Absolute quantification of regional cerebral glucose utilization in mice by 18F-FDG small animal PET scanning and 2-14C-DG autoradiography.

The purpose of this study was to evaluate the feasibility of absolute quantification of regional cerebral glucose utilization (rCMR(glc)) in mice by use of (18)F-FDG and a small animal PET scanner. rCMR(glc) determined with (18)F-FDG PET was compared with values determined simultaneously by the autoradiographic 2-(14)C-DG method. In addition, we compared the rCMR(glc) values under isoflurane, ketamine and xylazine anesthesia, and awake states. METHODS: Immediately after injection of (18)F-FDG and 2-(14)C-DG into mice, timed arterial samples were drawn over 45 min to determine the time courses of (18)F-FDG and 2-(14)C-DG. Animals were euthanized at 45 min and their brain was imaged with the PET scanner. The brains were then processed for 2-(14)C-DG autoradiography. Regions of interest were manually placed over cortical regions on corresponding coronal (18)F-FDG PET and 2-(14)C-DG autoradiographic images. rCMR(glc) values were calculated for both tracers by the autoradiographic 2-(14)C-DG method with modifications for the different rate and lumped constants for the 2 tracers. RESULTS: Average rCMR(glc) values in cerebral cortex with (18)F-FDG PET under normoglycemic conditions (isoflurane and awake) were generally lower (by 8.3%) but strongly correlated with those of 2-(14)C-DG (r(2) = 0.95). On the other hand, under hyperglycemic conditions (ketamine/xylazine) average cortical rCMR(glc) values with (18)F-FDG PET were higher (by 17.3%) than those with 2-(14)C-DG. Values for rCMR(glc) and uptake (percentage injected dose per gram [%ID/g]) with (18)F-FDG PET were significantly lower under both isoflurane and ketamine/xylazine anesthesia than in the awake mice. However, the reductions of rCMR(glc) were markedly greater under isoflurane (by 57%) than under ketamine and xylazine (by 19%), whereas more marked reductions of %ID/g were observed with ketamine/xylazine (by 54%) than with isoflurane (by 37%). These reverse differences between isoflurane and ketamine/xylazine may be due to competitive effect of (18)F-FDG and glucose uptake to the brain under hyperglycemia. CONCLUSION: We were able to obtain accurate absolute quantification of rCMR(glc) with mouse (18)F-FDG PET imaging as confirmed by concurrent use of the autoradiographic 2-(14)C-DG method. Underestimation of rCMR(glc) by (18)F-FDG in normoglycemic conditions may be due to partial-volume effects. Computation of rCMR(glc) from (18)F-FDG data in hyperglycemic animals may require, however, alternative rate and lumped constants for (18)F-FDG.     

The FDG lumped constant in normal human brain.

The lumped constant (LC) is a correction factor used to infer glucose metabolic rate (MR(glc)) from FDG metabolic rate (MR(FDG)). METHODS: LC was determined in normal brain in 10 subjects (4 male, 6 female) by measuring regional MR(glc) and MR(FDG) independently using 1-(11)C-glucose and (18)F-FDG with dynamic positron tomographic imaging, arterial blood sampling, and region-of-interest time-activity curve analysis with appropriate compartmental models. RESULTS: The mean LC (+/-SD) for normal brain was found to be 0.89 +/- 0.08. The value for cerebellum was slightly lower, 0.78 +/- 0.11 (P = 0.006; 2-tailed paired t test). CONCLUSION: The LC values determined in this study are considerably higher than older values in the literature, probably because of methodologic differences, but agree with a recent study by Hasselbalch.     

