Fuhua Wen

S-11C-Methyl-L-Cysteine: A New Amino Acid PET Tracer for Cancer Imaging

S-11C-methyl-L-cysteine (11C-MCYS), an analog of S-11C-methyl-L-methionine (11C-MET), can potentially serve as an amino acid PET tracer for tumor imaging. The aim of this study was to investigate the radiosynthesis and perform a biologic evaluation of 11C-MCYS as a tumor imaging tracer. The results of the first human PET study are reported. Methods: 11C-MCYS was prepared by 11C-methylation of the precursor L-cysteine with 11CH3I and purification on commercial C18 cartridges. In vitro competitive inhibition experiments were performed with Hepa1–6 hepatoma cell lines, and biodistribution of 11C-MCYS was determined in normal mice. The incorporation of 11C-MCYS into tissue proteins was investigated. In vivo 11C-MCYS uptake studies were performed on hepatocellular carcinoma–bearing nude mice and inflammation models and compared with 11C-MET PET and 18F-FDG PET. In a human PET study, a patient with a recurrence of glioma after surgery was examined with 11C-MCYS PET and 18F-FDG PET. Results: The uncorrected radiochemical yield of 11C-MCYS from 11CH3I was more than 50% with a synthesis time of 2 min, the radiochemical purity of 11C-MCYS was more than 99%, and the enantiomeric purity was more than 90%. In vitro studies showed that 11C-MCYS transport was mediated through transport system L. Biodistribution studies demonstrated high uptake of 11C-MCYS in the liver, stomach wall, and heart and low uptake of 11C-MCYS in the brain. There was higher accumulation of 11C-MCYS in the tumor than in the muscles. The tumor-to-muscle and inflammatory lesion–to–muscle ratios were 7.27 and 1.62, respectively, for 11C-MCYS, 5.08 and 3.88, respectively, for 18F-FDG, and 4.26 and 2.28, respectively, for 11C-MET at 60 min after injection. Almost no 11C-MCYS was incorporated into proteins. For the patient PET study, high uptake of 11C-MCYS with true-positive results, but low uptake of 18F-FDG with false-negative results, was found in the recurrent glioma. Conclusion: Automated synthesis of 11C-MCYS is easy to perform. 11C-MCYS is superior to 11C-MET and 18F-FDG in the differentiation of tumor from inflammation and seems to have potential as an oncologic PET tracer for the diagnosis of solid tumors.

Radiosynthesis and preliminary biological evaluation of N-(2- [ 18 F]fluoropropionyl)-L-glutamine as a PET tracer for tumor imaging

In this study, radiosynthesis and biological evaluation of a new [18F]labeled glutamine analogue, N-(2-[18F]fluoropropionyl)-L-glutamine ([18F]FPGLN) for tumor PET imaging are performed. [18F]FPGLN was synthesized via a two-step reaction sequence from 4-nitrophenyl-2-[18F]fluoropropionate ([18F]NFP) with a decay-corrected yield of 30 ± 5% (n=10) and a specific activity of 48 ± 10 GBq/μmol after 125 ± 5 min of radiosynthesis. The biodistribution of [18F]FPGLN was determined in normal Kunming mice and high uptake of [18F]FPGLN was observed within the kidneys and quickly excreted through the urinary bladder. In vitro cell experiments showed that [18F]FPGLN was primarily transported by Na+-dependent system XAG− and was not incorporated into proteins. [18F]FPGLN displayed better stability in vitro than that in vivo. PET/CT studies revealed that intense accumulation of [18F]FPGLN were shown in human SPC-A-1 lung adenocarcinoma and PC-3 prostate cancer xenografts. The results support that [18F]FPGLN seems to be a possible PET tracer for tumor imaging.

Radiosynthesis and biological evaluation of N-(2-[18F]fluoropropionyl)-3,4-dihydroxy-l-phenylalanine as a PET tracer for oncologic imaging

