Positron Emission Tomography Experiments Research Articles

Synthesis of a fluorine-18 labeled derivative of epibatidine for in vivo nicotinic acetylcholine receptor PET imaging

Epibatidine (exo-2-(2′-chloro-5′-pyridyl)-7-azabicyclo[2.2.1]heptane), a natural compound isolated from the skin of the Ecuadorian poison frog Epipedobates tricolor, is the most potent nicotinic acetylcholine receptor (nAChR) agonist reported to date. In order to visualize and quantify in vivo these receptors in human brain using Positron Emission Tomography (PET), [18F]norchlorofluoroepibatidine (exo-2-(2′-[18F]fluoro-5′-pyridyl)-7-azabicyclo[2.2.1]heptane), a fluorine-18 (t1/2: 110min) radiolabeled derivative of epibatidine has been designed. The corresponding 2′-bromo-, 2′-iodo- and 2′-nitro exo-2-(5′-pyridyl)-7-azabicyclo[2.2.1]heptane analogues as labeling precursors, as well as norchlorofluoroepibatidine as a reference compound have been synthesized by reductive, stereoselective, palladium-catalyzed Heck-type coupling between an N-Boc protected azanorbornene and the corresponding halopyridine. [18F]Norchlorofluoroepibatidine has been radiolabeled with fluorine-18 by nucleophilic aromatic substitution from the corresponding Boc-protected halo- and nitro precursors using [18F]FK-K222 complex in DMSO by conventional heating (at 150–180°C for 10min) or microwave activations (at 100 Watt, for 1 to 2.5min), followed by TFA-removal of the protective group. Typically, using the microwave activation procedure, 60–80mCi (2.22–2.96 GBq) of pure [18F]norchlorofluoroepibatidine could be obtained in less than 2h (110–115min) from the bromo labeling precursor, with specific radioactivities of 1.5–2.5Ci/μmol (55.5–92.5GBq/μmol) calculated for End of Bombardment. The preliminary PET experiments in baboon (Papio papio) with [18F]norchlorofluoroepibatidine show a high uptake and a rapid accumulation of the radiotracer into the brain within 30min. In the thalamus, a nAChR rich area, uptake of radioactivity reached a maximum at 40min (10% I.D./100mL tissue). The ratio of radioactivity thalamus/cerebellum (the latter being a nAChR poor area) was 2 at 40min and increased with time, up to 4.3 at 160min. Its specific regiodistribution and its high ratio of specific-to-nonspecific binding confirm the ideal profile of [18F]norchlorofluoroepibatidine as a suitable radioligand for PET imaging of nAChRs in the brain.

Functional anatomy of perceptual and semantic processing for odors.

The functional anatomy of perceptual and semantic processings for odors was studied using positron emission tomography (PET). The first experiment was a pretest in which 71 normal subjects were asked to rate 185 odorants in terms of intensity, familiarity, hedonicity, and comestibility and to name the odorants. This pretest was necessary to select the most appropriate stimuli for the different cognitive tasks of the second experiment. The second one was a PET experiment in which 15 normal subjects were scanned using the water bolus method to measure regional cerebral blood flow (rCBF) during the performance in three conditions. In the first (perceptual) condition, subjects were asked to judge whether an odor was familiar or not. In the second (semantic) condition, subjects had to decide whether an odor corresponded to a comestible item or not. In the third (detection) condition, subjects had to judge whether the perceived stimulus was made of an odor or was just air. It was hypothetized that the three tasks were hierarchically organized from a superficial detection level to a deep semantic level. Odorants were presented with an air-flow olfactometer, which allowed the stimulations to be synchronized with breathing. Subtraction of activation images obtained between familiarity and control judgments revealed that familiarity judgments were mainly associated with the activity of the right orbito-frontal area, the subcallosal gyrus, the left inferior frontal gyrus, the left superior frontal gyrus, and the anterior cingulate (Brodmann's areas 11, 25, 47, 9, and 32, respectively). The comestibility minus familiarity comparison showed that comestibility judgments selectively activated the primary visual areas. In contrast, a decrease in rCBF was observed in these same visual areas for familiarity judgments and in the orbito-frontal area for comestibility judgments. These results suggest that orbito-frontal and visual regions interact in odor processing in a complementary way, depending on the task requirements.