Effect of rolipram on relative 14C-deoxyglucose uptake in inflammatory lesions and skeletal muscle

Purpose ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become a useful imaging tool for inflammatory diseases. In this study we investigated the effects of rolipram, a selective phosphodiesterase type 4 inhibitor, on ¹⁴C-deoxyglucose (DG) uptake in inflammatory lesions and other normal tissues, and attempted to improve the inflammation/muscle ratio.Methods To induce inflammation, mice were inoculated with turpentine oil. Inflammation-bearing mice were pretreated with rolipram (3 mg/kg i.p. or i.v.), and the effect on ¹⁴C-DG uptake was measured using a tissue dissection method and autoradiography. The inflammatory tissue samples were stained with haematoxylin and eosin.Results Rolipram (3 mg/kg i.p.) significantly decreased ¹⁴C-DG uptake in normal tissues like brain, heart and skeletal muscle (brain 31%, heart 60%, skeletal muscle 61%). On the other hand, ¹⁴C-DG uptake in inflammatory lesions was not significantly altered by pretreatment with rolipram. The inflammation/muscle ratio of ¹⁴C-DG uptake (30 min after tracer injection) was enhanced from 1.1 to 2.8 by rolipram. An autoradiographic study revealed heterogeneous distributions of ¹⁴C-DG in the inflammatory lesions and skeletal muscle of animals that were not treated with rolipram. Pretreatment with rolipram significantly attenuated the intramuscular distribution of ¹⁴C-DG, producing a relatively homogeneous distribution of radioactivity.Conclusion These results indicate that rolipram decreased ¹⁴C-DG uptake in skeletal muscle by activation of the adenosine 3,5-cyclic monophosphate system, whereas ¹⁴C-DG uptake in inflammatory lesions was not significantly altered. Therefore, rolipram may be a valuable tool for improving the visualisation of inflammatory lesions in clinical PET studies employing FDG.     

Comparison of regional blood-brain transport kinetics between glucose and fluorodeoxyglucose.

The fluorodeoxyglucose (FDG) method for estimating regional cerebral glucose metabolic rate (LCMRglc) requires that a fixed relationship (the "lumped constant") exists between net FDG and glucose (GLC) extraction throughout the brain. In addition to the relative rate of metabolism between FDG and GLC, this assumed constant is affected by the relative rate of blood-to-brain FDG transport compared to that of glucose. However, little data is available regarding the regional stability of the FDG versus GLC transport-rate relationship. We therefore used high resolution, quantitative dual-tracer digital autoradiography to directly compare the blood-to-brain transport rate constants (K1) of radiolabeled GLC and FDG in normal and pharmacologically-stimulated rats. The rats were given 45 sec terminal intravenous infusions of a mixture of 18F-FDG and 14C-GLC. Autoradiograms of the brain representing the FDG and GLC tracer concentrations were produced, digitized, and converted into digital images of K1. We found that the global K1 values of FDG and GLC were not significantly different from each other. However, detailed analysis revealed that some structures in the normal animals, such as the hippocampus and cerebellum, had different quantitative patterns of FDG transport compared to GLC transport. Thus, our results indicate that the relationship between GLC and FDG transport is not uniform throughout the brain as has previously been assumed. This observation suggests that regional variations in the type and distribution of glucose transporters may exist and that the fluorodeoxyglucose "lumped constant" may vary somewhat among different brain regions.     

Kinetic characterization of hexokinase isoenzymes from glioma cells: implications for FDG imaging of human brain tumors

Quantitative imaging of glucose metabolism of human brain tumors with PET utilizes 2-[(18)F]-fluorodeoxy-D-glucose (FDG) and a conversion factor called the lumped constant (LC), which relates the metabolic rate of FDG to glucose. Since tumors have greater uptake of FDG than would be predicted by the metabolism of native glucose, the characteristic of tumors that governs the uptake of FDG must be part of the LC. The LC is chiefly determined by the phosphorylation ratio (PR), which is comprised of the kinetic parameters (Km and Vmax) of hexokinase (HK) for glucose as well as for FDG (LC proportional to (Km(glc) x Vmax(FDG))/(Km(FDG) x Vmax(glc)). The value of the LC has been estimated from imaging studies, but not validated in vitro from HK kinetic parameters. In this study we measured the kinetic constants of bovine and 36B-10 rat glioma HK I (predominant in normal brain) and 36B-10 glioma HK II (increased in brain tumors) for the hexose substrates glucose, 2-deoxy-D-glucose (2DG) and FDG. Our principal results show that the KmGlc < KmFDG < Km2DG and that PR2DG < PRFDG. The FDG LC calculated from our kinetic parameters for normal brain, possessing predominantly HK I, would be higher than the normal brain LC predicted from animal studies using 2DG or human PET studies using FDG or 2DG. These results also suggest that a shift from HK I to HK II, which has been observed to increase in brain tumors, would have little effect on the value of the tumor LC.     

