Synthesis of enantiopure ¹⁸F-trifluoromethyl cysteine as a structure-mimetic amino acid tracer for glioma imaging

Abstract

Purpose 18 F-labeled amino acids (AAs) as tumor-speci c imaging agents play a critical role in hepatocellular carcinoma (HCC) imaging. In this work, we evaluated the synthesis and biological properties of a simple 18 F-labeled glutamate analogue, [ 18 F]AlF-1,4,7-triazacyclononane-1,4,7-triaceticacid-2-S-(4-isothiocyanatobenzyl))-l-glutamate ([ 18 F]AlF-NOTA-NSC-GLU) for HCC imaging via one-step reaction sequence. Methods [ 18 F]AlF-NOTA-NSC-GLU was synthesized via the one-step reaction sequence from NOTA-NSC-GLU. In order to investigate the imaging value of [ 18 F]AlF-NOTA-NSC-GLU in HCC, we conducted PET/CT imaging and competitive binding of [ 18 F]AlF-NOTA-NSC-GLU in human Hep3B tumor-bearing mice. The transport mechanism of [ 18 F]AlF-NOTA-NSC-GLU was determined by competitive inhibition and protein incorporation experiments in vitro. Results [ 18 F]AlF-NOTA-NSC-GLU was prepared without decay-corrected radiochemical yield of 29.3 ± 5.6% (n=10) within 20 min. In vitro competitive inhibition experiments demonstrated that Na +-dependent Systems X AG-, B0 + , ASC and minor X C were involved in the uptake of [ 18 F]AlF-NOTA-NSC-GLU, with Na +dependent System X AG possibly playing a more dominant role. Protein incorporation studies of the Hep3B human hepatoma cell line found almost no protein incorporation. Micro-PET/CT imaging with [ 18 F]AlF-NOTA-NSC-GLU showed good tumor-to-background contrast in Hep3B human hepatoma-bearing mouse models. After [ 18 F]AlF-NOTA-NSC-GLU injection, the tumor-to-liver uptake ratio of [ 18 F]AlF-NOTA-NSC-GLU was 2.06 ± 0.17 at 30 min post-injection. In vivo competitive binding experiments exhibited that the tumor-to-liver uptake ratio decreased by the addition of the inhibitors to block the system X AG-. Conclusion We have successfully synthesized [ 18 F]AlF-NOTA-NSC-GLU as a novel PET tracer with good radiochemical yield and high radiochemical purity. Our ndings indicate that [ 18 F]AlF-NOTA-NSC-GLU might have good clinical potential as a PET tumor-detecting agent for HCC imaging.

Ascorbic acid analogue 6-Deoxy-6-[18F] fluoro-L-ascorbic acid as a tracer for identifying human colorectal cancer with SVCT2 overexpression

“…Static PET imaging studies using 3.7 MBq of 18 F-DFA on tumor-bearing mice ( n = 5) were conducted 60 min after injection. To obtain an imaging region-of-interest (ROI)-derived%ID/g, the images were reconstructed by the previously described method [27] .…”

Biological Evaluation of [18F]AlF-NOTA-NSC-GLU as a Positron Emission Tomography Tracer for Hepatocellular Carcinoma

“…As shown in Figure 3C, when HCC Hep3B cells were treated with the different concentrations of sulfasalazine, an inhibitor of system X − C , the uptake of this agent was inhibited by 17.6 ± 5.64% (200 µM) and 23.8 ± 1.5% (300 µM). Therefore, [ 18 F]AlF-NOTA-NSC-GLU was primarily transported by the Na + -dependent system X − AG , with minor transportation by the Na + -dependent systems *Test tube method was introduced as previously described (Liu et al, 2019). HPLC, high-performance liquid chromatography.…”

“…(D) Plasma collected at 1 h post-injection of [ 18 F]AlF-NOTA-NSC-GLU. *Test tube method was introduced as previously described(Liu et al, 2019). HPLC, high-performance liquid chromatography.…”

Site‐Selective Trifluoromethylation Reactions of Oligopeptides

“…Preliminary biodistribution experiments evidenced the viability of the resulting 18 F‐SCF 3 tagged peptides for imaging techniques. In this regard, in vivo studies with related 18 F‐trifluoromethyl Cys residues, prepared from serine‐derived cyclic sulfamidates through a nucleophilic 18 F‐trifluoromethylthiolation followed by a final deprotection reaction, have recently shown high potential as efficient tracers for glioma imaging …”