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Positron Emission Tomography (PET) is an important nuclear medical imaging technique, and has been widely used in clinical applications, e.g., tumor detection and brain disease diagnosis. As PET imaging could put patients at risk of radiation, the acquisition of high-quality PET images with standard-dose tracers should be cautious. However, if dose is reduced in PET acquisition, the imaging quality could become worse and thus may not meet clinical requirement. To safely reduce the tracer dose and also maintain high quality of PET imaging, we propose a novel and effective approach to estimate high-quality Standard-dose PET (SPET) images from Low-dose PET (LPET) images. Specifically, to fully utilize both the rare paired and the abundant unpaired LPET and SPET images, we propose a semi-supervised framework for network training. Meanwhile, based on this framework, we further design a Region-adaptive Normalization (RN) and a structural consistency constraint to track the task-specific challenges. RN performs region-specific normalization in different regions of each PET image to suppress negative impact of large intensity variation across different regions, while the structural consistency constraint maintains structural details during the generation of SPET images from LPET images. Experiments on real human chest-abdomen PET images demonstrate that our proposed approach achieves state-of-the-art performance quantitatively and qualitatively.

N-(2- 18 F-fluoropropionyl)-l-glutamate ( 18 F-FPGLU), a new N-substituted 18 F-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 18 F-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 18 F-FPGLU in glioma. Establishment of orthotopic rat C6 glioma-bearing SD rats models was confirmed by MRI. Then PET imaging of 18 F-FPGLU was performed on the orthotopic C6 glioma-bearing SD rats and compared with that of 18 F-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 X AG - and Na + -independent system X C - are the mainly transporters of 18 F-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 18 F-FPGLU. High uptake and retention of 18 F-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 18 F-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. 18 F-FPGLU seems to be a better potential PET tracer than 18 F-FDG for brain glioma imaging with good visualization and ability to assess the tumor activity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: 2-[ 18 F]Fluoropropionic acid (RS-[ 18 F]FPA) has shown potential value as a short-chain fatty acid positron emission tomography (PET) tracer for the detection of liver cancer. However, RS-[ 18 F]FPA is a mixture of 2-R-[ 18 F]fluoropropionic acid (R-[ 18 F]FPA) and 2-S-[ 18 F]fluoropropionic acid (S-[ 18 F]FPA). The aim of this study is to validate the feasibility of R-[ 18 F]FPA in preclinical PET imaging of liver cancer and to compare the use of R-[ 18 F]FPA with that of RS-[ 18 F]FPA and S-[ 18 F]FPA., Procedures: A comparative study of R-[ 18 F]FPA, RS-[ 18 F]FPA, S-[ 18 F]FPA, and [ 18 F]FDG micro-PET imaging was performed in HepG2 and SK-Hep-1 tumor-bearing mice. A comparison of R-[ 18 F]FPA uptake with that of S-[ 18 F]FPA by HepG2 and SK-Hep-1 cells was made at different time points. Additionally, in vivo blocking experiments in HepG2 and SK-Hep-1 tumor models were conducted with orlistat and 3-nitropropionic acid (3-NP). In vitro blocking experiments with orlistat or 3-NP were performed with HepG2 and SK-Hep-1 cells., Results: The radioactivity uptake values of R-[ 18 F]FPA were comparable to those of RS-[ 18 F]FPA but were higher than those of S-[ 18 F]FPA and 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) in HepG2 tumors. The radioactivity uptake values of R-[ 18 F]FPA in large HepG2 tumors were lower than those of [ 18 F]FDG (P < 0.05), while R-[ 18 F]FPA PET was significantly superior to [ 18 F]FDG PET in detecting small tumors (both SK-Hep-1 and HepG2 tumors). The in vivo PET imaging experiments showed that R-[ 18 F]FPA uptake in HepG2 tumor-bearing mice was blocked by 19.3 % and 31.8 % after treatment with orlistat and 3-NP, respectively. The radioactivity uptake values of R-[ 18 F]FPA in SK-Hep-1 tumor-bearing mice was blocked by 39.5 % with orlistat., Conclusion: R-[ 18 F]FPA seems to be more potential than S-[ 18 F]FPA as an optically pure PET probe, with effective compensation for the deficiencies of [ 18 F]FDG, particularly in PET imaging of small liver cancer. The uptake mechanism of [ 18 F]FPA in liver cancer may be related to fatty acid synthesis and the tricarboxylic acid cycle. However, compared with the racemic RS-[ 18 F]FPA, the possible advantages of R-enantiomer R-[ 18 F]FPA still needs further research.