Distinct different intra-tumor distribution of FDG between early phase and late phase in mouse fibrosarcoma

An early image of intra-tumor distribution of 14C-labeled fluorodeoxy glucose (14C-FDG) was compared with a late image of 18F-labeled FDG (18F-FDG) using mouse fibrosarcoma. Heterogeneous intra-tumor distribution of 14C-FDG was observed 1 minute post injection of the tracer, whereas relatively homogeneous distribution of 18F-FDG was seen 30 minutes later. 14C-FDG was particularly taken up in the peripheral part of the tumor immediately after the tracer injection. A gradual and significant increase in 18F-FDG accumulation with time was seen in the central part of tumor, which indicated an enhancement of anaerobic glycolysis. An initial uptake of 18F-FDG was also compared with distribution of 14C-iodoantipyrine and 14C-thymidine uptake. Intratumoral distribution of initial uptake of 18F-FDG showed almost the same regional distribution of 14C-iodoantipyrine. A similar distribution of 14C-thymidine as the initial uptake of 18F-FDG was also observed. These results indicated that a high initial FDG uptake area seemed to be highly proliferative. A significant difference in the intratumoral distribution of FDG between early phase and late phase seemed to be related to heterogeneous biological characteristics of tumor cells.     

Glucose uptake and lumped constant variability in normal human hearts determined with [18F]fluorodeoxyglucose

Background  Myocardial glucose uptake can be measured with [¹⁸F]fluoro-2-deoxyglucose (FDG) and positron emission tomography (PET). However, changes of myocardial metabolism may alter the ratio between the net rates of FDG and glucose uptake, known as the lumped constant. We tested the hypothesis that the variability of the lumped constant determined in animals explains the disagreement between human net myocardial glucose uptake calculated from aortocoronary sinus dificits and measured with PET. Methods and Results  In the three-compartment model of glucose transfer into cells, the lumped constant is a function of the relationship between the net and the unidirectional rates of uptake of glucose and glucose tracers such as FDG. Using this principle, validated in the human brain and the animal heart under experimental conditions, we estimated the lumped constant of the human heart by PET in 10 healthy men under several metabolic conditions established by altering the circulating insulin level during a euglycemic clamp and with somatostatin and heparin infusions. The lumped constant varied systematically between 0.44 and 1.35. At insulin levels below 100 pmol/L, free fatty acids were inversely related to serum insulin levels and the lumped constant increased linearly with serum insulin concentration. At insulin levels above 100 pmol/L, free fatty acids were suppressed and the lumped constant varied in inverse proportion to the insulin level. When the lumped constant was estimated in this manner, net myocardial glucose uptake agreed with that determined in previous measurements of blood flow and aortocoronary sinus deficit. Conclusion  In the intact human organism, the cardiac lumped constant varies with the metabolic condition, as predicted from studies of the brain and animal heart under experimental conditions. Supported by grants from the Danish Heart Foundation and the Research Foundation of Aarhus University.     

