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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.)

Although 11 C-labelled sulfur-containing amino acids (SAAs) including L-methyl-[ 11 C]methionine and S -[ 11 C]-methyl-L-cysteine, are attractive tracers for glioma positron emission tomography (PET) imaging, their applications are limited by the short half-life of the radionuclide 11 C ( t 1/2 = 20.4 min). However, development of 18 F-labelled SAAs ( 18 F, t 1/2 = 109.8 min) without significant structural changes or relying on prosthetic groups remains to be a great challenge due to the absence of adequate space for chemical modification. Methods : We herein present 18 F-trifluoromethylated D- and L-cysteines which were designed by replacing the methyl group with 18 F-trifluoromethyl group using a structure-based bioisosterism strategy. These two enantiomers were synthesized stereoselectively from serine-derived cyclic sulfamidates via a nucleophilic 18 F-trifluoromethylthiolation reaction followed by a deprotection reaction. Furthermore, we conducted preliminary in vitro and in vivo studies to investigate the feasibility of using 18 F-trifluoromethylated cysteines as PET tracers for glioma imaging. Results : The two-step radiosynthesis provided the desired products in excellent enantiopurity ( ee > 99%) with 14% ± 3% of radiochemical yield. In vitro cell study demonstrated that both enantiomers were taken up efficiently by C6 tumor cells and were mainly transported by systems L and ASC. Among them, the D-enantiomer exhibited relatively good stability and high tumor-specific accumulation in the animal studies. Conclusion : Our findings indicate that 18 F-trifluoromethylated D-cysteine, a new SAA tracer, may be a potential candidate for glioma imaging. Taken together, our study represents a first step toward developing 18 F-trifluoromethylated cysteines as structure-mimetic tracers for PET tumor imaging., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Objectives: As acid-base imbalance is involved in many pathological processes, the capability to image tissue pH alterations in the clinic could offer new ways to detect disease and respond to treatment. In this study, the authors show that tissue pH can be imaged in vivo with 11 C-labeled bicarbonate (H 11 CO 3 - ) buffer and positron emission tomography (PET)., Methods: H 11 CO 3 - was produced by on-column NaOH adsorption. Biodistribution of H 11 CO 3 - in normal mice was determined. In addition, uptake studies and inhibition experiments of H 11 CO 3 - in the S180 fibrosarcoma-bearing mice and the inflammatory mice were investigated with PET imaging. The tumor and inflammatory interstitial pH was measured by a needle pH microelectrode., Results: PET imaging demonstrated the high uptake of H 11 CO 3 - in mice tumor tissues and inflammatory tissues, which showed that the average tumor or inflammatory interstitial pH was significantly lower than the surrounding tissue. Administration of sodium bicarbonate in the drinking water increased the measured tumor pH, while the uptake of H 11 CO 3 - in mice model tissues had no change. Similarly, administration with ammonium chloride (NH 4 Cl) decreased the pH, whereas the unchanged uptake of H 11 CO 3 - in mice model tissues was also found. However, after administration of acetazolamide, the low uptake of H 11 CO 3 - in mice model tissues was observed., Conclusions: H 11 CO 3 - solution is an endogenous bicarbonate buffer tracer that can be injected into patients without toxicity. H 11 CO 3 - PET can be used clinically to image pathological processes that are associated with acid-base imbalance, such as cancer and inflammation.

Introduction: Several 11 C and 18 F 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, 18 F-labeled N-substituted l-DOPA analogues have not been reported so far. In the current study, radiosynthesis and biological evaluation of a new 18 F-labeled l-DOPA analogue, N-(2-[ 18 F]fluoropropionyl)-3,4-dihydroxy-l-phenylalanine ([ 18 F]FPDOPA) for tumor PET imaging are performed., Methods: The synthesis of [ 18 F]FPDOPA was via a two-step reaction sequence from 4-nitrophenyl-2-[ 18 F]fluoropropionate ([ 18 F]NFP). The biodistribution of [ 18 F]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 [ 18 F]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: [ 18 F]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 [ 18 F]FPDOPA uptake in SPC-A-1 cells was primarily transported through Na + -independent system L, with Na + -dependent system B 0,+ and system ASC partly involved in it. Biodistribution data in mice showed that renal-bladder route was the main excretory system of [ 18 F]FPDOPA. PET imaging demonstrated intense accumulation of [ 18 F]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 18 F-labeled L-DOPA analogue [ 18 F]FPDOPA is synthesized and evaluated in vitro and in vivo. The results support that [ 18 F]FPDOPA seems to be a potential PET tracer for tumor imaging, especially be a better potential PET tracer than [ 18 F]fluoro-2-deoxy-d-glucose ([ 18 F]FDG) for brain tumor imaging., (Copyright © 2017 Elsevier Inc. All rights reserved.)