PET radiopharmaceuticals: state-of-the-art and future prospects

In this review we provide a conceptual overview of radiopharmaceuticals containing positron-emitting isotopes, not a catalog of radiopharmaceuticals or details of syntheses. We hope to provide an integrated framework for understanding the radiopharmaceuticals that are available at this time, describing both their strengths and weaknesses, and to look forward to some of the improvements that might be anticipated in the next decade. The range of biology that can be studied with positron emission tomography (PET) radiopharmaceuticals has greatly expanded, involving more sophisticated tracers and more sophisticated data analysis. PET measurements now encompass increasingly more specific aspects of human biochemistry and physiology as described in this review. As the biology being studied becomes more complex, the demands on the radiopharmaceutical and the methods of data analysis also become more complex. New synthetic chemistry and data analysis must develop in tandem. Radiopharmaceuticals must be designed to ensure that the rate determining step that is of interest is the one reflected in the data from the radiopharmaceutical. The challenge to the PET community of chemists, biologists, and physicians is to apply new knowledge of human biochemistry for developing and validating useful PET radiopharmaceuticals that will, in turn, produce useful nuclear medicine procedures. Initially the synthesis of a compound containing a short-lived radionuclide was a triumph in itself. However as the science advances the radiochemical synthesis becomes just the first step in a long trail that terminates in the compound being used to provide data on biological processes via a well-designed PET experiment. The resulting list of compounds and experiments should be as diverse as all of human biology and pathophysiology.

Characterisation of the Appearance of Radioactive Metabolites in Monkey and Human Plasma from the 5-HT 1A Receptor Radioligand, [ carbonyl- 11C]WAY-100635—Explanation of High Signal Contrast in PET and an Aid to Biomathematical Modelling

N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)- N-(2-pyridyl)cyclohexanecarboxamide (WAY-100635), labelled in its amido carbonyl group with 11C ( t 1/2 = 20.4 min), is a promising radioligand for the study of brain 5-HT 1A receptors with positron emission tomography (PET). Thus, in PET experiments in six cynomolgus monkeys and seven healthy male volunteers, [ carbonyl- 11C]WAY-100635 was taken up avidly by brain. Radioactivity was retained in regions rich in 5-HT 1A receptors, such as occipital cortex, temporal cortex and raphe nuclei, but cleared rapidly from cerebellum, a region almost devoid of 5-HT 1A receptors. [ Carbonyl- 11C]WAY-100635 provides about 3- and 10-fold higher signal contrast (receptor-specific to nonspecific binding) than [ O-methyl- 11C]WAY-100635 in receptor-rich areas of monkey and human brain, respectively. To elucidate the effect of label position on radioligand behaviour and to aid in the future biomathematical interpretation of the kinetics of regional cerebral radioactivity uptake in terms of receptor-binding parameters, HPLC was used to measure [ carbonyl- 11C]WAY-100635 and its radioactive metabolites in plasma at various times after intravenous injection. Radioactivity cleared rapidly from monkey and human plasma. Parent radioligand represented 19% of the radioactivity in monkey plasma at 47 min and 8% of the radioactivity in human plasma at 40 min. [ Carbonyl- 11C]desmethyl-WAY-100635 was below detectable limits in monkey plasma and at most a very minor radioactive metabolite in human plasma. [ 11C]Cyclohexanecarboxylic acid was identified as a significant radioactive metabolite. In human plasma this maximally represented 21% of the radioactivity at 10 min after radioligand injection. All other major radioactive metabolites in monkey and human plasma were even more polar. No-carrier-added [ carbonyl- 11C]cyclohexanecarboxylic acid was prepared in the laboratory and after intravenous administration into cynomolgus monkey was shown with PET to give only a low uptake of radioactivity into brain tissue. The acid rapidly gave rise to several radioactive metabolites of higher polarity in plasma. The observed lack of any significant metabolism of [ carbonyl- 11C]WAY-100635 to highly lipophilic or pharmacologically potent radioactive compounds is consistent with its high signal contrast in primate brain.