Augmented uptake of 2-C-14-D-deoxyglucose in reversibly-injured myocardium

We studied the cardiac uptake of 2-14C-D-deoxyglucose (14C-DG) in 6 dogs subjected to a 15 min left anterior descending coronary artery (LAD) occlusion followed by 30 min reflow. Coronary arterial flows during occlusion were determined with 46Sc microspheres. After 30 min reflow, 50 microCi 14C-DG were given intravenously to determine cardiac uptake. The animal was killed 45 min later and 46Sc counts/min were determined in gamma and beta counters. Quenching was determined with non radioactive blood for both isotopes in the beta counter. Contribution of 46Sc counts/min to the 14C channel was subtracted. 14C uptake was in DPM/g and was higher in the cardiac ischemic regions of four of the six dogs. In three of the six animals there was an inverse curvilinear relation between 14C-DG cardiac uptake and occlusion flow. This observation was further confirmed by high resolution autoradiography, indicating that enhanced cardiac uptake of radiolabeled DG may be a useful positron emission tomographic marker for reversible myocardial ischemia.     

<Superscript>99m</Superscript>Tc-Hynic-annexin V imaging to evaluate inflammation and apoptosis in rats with autoimmune myocarditis

Inflammation and cell death are two important components of myocarditis. We evaluated the distribution of inflammation and apoptotic cell death in rats with autoimmune myocarditis using two radiotracers - technetium-99m Hynic-annexin V ((99m)Tc-annexin) as a marker of apoptotic cell death and carbon-14 deoxyglucose ((14)C-DG) as a marker of inflammation - in comparison with histologic findings. Three, 7 and 14 weeks after immunization with porcine cardiac myosin (acute, subacute, and chronic phases, respectively) (99m)Tc-annexin and (14)C-DG were injected. The uptake in the total heart was determined as the percentage of injected dose per gram (% ID/g) by tissue counting. Dual-tracer autoradiography with (99m)Tc-annexin and (14)C-DG was performed. The distribution of each of these agents was compared with the results of hematoxylin and eosin staining to identify areas of inflammation, and TUNEL staining to identify areas of apoptosis. Total cardiac uptake of (99m)Tc-annexin in the acute phase of myocarditis was significantly higher than that in normal rats (1.28%+/-0.30% vs 0.46%+/-0.01%; P<0.0001); it then decreased in the subacute phase and reached normal levels (0.56%+/-0.08% vs 0.60%+/-0.08%; P=NS). Total cardiac uptake of (14)C-DG in the acute phase of myocarditis was significantly higher than that in normal rats (2.78%+/-0.95% vs 1.02%+/-0.25%; P<0.0001); it then decreased in the subacute phase, but still remained higher than in controls (2.06%+/-0.52% vs 1.37%+/-0.46%; P<0.05). Using autoradiography and staining of tissue specimens, it was found that most histologic inflammatory foci corresponded to areas of high (14)C-DG uptake; some also corresponded to areas of high (99m)Tc-annexin uptake in the acute phase of myocarditis. (99m)Tc-annexin localization was strongly correlated with the number of TUNEL-positive cells (P<0.0001, r=0.83), but the uptake of (14)C-DG showed no relationship with it. There is a marked difference in the distribution of inflammation and apoptotic cell death in the myocardium of animals with immune myocarditis. These changes are mirrored by the localization of (14)C-DG and (99m)Tc-annexin. Sites of inflammation and zones of apoptotic cell death change over the course of immune myocarditis.     

