Ui, Takashi Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Ueda, Masashi Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University ORCID Kaken ID publons researchmap
Higaki, Yusuke Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama Universit Kaken ID
Kamino, Shinichiro Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University ORCID Kaken ID
Sano, Kohei Graduate School of Pharmaceutical Sciences, Kyoto University
Kimura, Hiroyuki Graduate School of Pharmaceutical Sciences, Kyoto University
Saji, Hideo Graduate School of Pharmaceutical Sciences, Kyoto University
Enomoto, Shuichi RIKEN Center for Life Science Technologies
Pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal cancers. Since the majority of patients are diagnosed at an advanced stage, development of a detection method for PDAC at an earlier stage of disease progression is strongly desirable. Integrin αVβ6 is a promising target for early PDAC detection because its expression increases during precancerous changes. The present study aimed to develop an imaging probe for positron emission tomography (PET) which targets αVβ6 integrin-positive PDAC. We selected A20FMDV2 peptide, which binds specifically to αvβ6 integrin, as a probe scaffold, and 68Ga as a radioisotope. A20FMDV2 peptide has not been previously labeled with 68Ga. A cysteine residue was introduced to the N-terminus of the probe at a site-specific conjugation of maleimide-NOTA (mal-NOTA) chelate. Different numbers of glycine residues were also introduced between cysteine and the A20FMDV2 sequence as a spacer in order to reduce the steric hindrance of the mal-NOTA on the binding probe to αVβ6 integrin. In vitro, the competitive binding assay revealed that probes containing a 6-glycine linker ([natGa]CG6 and [natGa]Ac-CG6) showed high affinity to αVβ6 integrin. Both probes could be labeled by 67/68Ga with high radiochemical yield (>50%) and purity (>98%). On biodistribution analysis, [67Ga]Ac-CG6 showed higher tumor accumulation, faster blood clearance, and lower accumulation in the surrounding organs of pancreas than did [67Ga]CG6. The αVβ6 integrin-positive xenografts were clearly visualized by PET imaging with [68Ga]Ac-CG6. The intratumoral distribution of [68Ga]Ac-CG6 coincided with the αVβ6 integrin-positive regions detected by immunohistochemistry. Thus, [68Ga]Ac-CG6 is a useful peptide probe for the imaging of αVβ6 integrin in PDAC.
Pancreatic ductal adenocarcinoma
Positron emission tomography
This fulltext is available in Nov. 2021.
Bioorganic & Medicinal Chemistry
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