New method for the analysis of multiple positron emission tomography dynamic datasets: an example applied to the estimation of the cerebral metabolic rate of oxygen.

Positron emission tomography (PET) provides the ability to extract useful quantitative information not available through other radiological techniques. In certain studies, the physiological parameters of interest cannot be determined from the data obtained from a single PET experiment alone. In this case, multiple experiments are required. At present, the methods used to analyse measurements acquired from multiple experiments often involve considering them separately during the modelling procedures. These methods of analysis may cause errors to be propagated through successive modelling procedures and do not fully utilise the information content provided by the PET measurements. A new method is presented, based on linear least squares for the analysis of PET dynamic data acquired from multiple experiments. This method simultaneously considers the complete set of measurements obtained and provides reliable parameter estimates. The efficient use of the information content provided by multiple experiments is considered and the propagation of errors is discussed. To facilitate our discussion, we apply this new method to the estimation of the cerebral metabolic rate of oxygen and the parameters of the oxygen utilisation model as a practical example. The results demonstrate a significant improvement in the reliability and estimation accuracy of the estimates for this new method. Furthermore, this method reduced the likelihood of errors being propagated. Therefore, the proposed method is suitable for the analysis of multiple PET dynamic datasets.

Use of positron emission tomography to measure the effects of nalmefene on D1 and D2 dopamine receptors in rat brain

Positron emission tomography (PET) has been used in humans and in non-human primates to image and measure radioligand binding to neuroreceptors. The present study evaluated the feasibility of performing high-resolution PET experiments in a rodent model to measure receptor kinetics. The effects of acute and chronic administration of the opioid antagonist, nalmefene, on the binding activity of [11C]SCH23390 and [11C]N-methylspiperone at D1 and D2 dopamine receptors, respectively, was investigated in the rat. The interaction between central opioid and dopaminergic systems has been the focus of much attention due to their interactive role in mediating reinforcement and locomotor activity. In the present study, adult male Sprague–Dawley rats received either a single injection of 10 mg/kg of nalmefene or control vehicle solution 1 h prior to the PET scan or were chronically administered 10 mg/kg/day of nalmefene or vehicle for 7 days by an osmotic minipump. Following acute administration of nalmefene, the binding potential of [11C]SCH23390 in the striatum was significantly increased. No changes in [11C]N-methylspiperone binding were found. Following chronic nalmefene administration, no significant change in either [11C]SCH23390 binding potential or [11C]N-methylspiperone binding was detected. These results suggest that nalmefene administration produces transient changes in the binding potential of D1-receptors in the striatum that are normalized after 1 week of steady-state administration.

Evaluation of d-amphetamine effects on the binding of dopamine D-2 receptor radioligand, 18F-fallypride in nonhuman primates using positron emission tomography.

