Increased [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) yield with recycled target [18O]water: factors affecting the [18F]FDG yield.

The reuse of [18O] water after being purified by distillation has been reported to give lower [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) yields, probably due to the presence of organic impurities. In our routine production of [18F]FDG, however, we observed increased [18F]FDG yields with recycled [18O]water. Thus, factors affecting [18F]FDG yield were examined using as-purchased (virgin) and recycled (by photochemical combustion and distillation) [18O]water. [18F]FDG was synthesized by nucleophilic 18F-fluorination on a quaternary 4-aminopyridinium resin. The recycled [18O]water gave an [18F]FDG yield significantly higher than did the virgin water, without any significant difference in the [18F]fluoride yield. Levels of several ionic impurities including Cl- and Ca2+ were significantly higher in the virgin [18O]water than in the recycled water, while significantly larger amounts of organic impurities were detected in the former. Hence, trace amounts of organic impurities were not responsible for the lower [18F]FDG yield. Chloride anion in the [18O]water may compete with [18F]fluoride to lower the [18F]FDG yield.     

Fully automated synthesis of [18F]fluoromisonidazole using a conventional [18F]FDG module

We developed a new fully automated method for the synthesis of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) by modifying a commercial FDG synthesizer and its disposable fluid pathway. A three-step procedure was used to prepare the tosylate precursor, 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydrofuranyl-3-O-toluenesulfonylpropanediol. Using glycerol as the starting material, the precursor was synthesized with a yield of 21%. The optimal labeling conditions for the automated synthesis of [¹⁸F]FMISO was 10 mg of precursor in acetonitrile (2 ml heated at 105°C for 360 s, followed by heating at 75°C for 280 s and hydrolysis with 1 N HCl at 105°C for 300 s. Using 3.7 GBq of [¹⁸F]F⁻ as a starting activity, [¹⁸F]FMISO was obtained with high end-of-synthesis (EOS) radiochemical yields of 58.5±3.5% for 60.0±5.2 min with high-performance liquid chromatography (HPLC) purification. When solid-phase purification steps were added, the EOS radiochemical yields were 54.5±2.8% (337±25 GBq/μmol) for 70.0±3.8 min (n=10 for each group, decay-corrected). With a high starting radioactivity of 37.0 GBq, we obtained radiochemical yields of 54.4±2.9% and 52.8±4.2%, respectively (n=3). The solid-phase purification removed unreacted [¹⁸F]fluoride and polar impurities before the HPLC procedure. Long-term tests showed a good stability of 98.2±1.5%. This new automated synthesis procedure combines high and reproducible yields with the advantage of using a disposable cassette system.     

Simple devices for dispensing [18F]FDG.

High dose [18F]FDG is prepared routinely using an automated synthesizer. Accordingly, an automated dispenser is needed to dispense [18F]FDG at the desired dose while reducing the operator's radiation exposure, and no dispenser capable of vial-to-vial and vial-to-syringe dispensing in one system is commercially available. Here, we describe simple devices for the vial-to-vial and vial-to-syringe dispensing of [18F]FDG.     

Grading liposarcomas with PET using [18F]FDG

Five patients with liposarcomas of the thigh were studied using positron emission tomography (PET) with [18F]2-deoxy-2-fluoroglucose (FDG). There were three low-grade tumors (all National Cancer Institute Grade 1 myxoid liposarcomas) and two high-grade tumors (both pleomorphic liposarcomas, Grades 2 and 3). The low-grade liposarcomas were easily identified with an average dose uptake ratio (DUR) of 1.38 +/- 0.045 (mean +/- SD). The high-grade lesions were more avid for FDG with a mean DUR of 2.45 +/- 0.24. There was a significant difference (p = 0.004) in the DUR for the two groups and the histological grade of malignancy was highly correlated with the DUR for FDG (Rho = 0.89). These findings suggest that FDG-PET may be useful for distinguishing between low-grade and high-grade liposarcomas.     

[99mTc]3PRGD2 for integrin receptor imaging of esophageal cancer: a comparative study with [18F]FDG PET/CT

Annals of Nuclear Medicine - This study was designed to investigate the efficacy of 99mtechnetium-three polyethylene glycol spacers-arginine–glycine–aspartic acid ([99mTc]3PRGD2) in the...     