Biodistribution of 99Tcm-labelled 5-thio-D-glucose

We studied the biodistribution and tumour localization of 99Tcm-labelled-5-thio-D-glucose (99Tcm-TG). 5-Thio-D-glucose was labelled with 99Tcm by direct stannous ion reduction. The biodistribution of 99Tcm-TG was investigated in normal rabbits and in mice bearing experimental tumours. In rabbits, the plasma and clearance of 99Tcm-TG was 14.5 +/- 2.0 and 11.3 +/- 3.0 ml.min-1 respectively. Urinary excretion at 1 h was 53 +/- 5%. 99Tcm-TG was injected intravenously in mice bearing MC26 colon carcinoma and tissue samples were analysed by gamma scintillation counting at various times. Uptake of 99Tcm-TG in tumour at 1 and 3 h was 1.6 +/- 0.3% and 1.2 +/- 0.3%; the tumour to muscle ratios were 2.7:1 and 4:1 respectively. The autoradiographic biodistribution of 99Tcm-TG in MX-1 human breast xenografted nude mice showed more persistent tumour uptake of 99Tcm-TG than 14C-2-deoxyglucose (14C-DG). 99Tcm-TG accumulated in the centre of the tumours; 14C-DG was decreased in this central region probably because of zones of infarction on necrosis. The discordance between the tumour uptake of 99Tcm-TG and 14C-DG indicates that 99Tcm-TG does not act like a glucose analog, suggesting 99Tcm-TG avidity for zones of infarction or necrosis. The further study of 99Tcm-TG in tumours and ischaemic injury is warranted.     

A method for measuring cerebral glucose metabolism in vivo by 13C-NMR spectroscopy.

Current methods for estimating the rate of cerebral glucose utilization (CMR(glc)) typically measure metabolic activity for 40 min or longer subsequent to administration of [(13)C]glucose, 2-[(14)C]deoxyglucose, or 2-[(18)F]deoxyglucose. We report preliminary findings on estimating CMR(glc) for a period of 15 min by use of 2-[6-(13)C]deoxyglucose. After a 24-hr fast, rats were anesthetized, infused with [1-(13)C]glucose for 50 min, and injected with 2-[6-(13)C]deoxyglucose (500 mg/kg). During the subsequent 12.95 min the estimated value of CMR(glc) was 0.6 +/- 0.4 micromol/min/g (mean +/- SD, N = 7), in agreement with values reported for anesthetized rats studied with the 2-[(14)C]deoxyglucose method and other (13)C-NMR methods that measure CMR(glc). In rats injected with bicuculline methiodide (a known stimulant of CMR(glc)), CMR(glc) increased by more than 75% during 12.95 min following injection of bicuculline (Wilcoxon signed rank test, P = 0.042, N = 8).     

Comparison of intratumoral distribution of 99mTc-MIBI and deoxyglucose in mouse breast cancer models.

The aims of this study were to evaluate the distribution of 99mTc-methoxyisobutylisonitrile (MIBI) in 3 animal models of breast cancer, the effect of radiotherapy on 99mTc-MIBI uptake, and the relationship between uptake and microvessel density. METHODS: We used syngeneic, subcutaneously transplanted FM3A, MM48, and Ehrlich mouse breast cancer. 99mTc-MIBI and FDG were injected intravenously, and tumor uptake was measured 30 min later. Double-tracer macroautoradiography (ARG) images were prepared with 99mTc-MIBI and 2-deoxy-D-[1-14C]-glucose (14C-DG), analyzed quantitatively, and compared with histology. The radiotherapeutic effects of 20 Gy x-ray irradiation were monitored by measuring tumor volume, tumor uptake, and ARG findings using 99mTc-MIBI and FDG in FM3A tumors. Microvessel density was quantified by immunohistochemical staining for CD34 and compared with ARG using 99mTc-MIBI in FM3A tumors. RESULTS: FM3A, MM48, and Ehrlich tumors showed different growth rates and radiosensitivities. Uptake of FDG, but not of 99mTc-MIBI, correlated significantly with growth rates. Compared with 14C-DG, 99mTc-MIBI accumulated more in cancer cells and less in infiltrating fibroblasts and macrophages in all tumor models. Irradiation significantly decreased 99mTc-MIBI uptake, but a rapid increase was noted at recurrence on day 7. Changes in FDG uptake were not significant at recurrence. Microvessel density in tumor tissue correlated significantly with 99mTc-MIBI uptake on ARG. CONCLUSION: Accumulation of 99mTC-MIBI in cancer cells is preferential and can be used as a sensitive marker to examine the response to radiotherapy. Angiogenesis seems to enhance accumulation of 99mTc-MIBI in tumors. These characteristics may be favorable for tumor imaging using 99mTC-MIBI.     

