N-(2-18F-fluoropropionyl)-l-glutamate as a potential oncology tracer for PET imaging of glioma.

N-(2-18F-fluoropropionyl)-l-glutamate (18F-FPGLU), a new N-substituted 18F-labeling l-glutamate, is a potential amino acid tracer for oncology PET imaging with good tumor-to-background contrast in several tumor-bearing mice. Herein, we evaluated the potential value of 18F-FPGLU for PET imaging of glioma in orthotopic glioma-bearing SD rats. A series of competitive inhibition experiments with various types of inhibitors were conducted with C6 cells to investigate the transport mechanism of 18F-FPGLU in glioma. Establishment of orthotopic rat C6 glioma-bearing SD rats models was confirmed by MRI. Then PET imaging of 18F-FPGLU was performed on the orthotopic C6 glioma-bearing SD rats and compared with that of 18F-FDG. After the rats sacrificed, the whole brain was collected and immunofluorescence staining of glial fibrillary acidic protein (GFAP) and matrix metalloproteinase 2 (MMP2) were processed. Na+-dependent system XAG- and Na+-independent system XC- are the mainly transporters of 18F-FPGLU in C6 cells. N-methyl-d-aspartate (NMDA) receptor, which is associated with the invasiveness and proliferation of glioma cells, is also involved in the uptake of 18F-FPGLU. High uptake and retention of 18F-FPGLU was observerd in orthotopic glioma with good visualization and the tumor/background ratio reached 2.35 at 60 min post-injection, which was significantly higher than that of 18F-FDG (1.72) in small-animal PET images. High expression of MMP-2 and GFAP was observed in the immunofluorescence staining of glioma xerography slices. 18F-FPGLU seems to be a better potential PET tracer than 18F-FDG for brain glioma imaging with good visualization and ability to assess the tumor activity.

Excitatory glutamate transporter EAAC1 as an important transporter of N-(2-[18F]fluoropropionyl)-L-glutamate in oncology PET imaging.

INTRODUCTION: We have reported that N-(2-[18F]fluoropropionyl)-L-glutamate ([18F]FPGLU) was a potential amino acid tracer for tumor imaging with positron emission tomography (PET). In this study, the relationship between glutamate transporter excitatory amino acid carrier 1 (EAAC1) expression and [18F]FPGLU uptake in rat C6 glioma cell lines and human SPC-A-1 lung adenocarcinoma cell lines was investigated. METHODS: The uptake of [18F]FPGLU was assessed in ATRA-treated and untreated C6 cell lines, and also in EAAC1 knock-down SPC-A-1(shRNA) cells and SPC-A-1(NT) control cells. PET imaging of [18F]FPGLU was performed on the SPC-A-1 and SPC-A-1 (shRNA)-bearing mice models. RESULTS: The uptake of [18F]FPGLU in C6 cells increased significantly after induced by ATRA for 24, 48, and 72 h, which was closely related to expression of EAAC1 in C6 cells (R2 = 0.939). Compared with the SPC-A-1(NT) control cells, the uptake of [18F]FPGLU on EAAC1 knock-down SPC-A-1(shRNA) cells significantly decreased to 64.0%. Moreover, the uptake of [18F]FPGLU in EAAC1 knock-down SPC-A-1(shRNA) xenografts was significantly lower than that in SPC-A-1 xenografts, with tumor/muscle ratios of 3.01 vs. 1.67 at 60 min post-injection of [18F]FPGLU. CONCLUSION: The transport mechanism of [18F]FPGLU in glioma C6 and lung adenocarcinoma SPC-A-1 cell lines mainly involves in glutamate transporter EAAC1. EAAC1 is an important transporter of N-(2-[18F]fluoropropionyl)-L-glutamate in oncologic PET imaging.

Simple and rapid radiosynthesis of N-18F-labeled glutamic acid as a hepatocellular carcinoma PET tracer.

INTRODUCTION: We have reported that N-(2-18F-fluoropropionyl)-L-glutamate (18F-FPGLU) showed good tumor-to-background contrast and 18F-FPGLU was prepared via complex multi-step reaction sequence; here, it is synthesized by a facile two-step reaction sequence. The objectives of this study are to synthesize 18F-FPGLU via a two-step reaction sequence and to evaluate the value of 18F-FPGLU in nude mice bearing human hepatocellular carcinoma SMCC-7721 (HCC SMCC-7721). METHODS: 18F-FPGLU was synthetized from the precursor (2S)-dimethyl 2-(2-bromopropanamido)pentanedioate via the two-step on-column hydrolysis using a modified commercial FDG synthesizer. To investigate the transport mechanism of 18F-FPGLU, we conducted a series of competitive inhibition experiments on HCC SMCC-7721 cells in the absence or presence of Na+ and various types of inhibitors. Small-animal PET-CT imaging was performed on tumor-bearing nude mice using 18F-FPGLU and 2-18F-2-deoxy-D-glucose (18F-FDG). RESULTS: The radiochemical yield of 18F-FPGLU was up to 15±5% (EOS, n=10) in 35min with the two-step procedure and the radiochemical purity was higher than 95% with a specific activity of 30-40GBq/µmol. In vitro cell experiments show that 18F-FPGLU is primarily transported through the Na+-dependent system XAG- and Na+-independent system XC-. PET imaging in a tumor model indicates that 18F-FPGLU may be superior to 18F-FDG for hepatocellular carcinoma (HCC) imaging. CONCLUSION: An optimized route to prepare 18F-FPGLU was developed and 18F-FPGLU was synthetized from the precursor ((2S)-dimethyl 2-(2-bromopropanamido)pentanedioate) via the two-step on-column hydrolysis. 18F-FPGLU was a potential novel PET tracer for HCC imaging.

Radiation dosimetry estimation of N-(2-[(18)F]fluoropropionyl)- L-glutamate based on the mice distribution data.

N-(2-[(18)F]fluoropropionyl)-l-glutamate([(18)F]FPGLU) was a recently developed potential amino acid tracer for tumor imaging with positron emission tomography-computer tomography (PET-CT). The absorbed and effective radiation doses resulting from the intravenous administration of [(18)F]FPGLU were estimated using biodistribution data from normal mice. The methodology recommended by Medical Internal Radiation Dose Committee (MIRD) was used to estimate the doses. The highest uptake of [(18)F]FPGLU was found in the kidneys, followed by the liver and lung. The kidneys were the organ received the highest absorbed dose, 58.4µGy/MBq, the brain received the lowest dose, 5.5µGy/MBq, and other organs received doses in the range of 8.3-11.9µGy/MBq. The effective dose was 17.0µSv/MBq. The data show that a 370MBq (10mCi) injection of [(18)F]FPGLU would lead to an estimated effective dose of 6.3mSv, which is within the accepted range of routine nuclear medicine investigations.