Registration of [18F]FDG microPET and small-animal MRI

This paper describes a voxel-based method for coregistering microPET [(18)F]FDG emission images and MRI data without the need for fiducial markers. [(18)F]FDG has a well-characterized biodistribution in normal mice and thus may be useful for image registration. Female BALB/c mice were implanted with EMT-6 mouse mammary carcinoma 1 week prior to imaging. Three imaging sessions were performed in which a [(18)F]FDG microPET-R4 emission scan was taken followed by small-animal MRI with and without Gd-based contrast agent. MicroPET and MR images were registered using a voxel-based algorithm that computes rigid-body image transformations based on the alignment of intensity gradients. Registration accuracy was assessed on the basis of dual-modality external fiducial line sources incorporated into the mouse bed. The root mean square (rms) registration errors were 0.74 mm translation and 1.44 degrees rotation without contrast and 0.72 mm translation and 0.89 degrees rotation with contrast. Generally, good registration was evident upon inspection of fused microPET/MR images. Accurate automated, voxel-based microPET-MR image coregistration, utilizing image intensity gradients, is feasible. Our technique requires no manual identification of image features and makes no use of surgically implanted or external fiducial markers or stereotactic apparatus.     

Radioactive byproducts in [18O]H2O used to produce 18F for [18F]FDG synthesis.

Potential radioactive byproducts in [(18)O]H(2)O irradiated with 9.6 MeV protons to produce (18)F were analyzed theoretically and experimentally. Twenty two nuclear reaction cross sections included in the National Nuclear Data Center's (NNDC) data base were selected from the possible nuclear reactions between 9.6 MeV protons and a silver havar target. Ten radionuclides: (52)Mn, (55)Fe, (55)Co, (56)Co, (57)Co, (58)Co, (59)Ni, (95)Tc, (96)Tc and (109)Cd were detected experimentally in [(18)O]H(2)O by using high purity germanium semiconductor detectors. The activities of the 10 radionuclides were distributed between 4B q and 1.2k Bq. These activities were less than the reference values given in the International Basic Safety Standards. The radionuclides derived from nuclear reactions between a silver target body and 9.6 MeV protons at a beam current 25 microA for 60 min irradiation would be exempt from restrictions for radioactive waste. The purified [(18)F]FDG prepared from (18)F produced by irradiating a silver havlar target with 9.6 MeV protons was not contaminated by the radionuclides.     

Biodistribution,pharmacokinetics and PET Imaging of [18F]FMISO, [18F]FDG and [18F]FAc in a sarcoma- and inflammation-bearing mouse model

2-Deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG), [¹⁸F]fluoroacetate ([¹⁸F]FAc) and [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) were all considered to be positron emission tomography (PET) probes for tumor diagnosis, though based on different rationale of tissue uptake. This study compared the biodistribution, pharmacokinetics and imaging of these three tracers in a sarcoma- and inflammation-bearing mouse model.MethodsC3H mice were inoculated with 2×10⁵ KHT sarcoma cells in the right thigh on Day 0. Turpentine oil (0.1 ml) was injected in the left thigh on Day 11 to induce inflammatory lesion. Biodistribution, pharmacokinetics and microPET imaging of [¹⁸F]FMISO, [¹⁸F]FDG and [¹⁸F]FAc were performed on Day 14 after tumor inoculation.ResultsThe inflammatory lesions were clearly visualized by [¹⁸F]FDG/microPET and autoradiography at 3 days after turpentine oil injection. The tumor-to-muscle and inflammatory lesion-to-muscle ratios derived from microPET imaging were 6.79 and 1.48 for [¹⁸F]FMISO, 8.12 and 4.69 for [¹⁸F]FDG and 3.72 and 3.19 for [¹⁸F]FAc at 4 h post injection, respectively. Among these, the tumor-to-inflammation ratio was the highest (4.57) for [¹⁸F]FMISO compared with that of [¹⁸F]FDG (1.73) and [¹⁸F]FAc (1.17), whereas [¹⁸F]FAc has the highest bioavailability (area under concentration of radiotracer vs. time curve, 116.2 h×percentage of injected dose per gram of tissue).ConclusionsMicroPET images and biodistribution studies showed that the accumulation of [¹⁸F]FMISO in the tumor is significantly higher than that in inflammatory lesion at 4 h post injection. [¹⁸F]FDG and [¹⁸F]FAc delineated both tumor and inflammatory lesions. Our results demonstrated the potential of [¹⁸F]FMISO/PET in distinguishing tumor from inflammatory lesion.     