We have investigated the ability of dopamine to compete with the binding of the high affinity dopamine D2 receptor positron emission tomography (PET) radioligand, 18F-fallypride. In vitro dissociation of 18F-fallypride with dopamine in rat striatal homogenates exhibited a dissociation rate, k(off), of 1.76 x 10(-2) min(-1) while the association rate constant, k(on), was found to be 5.30 x 10(8) M(-1) min(-1). This resulted in a dissociation constant, K(D) of 33 pM for 18F-fallypride. For in vivo studies, we investigated the effects of reserpine and d-amphetamine treatment on 18F-fallypride in an attempt to study competition of endogenous dopamine with the radioligand at the receptor sites in rats and monkeys. PET experiments with 18F-fallypride in two male rhesus monkeys were carried out in a PETT VI scanner. In control experiments, rapid specific uptake of 18F-fallypride in the striata was observed (0.05-0.06% injected dose (ID)/g) while nonspecifically bound tracer cleared from other parts of the brain. Striata/cerebellum ratios for 18F-fallypride were approximately 8 at 80 min postinjection, respectively. The monkeys received various doses (0.25 to 1.50 mg/kg) of d-amphetamine (AMPH) pre- and postinjection of the radioligand. There was a decrease of specifically bound 18F-fallypride as well as evidence of an enhanced clearance of specifically bound 18F-fallypride after administering AMPH in the two monkeys. The dissociation rates, k(off), of 18F-fallypride without AMPH was <10(-4) min(-1) but after 25 min preadministration of AMPH (1 mg/kg), it was 4.1 x 10(-3) min(-1) and after 17, 45 and 90 min postadministration of AMPH (1 mg/kg) it was 3.6 x 10(-3) to 4.0 x 10(-3) min(-1). Lower doses of AMPH (0.25 mg/kg) had a reduced effect on the binding of 18F-fallypride. No effect was seen until about 30 minutes after the injection of AMPH. Studies with various doses indicated that 18F-fallypride has a maximum response at doses of 0.75-1.50 mg/kg, with an approximately 16%/hour reduction in binding. These results indicate that AMPH stimulated release of endogenous dopamine reduces the specific binding of 18F-fallypride.

Three-dimensional visualization and quantification of the benzodiazepine receptor population within a living human brain using PET and MRI.

Positron emission tomography (PET) in combination with receptor-selective high-affinity radioligands allows the characterization of neuroreceptor distributions in the living human brain. Thus far, the visualization and quantification of receptors with PET have been limited to series of two-dimensional (2D) image planes of the anatomic receptor distribution. The development of high-resolution PET has increased the number of planes to approximately 50, supplying an excessive amount of image information from a single experiment. The inherent limitations of 2D techniques make them insufficient to apprehend and efficiently analyze this cumbersome amount of data. In the present communication we describe procedures to visualize and quantify in three dimensions (3D) the total image information from the compound set of 47 2D planes of a PET experiment using commercially available software. Three-dimensional computer graphic and volume rendering techniques were used to analyze and display the results. For the experimental application the benzodiazepine (BZ) antagonist [11C]flumazenil was used as radioligand to visualize the BZ receptor (BZR) population in the brain of a healthy human subject. Three-dimensional images of the radioligand binding receptor population were displayed with regard to volume and form in relation to the corresponding anatomic structures in the brain reconstructed from MR images. The volume-rendering technique allowed the inspection of PET signals representing BZR populations in the interior of the hemisphere as viewed from the medial projection. Thresholding and seeding techniques were used to define volumes and quantities. Using the PET data and volume rendering, the total amount of cerebral BZRs (NCerebrum) and the apparent volume they take into account (V(BZR, Cerebrum)app) could he calculated for the first time using an automated procedure. The cerebrum of the healthy subject contained 17.6 nmol of BZRs in a volume of approximately 1.25 L. The principles and application of the technical development described offer new dimensions to clinical neuroscience and should be practically useful for automated quantitative determination of neuroreceptor number in brain regions of patients with neuropsychiatric disorders and in relation to drug treatment.

Synthesis and 11C-labelling of two selective high affinity nicotinic cholinergic agonists for evaluation as radioligands for PET studies

ABT-418 ((S)-3-methyl-5-[1-methyl-2-pyrrolidinyl]isoxazole) and N-methylcytisine (N-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido-[1,2-a][1,5]diazocin-8-one) are two high affinity nicotinic cholinergic agonists. ABT-418 was synthesized in 7 steps from commercially available (S)-Boc-proline in 35% overall yield. Methylation of commercial cytisine cleanly gave N-methylcytisine. ABT-418 and N-methylcytisine were labelled using [ 11 C]methyl iodide by methylation of the corresponding nor-precursors for their in vivo evaluation as positron emission tomography (PET) probes of the nicotinic cholinergic receptors in baboon brain. As for [ 11 C]nicotine, specific binding in vivo could not be demonstrated for ABT-418. Therefore, further experiments are needed to determine the full PET pharmacological profile and the subsequent potential clinical applications of ABT-418 as a tracer for PET experiments. For labelled N-methyl-cytisine, radioactivity in the cerebral cortex and in the blood were similar. Thus, 11 C-labelled N-methylcytisine does not appear to be a suitable ligand for mapping brain nAChR.