Purpose: The purpose of this study was to assess the potential utility of small-molecule apoptotic radiotracer, 2-(5-[ 18 F]fluoropentyl)-2-methyl malonic acid ([ 18 F]ML-10), for positron emission tomography (PET)/computed tomography (CT) monitoring the progression of pulmonary fibrosis in a rat model., Procedures: Male Sprague-Dawley rats were used to establish a rat model of pulmonary fibrosis by means of bleomycin (BLM) administration; control rats received saline (n = 12 per group). PET/CT with [ 18 F]ML-10 and 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) was performed in two groups at different stages of pulmonary fibrosis. The fibrotic response and the cell apoptosis were assessed with histologic examination. Differences in the apoptosis rate, fibrotic activity, and the lung uptake of [ 18 F]ML-10 and [ 18 F]FDG between two groups were determined with Student t test., Results: Compared with control group, BLM group showed a higher lung uptake of [ 18 F]ML-10 at all imaging time points (all P < 0.001). During the fibrotic phase of this disease model (days 21 and 28), the lung uptake of [ 18 F]ML-10 was higher than that of [ 18 F]FDG in the BLM group (all P < 0.001). Moreover, accumulation of [ 18 F]ML-10 in the lung tissues increased in proportion to the apoptosis rate (R 2  = 0.9863, P < 0.0001) and fibrotic activity (R 2  = 0.9631, P < 0.0001) of rat pulmonary fibrosis. Conversely, no correlation between [ 18 F]FDG uptake and fibrotic activity was found., Conclusions: [ 18 F]ML-10 PET/CT enabled monitoring the progression of rat pulmonary fibrosis, whereas [ 18 F]FDG PET/CT could not. Implications for noninvasive diagnosis of pulmonary fibrosis, assessment of fibrotic activity, and evaluation of antifibrotic therapy are expected.

Objective: To evaluate the preclinical value of 18 F-fluoropropionic acid ( 18 F-FPA) and 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) for imaging HCCs., Methods: The 18 F-FPA and 18 F-FDG uptake patterns in 3 HCC cell lines (Hep3B, HepG2, and SK-Hep1) were assessed in vitro and in vivo. The 18 F-FPA uptake mechanism was investigated using inhibition experiments with orlistat and 5-tetradecyloxy-2-furoic acid. The 18 F-FPA PET imaging was performed in different tumor animal models and compared with 18 F-FDG. We also evaluated the expressions of glucose transporter-1 (GLUT1), fatty acid synthase (FASN), and matrix metalloproteinase-2 (MMP2) in these cell lines., Results: In vitro experiments showed that the radiotracer uptake patterns were complementary in the HCC cell lines. Orlistat and 5-tetradecyloxy-2-furoic acid decreased the uptake of 18 F-FPA. The tumor-to-liver ratio of 18 F-FPA was superior to that of 18 F-FDG in the SK-Hep1 and HepG2 tumors ( P < .05). However, in the Hep3B tumors, the tumor-to-liver normalized uptake of 18 F-FDG was higher than 18 F-FPA ( P < .01). FASN was highly expressed in cell lines with high 18 F-FPA uptake, whereas GLUT1 was highly expressed in cell lines with high 18 F-FDG uptake. The 18 F-FPA uptake correlated with FASN ( r = 0.89, P = .014) and MMP2 ( r = 0.77, P = .002) expressions., Conclusions: PET imaging with 18 F-FPA combined with 18 F-FDG can be an alternative for detecting HCC.

