Biological evaluation of [18F]AIF-NOTA-NSC-GLU as a PET tracer for hepatocellular carcinoma

Abstract

Purpose 18F-labeled amino acids (AAs) as tumor-specific imaging agents play a critical role in hepatocellular carcinoma (HCC) imaging. In this work, we evaluated the synthesis and biological properties of a simple 18F-labeled glutamate analogue, [18F]AIF-1,4,7-triazacyclononane-1,4,7-triacetic-acid-2-S-(4-isothiocyanatobenzyl))-l-glutamate ([18F]AIF-NOTA-NSC-GLU) for HCC imaging via one-step reaction sequence. Methods [18F]AIF-NOTA-NSC-GLU was synthesized via the one-step reaction sequence from NOTA-NSC-GLU. In order to investigate the imaging value of [18F]AIF-NOTA-NSC-GLU in HCC, we conducted PET/CT imaging and competitive binding of [18F]AIF-NOTA-NSC-GLU in human Hep3B 2.1-7 tumor-bearing mice. The transport mechanism of [18F]AIF-NOTA-NSC-GLU was determined by competitive inhibition and protein incorporation experiments in vitro. Results [18F]AIF-NOTA-NSC-GLU was prepared with decay-corrected radiochemical yield of 29.3 ± 5.6% (n=10) within 20 min. In vitro competitive inhibition experiments demonstrated that Na+-dependent Systems XAG-, B0+, ASC and minor XC- were involved in the uptake of [18F]AIF-NOTA-NSC-GLU, with Na+-dependent System XAG- possibly playing a more dominant role. Protein incorporation studies of the Hep3B 2.1-7 human hepatoma cell line found almost no protein incorporation. Micro-PET/CT imaging with [18F]AIF-NOTA-NSC-GLU showed good tumor-to-background contrast in Hep3B 2.1-7 human hepatoma-bearing mouse models. After [18F]AIF-NOTA-NSC-GLU injection, the tumor-to-liver uptake ratio of [18F]AIF-NOTA-NSC-GLU reached the peak at 30 min post-injection (2.06 ± 0.17). In vivo competitive binding experiments exhibited that the tumor-to-liver uptake ratio decreased by the addition of the inhibitors to block the system XAG-. Conclusion We have successfully synthesized [18F]AIF-NOTA-NSC-GLU as a novel PET tracer with good radiochemical yield and high radiochemical purity. Our findings indicate that [18F]AIF-NOTA-NSC-GLU might have good clinical potential as a PET tumor-detecting agent for HCC imaging.