Non-invasive estimation of hepatic glucose uptake from [18F]FDG PET images using tissue-derived input functions

Purpose

The liver is perfused through the portal vein and hepatic artery. Quantification of hepatic glucose uptake (HGU) using PET requires the use of an input function for both the hepatic artery and portal vein. The former can be generally obtained invasively, but blood withdrawal from the portal vein is not practical in humans. The aim of this study was to develop and validate a new technique to obtain quantitative HGU by estimating the input function from PET images.

Methods

Normal pigs (n?=?12) were studied with [¹⁸F]FDG PET, in which arterial and portal blood time-activity curves (TAC) were determined invasively to serve as reference measurements. The present technique consisted of two characteristics, i.e. using a model input function and simultaneously fitting multiple liver tissue TACs from images by minimizing the residual sum of square between the tissue TACs and fitted curves. The input function was obtained from the parameters determined from the fitting. The HGU values were computed by the estimated and measured input functions and compared between the methods.

Results

The estimated input functions were well reproduced. The HGU values, ranging from 0.005 to 0.02 ml/min per ml, were not significantly different between the two methods (r?=?0.95, p?<?0.001). A Bland-Altman plot demonstrated a small overestimation by the image-derived method with a bias of 0.00052 ml/min per g for HGU.

Conclusion

The results presented demonstrate that the input function can be estimated directly from the PET image, supporting the fully non-invasive assessment of liver glucose metabolism in human studies.     

Chemical impurities in [18F]FDG preparations produced by solid-phase 18F-fluorination

[18F]FDG was produced by solid-phase 18F-fluorination (resin method) and chemical impurities were determined in the [18F]FDG preparations by ion chromatography. The major chemical impurities were D-glucose (90.5 +/- 6.4 microg/mL), 2-chloro-2-deoxy-D-glucose (11.8 +/- 2.7 microg/mL), and D-mannose (1.7 +/- 0.7 microg/mL), which were expected to be present by considering the synthetic routes. An FDG mass (0.5 +/- 0.2 microg/mL) was also detected in the preparations. No notable radiochemical impurities, including 2-[18F]fluoro-2-deoxy-D-mannose, were detected in the [18F]FDG preparations. Thus, the levels of several chemical impurities were determined in the [18F]FDG preparations produced by solid-phase 18F-fluorination.     

Differential uptake of [18F]FET and [3H]l-methionine in focal cortical ischemia

Amino acids such as [(11)C-methyl]l-methionine are particularly useful in brain tumor diagnosis, but unspecific uptake (e.g., in cerebral ischemia) has been reported. O-(2-[(18)F]fluoroethyl)-l-tyrosine ([(18)F]FET) shows a clinical potential similar to that of l-methionine (MET) in brain tumor diagnosis but is applicable on a wider clinical scale. The aim of this study was to evaluate the uptake of [(18)F]FET and [(3)H]MET in focal cortical ischemia in rats by dual-tracer autoradiography. METHODS: Focal cortical ischemia was induced in 25 CDF rats using the photothrombosis (PT) model. At different time points up to 6 weeks after the induction of PT, [(18)F]FET and [(3)H]MET were injected intravenously. Additionally, contrast-enhanced magnetic resonance imaging (MRI) was performed in 10 animals. One hour after tracer injection, brains were cut in coronal sections and evaluated by dual-tracer autoradiography. Lesion-to-brain (L/B) ratios were calculated by dividing the maximal uptake in the lesion by the mean uptake in the brain. An L/B ratio of >2.0 was considered indicative of pathological uptake. Histological slices were stained by cresyl violet and supplemented by immunostainings for glial fibrillary acidic protein (GFAP) and CD68 in selected cases. RESULTS: A variably increased uptake of both tracers was observed in the PT lesion and its demarcation zone up to 7 days after PT for [(18)F]FET and up to 6 weeks for [(3)H]MET. The cutoff level of 2.0 was exceeded in 12/25 animals for [(18)F]FET and in 18/25 animals for [(3)H]MET. Focally increased tracer uptake matched contrast enhancement in MRI in 3/10 cases for [(18)F]FET and in 5/10 cases for [(3)H]MET. Immunohistochemical staining in lesions with differential uptake of [(18)F]FET and [(3)H]MET revealed that selective uptake of [(18)F]FET was associated with GFAP-positive astrogliosis while selective [(3)H]MET uptake correlated with CD68-positive macrophage infiltration. CONCLUSIONS: [(18)F]FET, like [(3)H]MET, may exhibit significant uptake in the periphery of cortical infarctions, which has to be considered in the differential diagnosis of unknown brain lesions. There are discrepancies between [(18)F]FET and [(3)H]MET uptake in the area of infarctions that appear to be caused by the preferential uptake of [(18)F]FET in reactive astrocytes versus the preferential uptake of [(3)H]MET in macrophages.     