An experimental study onO-[18F]fluoromethyl-L-tyrosine for differentiation between tumor and inflammatory tissues

OBJECTIVE: O-[18F]fluoromethyl-L-tyrosine (18F-FMT) is a recently developed tumor-detecting agent with simple preparation and high radiochemical yields. The aim of this study was to assess the potency of 18F-FMT for differentiating tumor and inflammatory tissues using an animal model with an implanted tumor and experimentally induced inflammatory foci. METHODS: An ascites hepatoma cell line, AH109A, turpentine oil and Staphylococcus aureus were inoculated subcutaneously into Donryu rats as a tumor model, aseptic inflammation model and bacterial infection model, respectively. The biodistribution of radioactivity was assessed in rats at 5, 10, 30, 60, and 120 min after injection with 18F-FMT. Dual tracer whole-body and macro autoradiographies were performed 60 min after injection with a mixture of 18F-FMT and 2-deoxy-D-[1-14C]glucose (14C-DG). RESULTS: Tumor uptake of 18F-FMT was on average 1.27% injected dose per gram of tissue (%ID/g) and 1.43% ID/g at 30 min and 60 min, respectively and significantly higher than that in other normal tissues, except the pancreas (3.48% ID/g at 60 min). The uptakes in the aseptic and bacterial inflammatory tissues were very low and were not different from those of the background tissues. Dual tracer whole-body and macro autoradiographic studies showed that tumor uptake of 18F-FMT was clearly higher than uptake by the other tissues, while 18F-FMT accumulated much less both in aseptic and bacterial inflammatory tissues. In contrast, the 14C-DG images showed high accumulations not only in tumors but also in aseptic and bacterial inflammatory tissues. CONCLUSION: 18F-FMT seems to be a promissing tracer for the differentiation between tumor and inflammation because of higher specificity to tumor.     

Augmented uptake of 2-C-14-v-deoxyglucose in reversibly-injured myocardium

We studied the cardiac uptake of 2-¹⁴C-D-deoxy-glucose (¹⁴C-DG) in 6 dogs subjected to a 15 min left anterior descending coronary artery (LAD) occlusion followed by 30 min reflow. Coronary arterial flows during occlusion were determined with⁴⁶Sc microspheres. After 30 min reflow, 50 μCi¹⁴C-DG were given intravenously to determine cardiac uptake. The animal was killed 45 min later and⁴⁶Sc counts/min were determined in gamma and beta counters. Quenching was determined with non radioactive blood for both isotopes in the beta counter. Contribution of⁴⁶Sc counts/min to the¹⁴C channel was subtracted.¹⁴C uptake was in DPM/g and was higher in the cardiac ischemic regions of four of the six dogs. In three of the six animals there was an inverse curvilinear relation between¹⁴C-DG cardiac uptake and occlusion flow. This observation was further confirmed by high resolution autoradiography, indicating that enhanced cardiac uptake of radiolabeled DG may be a useful positron emission tomographic marker for reversible myocardial ischemia. This work was presented in part at the 36th Annual Scientific Sessions, American College of Cardiology, March 8–12, 1987, New Orleans, Louisiana. Supported by NIH ROI Grant No. HL33514-01A1     

A cell-culture reactor for the on-line evaluation of radiopharmaceuticals: evaluation of the lumped constant of FDG in human glioma cells.