[ 18 F]ML-10 (2-(5-[ 18 F]fluoro-pentyl)-2-methylmalonic acid) is a small molecule positron emission tomography (PET) probe for apoptosis imaging. Automated synthesis of [ 18 F]ML-10 was developed by using two different purification methods through a direct saponification procedure on a modified commercial [ 18 F]Fluoro-2-Deoxyglucose ([ 18 F]FDG) synthesizer. C18 purification method 1: The final [ 18 F]ML-10 solution containing ethanol was obtained with radiochemical yields of 60±5% (n=5) at the end of bombardment (EOB) and radiochemical purity of 98% in 35min. Al 2 O 3 and SCX purification method 2: To avoid possible side effects of a conventional ethanol-containing formulation, an new ethanol-free solution of [ 18 F]ML-10 was also developed, the radiochemical yields was 50±5% (n=5, EOB) within 45min and the radiochemical purity was 98%., (Copyright © 2017. Published by Elsevier Ltd.)

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., Competing Interests: There is no conflict of interest.

Purpose: S-C-Methyl-L-cysteine (C-MCYS) is a recently developed amino acid PET tracer for tumor imaging. The present study estimated human radiation absorbed dose of C-MCYS in healthy volunteers based on whole-body PET imaging., Methods: Five sequential whole-body PET scans were performed on 6 healthy volunteers after injection of C-MCYS. Each scan contained of approximately 7 to 10 bed positions, and total scan time of each volunteer was approximately 70 to 85 minutes. Regions of interest were drawn on PET images of source organs. Residence times of 13 source organs for men and 14 source organs for women were calculated from the organ-specific time-activity curves. Absorbed dose estimates were performed from organ residence time by using the medical internal radiation dosimetry method., Results: All volunteers showed initial high uptake in liver, heart, kidneys, pancreas, spleen, and uterus (only women), and followed by rapid clearance. There was very little activity residual in most of the organs except for the liver at the last emission scan time (approximately 75 minutes). The liver was the dose-limiting critical organ with the highest radiation-absorbed dose (1.01E-02 ± 2.64E-03 mGy/MBq), followed by the heart (9.09E-03 ± 1.40E-03 mGy/MBq), and the kidneys (7.12E-03 ± 9.44E-04 mGy/MBq). The effective dose to the whole body was 4.03E-03 ± 1.65E-04 mSv/MBq. A routine injection of 555 MBq (15 mCi) of C-MCYS would lead to an estimated effective dose of 2.24 ± 0.092 mSv., Conclusions: The potential radiation risks associated with C-MCYS PET imaging are within accepted limits. C-MCYS is a safe amino acid PET tracer for tumor imaging and can be used in further clinical studies.

Radiolabeled cyclic arginine-glycine-aspartic (RGD) peptides can be used for noninvasive determination of integrin αvβ3 expression in tumors. In this study, we performed radiosynthesis and biological evaluation of a new 18F-labeled RGD homodimeric peptide with one 8-amino-3,6-dioxaoctanoic acid (PEG2) linker on the glutamate β-amino group (18F-FP-PEG2-β-Glu-RGD2) as a symmetric PET tracer for tumor imaging. Biodistribution studies showed that radioactivity of 18F-FP-PEG2-β-Glu-RGD2 was rapidly cleared from blood by predominately renal excretion. MicroPET-CT imaging with 18F-FP-PEG2-β-Glu-RGD2 revealed high tumor contrast and low background in A549 human lung adenocarcinoma-bearing mouse models, PC-3 prostate cancer-bearing mouse models, and orthotopic transplanted C6 brain glioma models. 18F-FP-PEG2-β-Glu-RGD2 exhibited good stability in vitro and in vivo. The results suggest that this tracer is a potential PET tracer for tumor imaging.