Synthesis and 11C-labelling of two selective high affinity nicotinic cholinergic agonists for evaluation as radioligands for PET studies

ABT-418 ((S)-3-methyl-5-[1-methyl-2-pyrrolidinyl]isoxazole) and N-methylcytisine (N-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido-[1,2-a][1,5]diazocin-8-one) are two high affinity nicotinic cholinergic agonists. ABT-418 was synthesized in 7 steps from commercially available (S)-Boc-proline in 35% overall yield. Methylation of commercial cytisine cleanly gave N-methyl-cytisine. ABT-418 and N-methylcytisine were labelled using [11C]methyl iodide by methylation of the corresponding nor-precursors for their in vivo evaluation as positron emission tomography (PET) probes of the nicotinic cholinergic receptors in baboon brain. As for [11C]nicotine, specific binding in vivo could not be demonstrated for ABT-418. Therefore, further experiments are needed to determine the full PET pharmacological profile and the subsequent potential clinical applications of ABT-418 as a tracer for PET experiments. For labelled N-methyl-cytisine, radioactivity in the cerebral cortex and in the blood were similar. Thus, 11C-labelled N-methylcytisine does not appear to be a suitable ligand for mapping brain nAChR.

The human cerebellum and temporal information processing--results from a PET experiment.

Changes of cerebellar blood flow were studied in normal humans using positron emission tomography (PET). A motor driven peg marked pairs of lines on subjects' right hands at different velocities. Subjects had to decide whether the second line was marked slower or faster than the first. Estimation of velocity (compared with control, i.e. presentation of lines at constant velocity) led to increases of regional cerebral blood flow (rCBF) in the left cerebellar hemisphere and vermis. Presentation of lines at constant velocity (compared with rest) activated the right cerebellar hemisphere. We conclude that the cerebellum is involved in temporal information processing even in the absence of motor output. This process can be separated from mere presentation of somatosensory stimuli.

Test-retest reliability of central [ 11C]raclopride binding at high D 2 receptor occupancy. A PET study in haloperidol-treated patients

Central D 2 dopamine receptor occupancy may be a useful measure to establish clinical guidelines for optimal antipsychotic drug treatment. The use of positron emission tomography (PET) to explore quantitative relationships among D 2 receptor occupancy and clinical effects depends on the reliability of such measurements. The calculation of D 2 receptor occupancy using [ 11C]raclopride is routinely based on a ratio-equilibrium analysis, in which the ratio of radioactivity concentration in the striatum to that in the cerebellum is determined. To examine the reliability of such ratios, a test-retest analysis was performed in four schizophrenic patients treated with haloperidol decanoate. PET experiments with [ 11C]raclopride were repeated in each subject during the same day. The putamen to cerebellum ratio ( P C ratio) ranged from 1.44 to 1.07 among the four patients, corresponding to a D 2 receptor occupancy of 62 to 71%. In each subject, the P C ratios remained highly similar, with quotients 0.98, 1.01, 1.04 and 1.06 between the two experiments. The high test-retest reproducibility of the P C ratios indicates that measurements of D, receptor occupancy with the present methods are highly reliable, and support the further use of PET to optimize the drug treatment of schizophrenia.