N-(2-[ 18 F]Fluoropropionyl)-l-glutamic acid ([ 18 F]FPGLU) is a potential amino acid tracer for tumor imaging with positron emission tomography. However, due to the complicated multistep synthesis, the routine production of [ 18 F]FPGLU presents many challenging laboratory requirements. To simplify the synthesis process of this interesting radiopharmaceutical, an efficient automated synthesis of [ 18 F]FPGLU was performed on a modified commercial fluorodeoxyglucose synthesizer via a 2-step on-column hydrolysis procedure, including 18 F-fluorination and on-column hydrolysis reaction. [ 18 F]FPGLU was synthesized in 12 ± 2% (n = 10, uncorrected) radiochemical yield based on [ 18 F]fluoride using the tosylated precursor 2. The radiochemical purity was ≥98%, and the overall synthesis time was 35 minutes. To further optimize the radiosynthesis conditions of [ 18 F]FPGLU, a brominated precursor 3 was also used for the preparation of [ 18 F]FPGLU, and the improved radiochemical yield was up to 20 ± 3% (n = 10, uncorrected) in 35 minutes. Moreover, all these results were achieved using the similar on-column hydrolysis procedure on the modified fluorodeoxyglucose synthesis module., (Copyright © 2017 John Wiley & Sons, Ltd.)

Introduction: We have reported that N-(2- 18 F-fluoropropionyl)-L-glutamate ( 18 F-FPGLU) showed good tumor-to-background contrast and 18 F-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 18 F-FPGLU via a two-step reaction sequence and to evaluate the value of 18 F-FPGLU in nude mice bearing human hepatocellular carcinoma SMCC-7721 (HCC SMCC-7721)., Methods: 18 F-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 18 F-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 18 F-FPGLU and 2- 18 F-2-deoxy-D-glucose ( 18 F-FDG)., Results: The radiochemical yield of 18 F-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 18 F-FPGLU is primarily transported through the Na + -dependent system X AG - and Na + -independent system X C -. PET imaging in a tumor model indicates that 18 F-FPGLU may be superior to 18 F-FDG for hepatocellular carcinoma (HCC) imaging., Conclusion: An optimized route to prepare 18 F-FPGLU was developed and 18 F-FPGLU was synthetized from the precursor ((2S)-dimethyl 2-(2-bromopropanamido)pentanedioate) via the two-step on-column hydrolysis. 18 F-FPGLU was a potential novel PET tracer for HCC imaging., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

Unlabelled: Semiconductor quantum dots (QDs), after surface modification to provide water solubility and biocompatibility, have a promising future in biomedical applications. In this study, a dual receptor-targeting dual-modality PET/near-infrared fluorescence (NIRF) probe was developed for accurate assessment of the pharmacokinetics and tumor-targeting efficacy of QDs., Methods: QDs were modified by β-Glu-RGD-BBN (RGD is arginine-glycine-aspartate acid, and BBN is bombesin) peptides and then labeled with (18)F via the 4-nitrophenyl-2-(18)F-fluoropropionate prosthetic group. Cytotoxicity and cell-binding assay of QD-RGD-BBN were performed with PC-3 cells. In vivo dual-modality PET/NIRF imaging of prostate tumor-bearing mice was investigated using QD-RGD-BBN and 2-(18)F-fluoropropionyl-QD-RGD-BBN ((18)F-FP-QD-RGD-BBN). An in vivo biodistribution study of (18)F-FP-QD-RGD-BBN was performed on normal mice., Results: QD-RGD-BBN exhibited strong red luminescence (600-800 nm) with the same maximum fluorescence wavelength (705 nm) as QD705 and slightly lower toxicity than that of QD705 in PC-3 cells at concentrations of greater than 30 μg/mL. Uptake of QD-RGD-BBN in PC-3 cells showed no significant decrease in the presence of an excess amount of dimer arginine-glycine-aspartate acid (RGD2) or bombesin(7-14) (BBN) peptide but was blocked significantly in the presence of an excess amount of NH2-RGD-BBN. Dual-function PET/NIRF imaging is able to accurately assess the biodistribution and tumor-targeting efficacy of the (18)F-labeled functionalized QDs., Conclusion: The functionalized QD probe has great potential as a universal dual-targeting probe for detecting tumors in living subjects, opening up a new strategy for the development of multitargeting multimodality (18)F-labeled QD probes with improved tumor-targeting efficacy., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Introduction: N-position radiolabeled amino acids, such as N-(2-[(18)F]fluoropropionyl)-L-methionine ([(18)F]FPMET) as a derivative of L-methionine (MET), can potentially serve as a PET tracer for tumor imaging. In the current study, radiosynthesis and biological evaluation of [(18)F]FPMET as a new PET tumor agent are performed., Methods: [(18)F]FPMET was synthesized by reacting 4-nitrophenyl 2-[(18)F]fluoropropionate ([(18)F]NFP) with MET. In vitro competitive inhibition and protein incorporation experiments were performed with Hepa1-6 hepatoma cell lines. The biodistribution of [(18)F]FPMET was determined in S180 fibrosarcoma-bearing mice. PET/CT studies of [(18)F]FPMET were conducted in S180 fibrosarcoma-bearing mice, A549 lung adenocarcinoma-bearing nude mice, and PC-3 prostate cancer-bearing nude mice., Results: [(18)F]FPMET was synthesized in 72%± 4% uncorrected radiochemical yield (n=10) from [(18)F]NFP. In vitro experiments showed that [(18)F]FPMET was primarily transported through Na(+)-dependent system A, system ASC, and system B(0,+), and was not incorporated into protein. Biodistribution and PET/CT imaging studies indicated that [(18)F]FPMET could delineate S180 fibrosarcoma, A549 lung adenocarcinoma, and PC-3 prostate cancer., Conclusion: An efficient synthesis of N-position [(18)F]labeled amino acids with a classic [(18)F]NFP prosthetic group is developed. The results support that [(18)F]FPMET seems to be a potential tracer for tumor imaging with PET., (© 2013.)

