Hongliang Wang

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.

Synthesis and biological evaluation of N-(2-[18F]Fluoropropionyl)-L-methionine for tumor imaging☆

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.

In Vivo Cancer Dual-Targeting and Dual-Modality Imaging with Functionalized Quantum Dots

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 18F via the 4-nitrophenyl-2-18F-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 2-18F-fluoropropionyl-QD-RGD-BBN (18F-FP-QD-RGD-BBN). An in vivo biodistribution study of 18F-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 18F-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 18F-labeled QD probes with improved tumor-targeting efficacy.

Radiosynthesis and Biological Evaluation of N-[18F]Labeled Glutamic Acid as a Tumor Metabolic Imaging Tracer

We have previously reported that N-(2-[18F]fluoropropionyl)-L-methionine ([18F]FPMET) selectively accumulates in tumors. However, due to the poor pharmacokinetics of [18F]FPMET in vivo, the potential clinical translation of this observation is hampered. In this study, we rationally designed and synthesized [18F] or [11C]labeled N-position L-glutamic acid analogues for tumor imaging. N-(2-[18F]fluoropropionyl)-L-glutamic acid ([18F]FPGLU) was synthesized with a 30±10% (n = 10, decay-corrected) overall radiochemical yield and a specific activity of 40±25 GBq/μmol (n = 10) after 130 min of radiosynthesis. In vitro cell experiments showed that [18F]FPGLU was primarily transported through the XAG – system and was not incorporated into protein. [18F]FPGLU was stable in urine, tumor tissues, and blood. We were able to use [18F]FPGLU in PET imaging and obtained high tumor to background ratios when visualizing tumors tissues in animal models.

Radiosynthesis and biological evaluation of 5-(3-[18F]Fluoropropyloxy)-L-tryptophan for tumor PET imaging

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.

A Comparative Uptake Study of Multiplexed PET Tracers in Mice with Turpentine-Induced Inflammation

The potential value of multiplexed positron emission tomography (PET) tracers in mice with turpentine-induced inflammation was evaluated and compared with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) for glucose metabolism imaging. These PET tracers included [18F]fluoromethylcholine ([18F]FCH) for choline metabolism imaging, (S-[11C]methyl)-D-cysteine ([11C]DMCYS) for amino acid metabolism imaging, [11C]bis(zinc(II)-dipicolylamine) ([11C]DPA-Zn2+) for apoptosis imaging, 2-(4-N-[11C]-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) for β amyloid binding imaging, and [18F]fluoride (18F−) for bone metabolism imaging. In mice with turpentine-induced inflammation mice, the biodistribution of all the tracers mentioned above at 5, 15, 30, 45, and 60 min postinjection was determined. Also, the time-course curves of the tracer uptake ratios for inflammatory thigh muscle (IM) to normal uninflammatory thigh muscle (NM), IM to blood (BL), IM to brain (BR), and IM to liver (LI) were acquired, respectively. Moreover, PET imaging with the tracers within 60 min postinjection on a clinical PET/CT scanner was also conducted. [18F]FDG and 18F− showed relatively higher uptake ratios for IM to NM, IM to BL, IM to BR, and IM to LI than [18F]FCH, [11C]DPA-Zn2+, [11C]DMCYS and [11C]PIB, which were highly consistent with the results delineated in PET images. The results demonstrate that 18F− seems to be a potential PET tracer for inflammation imaging. [18F]FCH and [11C]DMCYS, with lower accumulation in inflammatory tissue than [18F]FDG, are not good PET tracers for inflammation imaging. As a promising inflammatory tracer, the chemical structure of [11C]DPA-Zn2+ needs to be further optimized.

Comparative uptake of 18F-FEN-DPAZn2, 18F-FECH, 18F-fluoride, and 18F-FDG in fibrosarcoma and aseptic inflammation

The aim of this study is to evaluate uptake of 2-(18)F-fluoroethyl-bis(zinc(II)-dipicolylamine) ((18)F-FEN-DPAZn2) as a promising cell death imaging agent, a choline analog (18)F-fluoroethylcholine ((18)F-FECH), (18)F-fluoride as a bone imaging agent, and a glucose analog 2-(18)F-fluoro-2-deoxy-d-glucose ((18)F-FDG) in the combined S180 fibrosarcoma and turpentine-induced inflammation mice models. The results showed that (18)F-FDG had the highest tumor-to-blood uptake ratio and tumor-to-muscle ratio, and high inflammation-to-blood ratio and inflammation-to-muscle ratio. (18)F -FECH showed moderate tumor-to-blood ratio and tumor-to-muscle ratio, and low inflammation-to-blood ratio and inflammation-to-muscle ratio. However, accumulation of (18)F FEN-DPAZn2 in tumor was similar to that in normal muscle. Also, (18)F-FEN-DPAZn2 and (18)F-fluoride exhibited the best selectivity to inflammation. (18)F-FECH positron emission tomography (PET) imaging demonstrates some advantages over (18)F-FDG PET for the differentiation of tumor from inflammation. (18)F FEN-DPAZn2 and (18)F-fluoride can be used for PET imaging of aseptic inflammation.