Correlation of Glut-1 glucose transporter expression with [18F]FDG uptake in non-small cell lung cancer

Positron emission tomography (PET) with [¹⁸F]2-fluoro-2-deoxy-D-glucose (FDG) may show negative results for bronchioloalveolar lung carcinoma. We investigated the correlation of Glut-1 glucose transporter expression with [¹⁸F]FDG uptake in non-small cell lung cancer. Thirty-two patients with 34 non-small cell lung cancers (7 bronchioloalveolar carcinomas, 23 non-bronchioloalveolar adenocarcinomas, 3 squamous cell carcinomas, and 1 adenosquamous cell carcinoma) were studied. Final diagnoses were established by histology (via thoracotomy) in all patients. [¹⁸F]FDG PET was performed 40 min after i.v. injection of 185 MBq [¹⁸F]FDG. For semi-quantitative analysis of [¹⁸F]FDG uptake, standardized uptake values (SUVs) were calculated. Glut-1 expression was studied in terms of the immunohistochemistry of paraffin sections using anti-Glut-1 antibody to determine the intensity (0-3) of Glut-1 immunoreactivity and percentage of the Glut-1-positive area. Of seven bronchioloalveolar carcinomas, six (85.7%) were negative for the expression of Glut-1, while only one (4.3%) of 23 non-bronchioloalveolar adenocarcinomas was negative (P<0.0001). The percentages of Glut-1-positive area, as well as the SUVs, were significantly lower in bronchioloalveolar carcinomas (n=7) (2.86%lj.56% and 1.25ǂ.75, respectively) than in non-bronchioloalveolar adenocarcinomas (n=23) (54.83%ᆭ.64%, P<0.0001, and 3.94ǃ.93, P=0.001, respectively). The degree of cell differentiation correlated with the percentage of Glut-1-positive area and SUVs in adenocarcinoma of the lung. Correlations between SUVs and the intensity of Glut-1 immunoreactivity were also significant (intensities 0 and 1, n=11, SUV 1.47ǂ.63; intensities 2 and 3, n=23, SUV 4.78DŽ.13; P<0.0001). The percentage of Glut-1-positive area correlated significantly with SUVs (n=34, r=0.658, P<0.01). Overexpression of Glut-1 correlated with high [¹⁸F]FDG uptake. These findings suggest that Glut-1 expression is related to [¹⁸F]FDG uptake in non-small cell lung cancer. Glut-1 expression, as well as [¹⁸F]FDG uptake, correlated with the degree of cell differentiation in adenocarcinomas, and both Glut-1 expression and [¹⁸F]FDG uptake were significantly lower in bronchioloalveolar carcinomas than in non-bronchioloalveolar carcinomas.     

Preoperative [18F]FDG PET/CT maximum standardized uptake value predicts recurrence of uterine cervical cancer

Purpose  

To determine if preoperative [¹⁸F]FDG-PET/CT imaging has prognostic significance in patients with uterine cervical cancer.     