S-(11)C-methyl-L-cysteine (LMCYS) is an attractive amino acid tracer for clinical tumor positron emission tomography (PET) imaging. D-isomers of some radiolabeled amino acids are potential PET tracers for tumor imaging. In this work, S-(11)C-methyl-D-cysteine (DMCYS), a D-amino acid isomer of S-(11)C-methyl-cysteine for tumor imaging was developed and evaluated. DMCYS was prepared by (11)C-methylation of the precursor D-cysteine, with an uncorrected radiochemical yield over 50 % from (11)CH3I within a total synthesis time from (11)CO2 about 12 min. In vitro competitive inhibition studies showed that DMCYS uptake was primarily transported through the Na(+)-independent system L, and also the Na(+)-dependent system B(0,+) and system ASC, with almost no system A. In vitro incorporation experiments indicated that almost no protein incorporation was found in Hepa 1-6 hepatoma cell lines. Biodistribution studies demonstrated higher uptake of DMCYS in pancreas and liver at 5 min post-injection, relatively lower uptake in brain and muscle, and faster radioactivity clearance from most tissues than those of L-isomer during the entire observation time. In the PET imaging of S180 fibrosarcoma-bearing mice and turpentine-induced inflammatory model mice, 2-(18)F-fluoro-2-deoxy-D-glucose (FDG) exhibited significantly high accumulation in both tumor and inflammatory lesion with low tumor-to-inflammation ratio of 1.40, and LMCYS showed low tumor-to-inflammation ratio of 1.64 at 60 min post-injection. By contrast, DMCYS showed moderate accumulation in tumor and very low uptake in inflammatory lesion, leading to relatively higher tumor-to-inflammation ratio of 2.25 than (11)C-methyl-L-methionine (MET) (1.85) at 60 min post-injection. Also, PET images of orthotopic transplanted glioma models demonstrated that low uptake of DMCYS in normal brain tissue and high uptake in brain glioma tissue were observed. The results suggest that DMCYS is a little better than the corresponding L-isomers as a potential PET tumor-detecting agent and is superior to MET and FDG in the differentiation of tumor from inflammation.

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The noninvasive imaging of cell death, including apoptosis and necrosis, is an important tool for the assessment of degenerative diseases and in the monitoring of tumor treatments. Duramycin is a peptide of 19-amino acids. It binds specifically to phosphatidylethanolamine a novel molecular target for cell death. N-(2-(18)F-Fluoropropionyl)duramycin ([(18)F]FPDuramycin) was prepared as a novel positron emission tomography (PET) tracer from the reaction of duramycin with 4-nitrophenyl 2-[(18)F]fluoropropionate ([(18)F]NFP). Compared with control cells (viable tumor cells), the in vitro binding of [(18)F]FPDuramycin with apoptotic cells induced by anti-Fas antibody resulted in a doubling increase, while the binding of [(18)F]FPDuramycin with necrotic cells induced by three freeze and thaw cycles resulted in a threefold increase. Biodistribution study in mice exhibited its rapid blood and renal clearance and predominant accumulation in liver and spleen over 120 min postinjection. Small-animal PET/CT imaging with [(18)F]FPDuramycin proved to be a successful way to visualize in vivo therapeutic-induced tumor cell death. In summary, [(18)F]FPDuramycin seems to be a potential PET probe candidate for noninvasive visualization of in vivo cell death sites induced by chemotherapy in tumors.

Introduction: Automated synthesis of (11)C-acetate ((11)C-AC) as the most commonly used radioactive fatty acid tracer is performed by a simple, rapid, and modified solid-phase extraction (SPE) purification., Methods: Automated synthesis of (11)C-AC was implemented by carboxylation reaction of MeMgBr on a polyethylene Teflon loop ring with (11)C-CO2, followed by acidic hydrolysis with acid and SCX cartridge, and purification on SCX, AG11A8 and C18 SPE cartridges using a commercially available (11)C-tracer synthesizer. Quality control test and animals positron emission tomography (PET) imaging were also carried out., Results: A high and reproducible decay-uncorrected radiochemical yield of (41.0 ± 4.6)% (n=10) was obtained from (11)C-CO2 within the whole synthesis time about 8 min. The radiochemical purity of (11)C-AC was over 95% by high-performance liquid chromatography (HPLC) analysis. Quality control test and PET imaging showed that (11)C-AC injection produced by the simple SPE procedure was safe and efficient, and was in agreement with the current Chinese radiopharmaceutical quality control guidelines., Conclusion: The novel, simple, and rapid method is readily adapted to the fully automated synthesis of (11)C-AC on several existing commercial synthesis module. The method can be used routinely to produce (11)C-AC for preclinical and clinical studies with PET imaging., (Copyright © 2013 Elsevier Ltd. All rights reserved.)