INTRODUCTION Several 11C and 18F labeled 3,4-dihydroxy-l-phenylalanine (l-DOPA) analogues have been used for neurologic and oncologic diseases, especially for brain tumors and neuroendocrine tumors PET imaging. However, 18F-labeled N-substituted l-DOPA analogues have not been reported so far. In the current study, radiosynthesis and biological evaluation of a new 18F-labeled l-DOPA analogue, N-(2-[18F]fluoropropionyl)-3,4-dihydroxy-l-phenylalanine ([18F]FPDOPA) for tumor PET imaging are performed. METHODS The synthesis of [18F]FPDOPA was via a two-step reaction sequence from 4-nitrophenyl-2-[18F]fluoropropionate ([18F]NFP). The biodistribution of [18F]FPDOPA was determined in normal Kunming mice. In vitro competitive inhibition and protein incorporation experiments were performed with SPC-A-1 lung adenocarcinoma cell lines. PET/CT studies of [18F]FPDOPA were conducted in C6 rat glioma and SPC-A-1 human lung adenocarcinoma and H460 human large cell lung cancer-bearing nude mice. RESULTS [18F]FPDOPA was prepared with a decay-corrected radiochemical yield of 28±5% and a specific activity of 50±15GBq/μmol (n=10) within 125min. In vitro cell experiments showed that [18F]FPDOPA uptake in SPC-A-1 cells was primarily transported through Na+-independent system L, with Na+-dependent system B0,+ and system ASC partly involved in it. Biodistribution data in mice showed that renal-bladder route was the main excretory system of [18F]FPDOPA. PET imaging demonstrated intense accumulation of [18F]FPDOPA in several tumor xenografts, with (8.50±0.40)%ID/g in C6 glioma, (6.30±0.12)%ID/g in SPC-A-1 lung adenocarcinoma, and (6.50±0.10)%ID/g in H460 large cell lung cancer, respectively. CONCLUSION A novel N-substituted 18F-labeled L-DOPA analogue [18F]FPDOPA is synthesized and evaluated in vitro and in vivo. The results support that [18F]FPDOPA seems to be a potential PET tracer for tumor imaging, especially be a better potential PET tracer than [18F]fluoro-2-deoxy-d-glucose ([18F]FDG) for brain tumor imaging.

Efficient preparation of [11C]CH3Br for the labeling of [11C]CH3-containing tracers in positron emission tomography clinical practice.

Background and aim[11C]methyl iodide ([11C]CH3I) is the most extensively used methylation agent for the preparation of a majority of 11C-labeled positron emission tomography (PET) radiotracers, which is commonly produced by the wet method and the gas-phase method. On account of the complexity of the gas-phase method, a simple automated synthesis of [11C]methyl bromide ([11C]CH3Br) as an analog of [11C]CH3I is derived by the wet method in this study. Radiosynthesis of L-[S-methyl-11C]methionine (MET), L-[S-methyl-11C]cysteine (MCYS), [N-methyl-11C]choline (CH), [11C]methyl triflate ([11C]CH3OSO2CF3), and [11C]-2-&bgr;-carbomethoxy-3-&bgr;-(4-fluorophenyl)-tropane (CFT) by methylation reaction with [11C]CH3Br, and PET imaging of patients are also described. MethodsThe preparation of [11C]CH3Br by a one-pot wet method involved the following steps: reduction of [11C]carbon dioxide with lithium aluminium hydride (LiAlH4) solution, treatment with hydrobromic acid, and distillation of [11C]CH3Br under continuous nitrogen flow. [11C]methylation of L-homocysteine thiolactone hydrochloride, L-cysteine, 2-dimethylaminoethanol, silver triflate, and nor-&bgr;-CFT as precursors with [11C]CH3Br and purification with Sep-Pak cartridges gave MET, MCYS, CH, [11C]CH3OSO2CF3, and CFT, respectively. In addition, PET imaging of brain cancer and Parkinsons disease was carried out. ResultsThe uncorrected radiochemical yield of [11C]CH3Br was (37.8±2.5%) based on [11C]carbon dioxide within a total synthesis time of 10 min and the radiochemical purity of [11C]CH3Br was greater than 95%. The uncorrected yields of MET, MCYS, CH, [11C]CH3OSO2CF3, and CFT were 70.1±0.5%, 70.2±2.3%, 60.3±1.8%, 95.1±2.2%, and 60.1±1.5% (from [11C]CH3OSO2CF3) within a total synthesis time of 2, 2, 5, 1, and 8 min, respectively. The radiochemical purity of MET, MCYS, CH, [11C]CH3OSO2CF3, and CFT was more than 95%. Good PET images in the patients are obtained. ConclusionAutomated synthesis of [11C]CH3Br can be done by the wet method on the commercial [11C]CH3I synthesizer. [11C]CH3Br can be used for a [11C]methylation reaction to produce 11C-labeled tracers for clinical 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.