Introduction: [(18)F]FDG PET has difficulty distinguishing tumor from inflammation in the clinic because of the same high uptake in nonmalignant and inflammatory tissue. In contrast, amino acid tracers do not accumulate in inflamed tissues and thus provide an excellent opportunity for their use in clinical cancer imaging. In this study, we developed a new amino acid tracer 5-(3-[(18)F]Fluoropropyloxy)-L-tryptophan ([(18)F]-L-FPTP) by two-step reactions and performed its biologic evaluation., Methods: [(18)F]-L-FPTP was prepared by [(18)F]fluoropropylation of 5-hydroxy-L-tryptophan disodium salt and purification on C18 cartridges. The biodistribution of [(18)F]-L-FPTP was determined in normal mice and the incorporation of [(18)F]-L-FPTP into tissue proteins was investigated. In vitro competitive inhibition experiments were performed with Hepa1-6 hepatoma cell lines. [(18)F]-L-FPTP PET imaging was performed on tumor-bearing and inflammation mice and compared with [(18)F]-L-FEHTP PET., Results: The overall uncorrected radiochemical yield of [(18)F]-L-FPTP was 21.1 ± 4.4% with a synthesis time of 60 min, the radiochemical purity was more than 99%. Biodistribution studies demonstrate high uptake of [(18)F]-L-FPTP in liver, kidney, pancreas, and blood at the early phase, and fast clearance in most tissues over the whole observed time. The uptake studies in Hepa1-6 cells suggest that [(18)F]-L-FPTP is transported by the amino acid transport system B(0,+), LAT2 and ASC. [(18)F]-L-FPTP displays good stability and is not incorporated into proteins in vitro. PET imaging shows that [(18)F]-L-FPTP can be a better potential PET tracer for differentiating tumor from inflammation than [(18)F]FDG and 5-(3-[(18)F]fluoroethyloxy)-L-tryptophan ([(18)F]-L-FEHTP), with high [(18)F]-L-FPTP uptake ratio (2.53) of tumor to inflammation at 60 min postinjection., Conclusions: Using [(18)F]fluoropropyl derivatives as intermediates, the new tracer [(18)F]-L-FPTP was achieved with good yield and radiochemical purity, and the biological evaluation results of [(18)F]-L-FPTP showed that it was a hopeful tracer for PET tumor imaging., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The synthetic bis(zinc(II)-dipicolylamine) (DPAZn2) coordination complexes are known to have a high specific and selective affinity to target the exposed phosphatidylserine (PS) on the surface of dead and dying cells. An (18)F-labeled DPAZn2 complex (4-(18)F-Fluoro-benzoyl-bis(zinc(II)-dipicolylamine), (18)F-FB-DPAZn2) as positron emission tomography (PET) tracer was developed and evaluated for in vivo imaging of tumor treated with a chemical agent. The in vitro cell stain studies revealed that fluorescent DPAZn2 complexes (Dansyl-DPAZn2) stained the same cells (apoptotic and necrotic cells) as fluorescein isothiocyanate (FITC) labeled Annexin V (FITC-Annexin V). The radiosynthesis of (18)F-FB-DPAZn2 was achieved through the amidation the precursor bis(2,2'-dipicolylamine) derivative (DPA2) with the prosthetic group N-succinimidyl-4-[(18)F]-fluorobenzoate ((18)F-SFB) and chelation with zinc nitrate. In the biodistribution study, the fast clearance of (18)F-FB-DPAZn2 from blood and kidney was observed and high uptake in liver and intestine within 90 min postinjection was also found. For the PET imaging, significantly higher tumor uptake of (18)F-FB-DPAZn2 was observed in the adriamycin (ADM)-treated Hepa1-6 hepatocellular carcinoma-bearing mice than that in the untreated tumor-model mice, while a slightly decreased tumor uptake of (18)F-FDG was found in the ADM-treated tumor-bearing mice. The results indicate that (18)F-FB-DPAZn2 has the similar capability of apoptosis detection as FITC-Annexin V and seems to be a potential PET tracer for noninvasive evaluation and monitoring of anti-tumor chemotherapy. The high uptake of (18)F-FB-DPAZn2 in the abdomen needs to optimize the structure for improving its pharmacokinetics characteristics in the future work.