A fluidized-bed cell-culture reactor with on-line radioactivity detection was developed for the in vitro evaluation of radiopharmaceuticals. The technique was applied to measure the dependency of the lumped constant (LC) of FDG on the glucose concentration in the culture medium in a human glioma cell line. METHODS: Human glioblastoma cells (86HG39) immobilized in open porous microcarriers were cultivated in a continuously operating fluidized-bed bioreactor. At different glucose concentrations in the culture medium, step inputs (0.1 MBq/mL) of FDG were performed and the cellular uptake of FDG was measured on-line and compared with analyzed samples. From these results, the LC of FDG and its dependency on the glucose concentration were calculated. RESULTS: This fluidized-bed technique enabled precise and reproducible adjustment of all relevant experimental parameters, including radiotracer time-concentration course, medium composition, pH, dissolved oxygen and temperature under steady-state conditions, and an on-line determination of the intracellular radiotracer uptake. The immobilized glioma cells formed stable, 3-dimensional, tumor-like spheroids and were continuously proliferating, as proven by an S-phase portion of 25%-40%. For further examination of the cells, an enzymatic method for detachment from the carriers without cellular destruction was introduced. In the FDG experiments, a significant dependency of the LC on the glucose level was found. For normoglycemic glucose concentrations, the LC was determined to be in the range of 0.7+/-0.1, whereas in hypoglycemia LC increased progressively up to a value of 1.22+/-0.01 at a glucose concentration of 3 mmol/L. CONCLUSION: The bioreactor represents an improved in vitro model for the on-line evaluation of radiotracers and combines a wide range of experimental setups and 3-dimensional, tissue-like cell cultivation with a technique for on-line radioactivity detection.     

Autoradiographic method for quantitative evaluation of the blood-brain barrier effects of contrast media

Opening of the blood-brain barrier after intravenous injection of different contrast media has been investigated by a quantitative autoradiographic technique using 14C-aminoisobutyric acid (AIB) as the blood-brain barrier radiotracer. In this study, experiments were carried out in adult rats. Animals were injected intravenously with 2 ml/kg of the tested contrast medium, and immediately afterward with the blood-brain radiotracer AIB. The following contrast media have been tested: diatrizoate 38%, ioxithalamate 38%, ioxaglate 38%, the nonionic product metrizamide 40%, and a new nonionic product P-297, 400 mg l/ml. Control animals were injected intravenously with saline 0.9% (2 ml/kg) before the injection of the tracer. The degree of blood-brain barrier opening was quantitatively assessed by calculating the capillary rate constant for blood-to-brain transfer of AIB (ki) from the brain activity and the arterial integral for a 6 min experiment. Preliminary data seem to indicate that the intravenous injection of 2 ml/kg of a constant medium may produce a tiny opening of the blood-brain barrier. But, if this is so, this blood-brain barrier opening is of a very low magnitude in the normal brain and there are no obvious differences between the test contrast agents injected intravenously.     

Uptake of FDG (2-fluoro-2-deoxy-D-glucose) as a tumor imaging agent into erythrocytes and accumulation of FDG in tumor cells

Fluorine-18-2-fluoro-2-deoxy-D-glucose (18F-FDG) injectable was developed as a tumor imaging agent reflecting glucose metabolism. In membrane transportation studies, the uptake of 14C-FDG into erythrocytes decreased with an increase in glucose concentration, and Cytochalasin B, inhibitor of glucose transporter (GLUT), blocked the uptake about 75%. The results means FDG is transported into tumor cells mainly by GLUT as glucose analogues. 18F-FDG is recognized to be phosphorylated to 18F-FDG-6-phosphate with hexokinase. We found that FDG-6-phosphate was further isomerized to 18F-FDM-6-phosphate by phosphoglucose isomerase (PGI) in vitro. About 27% 18F-FDM-6-phosphate was generated at the reaction with 70 U PGI for 90 min. These results show that the 18F-FDG injectable manufactured by the commercial supply system has equivalent properties; membrane transportation characteristic and enzyme affinity, to FDG synthesized at each PET institution.     

