeted PET probe has a potential for sensitive molecular imaging of EDB-FN and early detection of pancreatic cancer to improve healthcare of the patients diagnosed with the disease.