Effect of hypoxia on the uptake of [methyl-3H]choline, [1-14C] acetate and [18F]FDG in cultured prostate cancer cells

IntroductionCholine, acetate and glucose ([2-¹⁸F]fluoro-2-deoxyglucose, [¹⁸F]FDG) analogs are under investigation as positron emission tomography (PET) tracers for the imaging of prostate cancer; however, their response to tumor hypoxia has not been clarified.MethodsThe uptake of [methyl-³H]choline, [1-¹⁴C]acetate and [¹⁸F]FDG was monitored in androgen-independent PC-3 cells and androgen-sensitive LNCaP cells under aerobic or anoxic conditions. The effect of androgen depletion was also examined.ResultsPC-3 cells exhibited aerobic choline and acetate uptake five to six times higher than FDG uptake, whereas LNCaP cells showed choline uptake 2.2-fold higher than acetate uptake and 10-fold higher than FDG uptake. After 4 h of anoxia, PC-3 cells showed an 85% increase in FDG uptake, a 15% decrease in choline uptake and a 36% increase in acetate uptake, whereas LNCaP cells showed a 212% increase in FDG uptake, a 28% decrease in choline uptake and no change in acetate uptake. Androgen depletion resulted in a marked decrease in the uptake of all tracers in LNCaP cells but no changes in PC-3 cells.ConclusionIn aerobic conditions, both PC-3 and LNCaP cells exhibited an order of uptake preference as follows: choline>acetate>FDG. In hypoxic cells, the order is reversed, reflecting diverse biochemical responses to hypoxia. These findings may help to explain PET imaging findings of the diverse responses of these tracers in different stages and locations of prostate cancer. Androgen depletion markedly suppressed the uptake of all three tracers in LNCaP cells, which suggests the potential for underestimation of the disease state when PET imaging is performed subsequent to antiandrogen therapy.     

Synthesis of [18F]2-deoxy-2-fluoro-d-glucose and [18F]3-deoxy-3-fluoro-d-glucose with [18F]fluoride from a water target

A combined study of the labelling methods of two important glucose-derivatives i.e. [¹⁸F]2-deoxy-2-fluoro-d-glucose ([¹⁸F]2-FDG) and [¹⁸F]3-deoxy-3-fluoro-d-glucose ([¹⁸F]3-FDG) is described. Using [¹⁸F]fluoride as reacting agent produced in a water target via the ¹⁸O(p, n)¹⁸F and ¹⁶O(³He, p)¹⁸F reaction, respectively, nucleophilic aliphatic substitution was performed at the corresponding precursors i.e. methyl-4-,6-O-benzylidene-2,3-O-cyclic-sulfato-β-d-mannopyranoside and 1,2:5,6-di-O-isopropylidene-3-O-trifluoromethanesulfonyl-α-d-allofuranose. After hydrolysis of the corresponding intermediate [¹⁸F]2-FDG and [¹⁸F]3-FDG were obtained as injectable solutions with yields of 22 and 40% (decay corrected), respectively.     

Fluorine-18 radiopharmaceuticals beyond [18F]FDG for use in oncology and neurosciences

Positron emission tomography (PET) is a rapidly expanding clinical modality worldwide thanks to the availability of compact medical cyclotrons and automated chemistry for the production of radiopharmaceuticals. There is an armamentarium of fluorine-18 (¹⁸F) tracers that can be used for PET studies in the fields of oncology and neurosciences. However, most of the ¹⁸F-tracers other than 2-deoxy-2-[18F]fluoro-D-glucose (FDG) are in less than optimum human use and there is considerable scope to bring potentially useful ¹⁸F-tracers to clinical investigation stage.The International Atomic Energy Agency (IAEA) convened a consultants' group meeting to review the current status of ¹⁸F-based radiotracers and to suggest means for accelerating their use for diagnostic applications. The consultants reviewed the developments including the synthetic approaches for the preparation of ¹⁸F-tracers for oncology and neurosciences. A selection of three groups of ¹⁸F-tracers that are useful either in oncology or in neurosciences was done based on well-defined criteria such as application, lack of toxicity, availability of precursors and ease of synthesis. Based on the recommendations of the consultants' group meeting, IAEA started a coordinated research project on “Development of ¹⁸F radiopharmaceuticals (beyond [¹⁸F]FDG) for use in oncology and neurosciences” in which 14 countries are participating in a 3-year collaborative program. The outcomes of the coordinated research project are expected to catalyze the wider application of several more ¹⁸F-radiopharmaceuticals beyond FDG for diagnostic applications in oncology and neurosciences.