Background and Aim: [C]methyl iodide ([C]CH3I) is the most extensively used methylation agent for the preparation of a majority of C-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 [C]methyl bromide ([C]CH3Br) as an analog of [C]CH3I is derived by the wet method in this study. Radiosynthesis of L-[S-methyl-C]methionine (MET), L-[S-methyl-C]cysteine (MCYS), [N-methyl-C]choline (CH), [C]methyl triflate ([C]CH3OSO2CF3), and [C]-2-β-carbomethoxy-3-β-(4-fluorophenyl)-tropane (CFT) by methylation reaction with [C]CH3Br, and PET imaging of patients are also described., Methods: The preparation of [C]CH3Br by a one-pot wet method involved the following steps: reduction of [C]carbon dioxide with lithium aluminium hydride (LiAlH4) solution, treatment with hydrobromic acid, and distillation of [C]CH3Br under continuous nitrogen flow. [C]methylation of L-homocysteine thiolactone hydrochloride, L-cysteine, 2-dimethylaminoethanol, silver triflate, and nor-β-CFT as precursors with [C]CH3Br and purification with Sep-Pak cartridges gave MET, MCYS, CH, [C]CH3OSO2CF3, and CFT, respectively. In addition, PET imaging of brain cancer and Parkinson's disease was carried out., Results: The uncorrected radiochemical yield of [C]CH3Br was (37.8±2.5%) based on [C]carbon dioxide within a total synthesis time of 10 min and the radiochemical purity of [C]CH3Br was greater than 95%. The uncorrected yields of MET, MCYS, CH, [C]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 [C]CH3OSO2CF3) within a total synthesis time of 2, 2, 5, 1, and 8 min, respectively. The radiochemical purity of MET, MCYS, CH, [C]CH3OSO2CF3, and CFT was more than 95%. Good PET images in the patients are obtained., Conclusion: Automated synthesis of [C]CH3Br can be done by the wet method on the commercial [C]CH3I synthesizer. [C]CH3Br can be used for a [C]methylation reaction to produce C-labeled tracers for clinical PET imaging.

Background: 9-(4-[F]fluoro-3-hydroxymethylbutyl) guanine ([F]FHBG) has been used as a reporter probe to image the expression of the herpes simplex virus type 1 thymidine kinase (TK) reporter gene in living organisms with positron emission tomography (PET). However, the routine production of [F]FHBG presents many challenging laboratory requirements., Aim: To develop a simple one-pot fully-automated synthesis procedure of [F]FHBG amenable for its routine use in reporter gene expression PET imaging studies., Methods: A TRACERlab FXF-N synthesizer was substantially modified and adapted to the synthesis of [F]FHBG through the two-step one-pot procedure. After the fluorination reaction of the tosylate precursor and the hydrolysis of the intermediate product in the same reaction vessel, the final product was purified by Sep-Pak cartridges instead of the high performance liquid chromatography system., Results: The fully automated synthesis of [F]FHBG with Sep-Pak purification was performed within a short synthesis time. The decay-uncorrected radiochemical yield of [F]FHBG was 8-14% (n=10), the radiochemical purity was more than 99%, and the entire synthesis time was less than 40 min. In addition, the PET image of theTK-transfected nude mice model indicated a much higher uptake of [F]FHBG in the TK-transfected tumor region than in the control tumor region., Conclusion: The automated synthesis of [F]FHBG is very easy to carry out using one-pot reactions combined with Sep-Pak purification. The synthetic [F]FHBG can be used for PET imaging and monitoring of in vivo herpes simplex virus type 1 TK gene expression.