Human radiation dose estimation of (11)C-CFT using whole-body PET.

Purpose 11C-Labeled 2-&bgr;-carbomethoxy-3-&bgr;-(4-fluorophenyl)tropane (11C-CFT) is a commonly used positron emission tomography (PET) tracer for dopamine transporters imaging. The present study estimated human radiation absorbed doses of 11C-CFT based on whole-body PET imaging in healthy subjects. Methods Whole-body PET was performed on 6 subjects after injection of 472.06 ± 116.47 MBq of 11C-CFT. 7 Frames were acquired for about 70 min in 7 segments of the body. Regions of interest were drawn on PET images of source organs. Residence time was calculated as the area under the time-activity curve. Radiation dosimetry was calculated from organ residence time using the medical internal radiation dosimetry (MIDR) method. Results The organs with the highest radiation-absorbed doses were the urinary bladder, followed the spleen, pancreas, kidneys, and stomach. The dose-limiting critical organ was the urinary bladder. The effective dose was 8.89E−03 mSv/MBq (22.9 mrem/mCi). Biexponential fitting of mean bladder activity demonstrated that 18% of activity was excreted via the urine. Conclusions The potential radiation risks of 11C-CFT associated with in this study are well within accepted limits. 11C-CFT demonstrates a favorable radiation dose profile in humans and allows multiple PET examinations on the same subject per year.

18F-FP-PEG2-β-Glu-RGD2: A Symmetric Integrin αvβ3-Targeting Radiotracer for Tumor PET Imaging

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.

The influence of residual nor-β-CFT in 11C CFT injection on the Parkinson disease diagnosis: a 11C CFT PET study.

Purpose Fully automated synthesis of 11C–labeled 2&bgr;-carbomethoxy-3&bgr;-(4-fluorophenyl)tropane (11C CFT) as a dopamine transporter positron emission tomography (PET) tracer is performed with Sep-Pak purification, which cannot separate 11C CFT from nor-&bgr;-CFT and will result in the residual precursor nor-&bgr;-CFT in the final 11C CFT injection. The aim of this study is to estimate the influence of the residual precursor nor-&bgr;-CFT in the 11C CFT injection on the Parkinson disease (PD) diagnosis results. Methods Automated synthesis of 11C CFT was performed using the different chemical amounts (0.10, 0.20, 0.25, and 0.30 mg) of nor-&bgr;-CFT with Sep-Pak purification. According to the given different amounts of nor-&bgr;-CFT in the radiosynthesis, clinically suspected 25 PD patients were randomly divided into the following 4 groups: 0.10 mg, 0.20 mg, 0.25 mg, and 0.30 mg, which had 5, 9, 5, and 6 cases, respectively. A normal control group with 0.10 mg of nor-&bgr;-CFT included 2 volunteers. After the brain PET images of the subjects were acquired, the regions of interests of striatum and cerebellum were drawn, and the standard uptake values of these regions were calculated. Finally, comparing the 18F FDG PET and clinical diagnosis, the coincidence rates of 11C CFT PET imaging for PD patients were determined. Results Given 0.25 mg of the precursor nor-&bgr;-CFT, high radiochemical yield (59.4%) and high radiochemical purity of 11C CFT were obtained using Sep-Pak purification within a short synthesis time. The 11C CFT standard uptake value ratios of striatum to cerebellum had no statistically significant difference (P > 0.05) between the 4 suspected PD groups. However, there was statistically significant difference (P < 0.05) between the suspected PD groups and the control group. Also, the coincidence rates between the PD diagnosis using 11C CFT PET imaging for different dose groups and the final clinical diagnosis result were greater than 80%, but difference between the coincidence rates was not statistically significant (P = 0.955). Conclusions A simple, rapid, and efficient automated synthesis of 11C CFT using 0.25 mg of nor-&bgr;-CFT with Sep-Pak purification is afforded, providing enough radioactivity for PD PET imaging routinely. The residual nor-&bgr;-CFT in the 11C CFT injection is not inhibit 11C CFT binding to dopamine transporter, and also has no influence on PET diagnosis results of PD.