Distribution of the 5-HT<Subscript>1A</Subscript> receptor antagonist [<Superscript>18</Superscript>F]FPWAY in blood and brain of the rat with and without isoflurane anesthesia

Purpose To determine whether brain and plasma equilibrium of a proposed PET tracer for 5-HT_1A, [¹⁸F]FPWAY, can be achieved in a sufficiently short time for practical use of the brain to plasma equilibrium distribution ratio (DR) to monitor receptor availability with and without isoflurane anesthesia. Methods Awake (n=4) and isoflurane-anesthetized (n=4) rats were administered a continuous 60 min intravenous infusion of [¹⁸F]FPWAY with timed arterial blood sampling. Brains of the isoflurane-anesthetized rats were scanned with the ATLAS small animal PET scanner; awake rats were not. All rats were killed at 60 min and scanned postmortem for 15 min, followed by brain slicing for autoradiography. Several regions of interest (ROIs) were defined in the PET images as well as in the autoradiographic images. Regional DRs were calculated as total activity in the brain ROI divided by plasma [¹⁸F]FPWAY activity. Results DRs in the anesthetized animals were constant between 30 and 60 min, indicating that near equilibrium between brain and plasma had been achieved by ∼30 min. DRs determined from postmortem PET data were higher in the isoflurane-anesthetized rats by 24% (not significant) and 33% (p=0.065) in whole brain and hippocampus, respectively. DRs determined from autoradiographic data were greater in isoflurane-anesthetized rats in medial hippocampus, lateral hippocampus, and cerebellum by 33% (p=0.054), 63% (p<0.01), and 32% (p<0.05), respectively. Conclusion [¹⁸F]FPWAY could be an appropriate ligand for monitoring changes in receptor availability in the serotonergic system using a bolus/infusion paradigm. One possible explanation for higher DRs in anesthetized rats may be a reduction in endogenous 5-HT secretion under isoflurane anesthesia.     

FDG-PET in pediatric posterior fossa brain tumors.

Seventeen pediatric patients with posterior fossa brain tumors were studied with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET). The FDG uptake was ranked by two observers, and the results were correlated with tumor histology. Increased FDG uptake was associated with more malignant and aggressive tumor types. Heterogeneity of FDG uptake was associated with previous therapy, including radiation therapy and chemotherapy. 2-[18F]Fluoro-2-deoxy-D-glucose PET will likely be an important adjunct in the management of pediatric posterior fossa tumors, much as in adult patients with brain tumors.     

Myocardial glucose uptake measured with fluorodeoxyglucose: a proposed method to account for variable lumped constants.

Quantitative assessment of myocardial glucose uptake by the glucose tracer analog 2-deoxy-2-[18F]fluoro-D-glucose (FDG) depends on a correction factor (lumped constant [LC]), which may vary. We propose that this variability is caused by different affinities of FDG and glucose for membrane transport and phosphorylation and can be predicted from the time course of FDG retention. We therefore measured the LC under steady-state metabolic conditions and compared the results with values predicted from the tracer retention alone. METHODS: We measured rates of myocardial glucose uptake by tracer ([2-3H]glucose) and tracer analog methods (FDG) in isolated working Sprague-Dawley rat hearts perfused with Krebs buffer and glucose, or glucose plus insulin or beta-hydroxybutyrate. In separate experiments, we established the theoretical upper and lower limits for the LC (Rt and Rp), which are determined by the relative rates of FDG and glucose membrane transport (Rt, 1.73 +/- 0.22) and the relative rates of FDG and glucose phosphorylation (Rp, 0.15 +/- 0.04). RESULTS: The LC was decreased in the presence of insulin or beta-hydroxybutyrate or both (from 1.14 +/- 0.3 to 0.58 +/- 0.16 [insulin], to 0.75 +/- 0.17 [beta-hydroxybutyrate] or to 0.53 +/- 0.17 [both], P < 0.05). The time-activity curves of FDG retention reflected these changes. Combining the upper and lower limits for the LC with the ratio between unidirectional and steady-state FDG uptake rates allowed the prediction of individual LCs, which agreed well with the actually measured values (r = 0.96, P < 0.001). CONCLUSION: The LC is not a constant but is a predictable quotient. As a result of the fixed relation between tracer and tracee for both membrane transport and phosphorylation, the quotient can be determined from the FDG time-activity curve and true rates of myocardial glucose uptake can be measured.