Characterization of the radioactive metabolites of the 5-HT 1A receptor radioligand, [O- methl- 11C]WAY-100635, in monkey and human plasma by HPLC: Comparison of the behaviour of an identified radioactive metabolite with parent radioligand in monkey using PET

N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)- N-(2-pyridyl)cyclohexanecarboxamide (WAY-100635), labelled in the O- methyl group with carbon-11 ( t 1 2 = 20.4 min ), is a promising radioligand for application with positron emission tomography (PET) to the study of 5-HT 1A receptors in living human brain. An understanding of the metabolism of this new radioligand is crucial to the development of a biomathematical model for the interpretation of the kinetics of radioactivity uptake in brain in terms of receptor-binding parameters. After intravenous injection of [O- methyl- 11C] WAY-100635 into humans, radioactivity was found to clear rapidly from blood and plasma. By using established methods for the analysis of radioactivity in plasma, it was found that intravenously injected [O- methyl- 11C]WAY-100635 is rapidly metabolised to more polar radioactive compounds in a cynomolgus monkey and in humans. Thus, at 60 min postinjection, parent radioligand represented 40% and 5% of the radioactivity in monkey and human plasma, respectively. In monkey and human, one of the radioactive metabolites was identified as the descyclohexanecarbonyl analogue of the parent radioligand, namely [O- methyl- 11C]WAY-100634. This compound is known to have high affinity for 5-HT 1A receptors and α 1-adrenoceptors. In a PET experiment it was demonstrated that, after IV injection of [O- methyl- 11C]WAY-100634 into a cynomolgus monkey, radioactivity was avidly taken up by brain. Uptake of radioactivity was higher in 5-HT 1A receptor-rich frontal cortex than in cerebellum, which is devoid of 5-HT 1A receptors. Polar radioactive metabolites appeared in plasma. The results suggest that the use of WAY-100635 labelled with carbon-11 in its cyclohexanecarbonyl moiety may provide enhanced signal contrast in PET studies and a possibility to develop a simple biomathematical model for regional brain radioactivity uptake.

Synthesis and in vivo studies of a specific monoamine oxidase B inhibitor: 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)- 1,3,4-oxadiazol-[11C]-2(3H)-one.

We report the radiochemical synthesis of a specific MAO B inhibitor, namely 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-[11C]-2(3 H)-one (2b) (in vitro IC50=4nM and selectivity over 71000 for MAO B), by cyclization of its hydrazide precursor 1 with [11C]phosgene. The reaction occurred within 2 min. The product obtained after HPLC purification, 2b, had a high specific activity (11.1-22.2 GBq/micromol), allowing its use in experiments as a radiotracer in vivo. Biodistribution of 2b in the CNS and in the peripheral organs of the rat, and positron emission tomography (PET) studies in the living baboon brain, pretreated or not with L-deprenyl (1mg/kg, 1h), an irreversible MAO B-specific inhibitor, were undertaken. The results showed a good uptake of 2b in all organs of the rat, with a rapid clearance from the blood (10 min). Metabolite analyses in plasma and in the diencephalon of the rat showed that 2b was the only radioactive compound in brain structure whereas in plasma three other radioactive products appeared. PET experiments show that in the L-deprenyl-pretreated baboon brain, specific binding of 2b represents around 70% of total radioactivity, whereas in the blood and plasma the radioactivity cleared rapidly (15 min).

Functional Imaging and Language

Positron emission tomography (PET) provides an unprecedented opportunity to study the organization of cognitive functions in the working brain of normal individuals. A number of PET experiments, based on well-established paradigms derived from cognitive psychology, have investigated several aspects of language processing. These studies show that word processing is carried out by a distributed network of cortical areas with functional specificity. Results of this research sometimes confirm--sometimes clearly contradict--classic axioms of language organization. This article illustrates some of the methodological issues in PET research, then provides an overview of the most relevant studies using PET. Integrated with other functional imaging methodologies and with behavioral data from cognitive psychology and lesion studies, PET will certainly continue to represent a precious tool to enhance our knowledge of the functional organization of language.

Positron emission tomography study of [ 11C]methyl-tetrahydroaminoacridine (methyl-tacrine) in baboon brain

THA (1,2,3,4-tetrahydro-9-amino-acridine, tacrine), a potential therapeutic agent for patients suffering from Alzheimer's disease, has multiple pharmacological sites of action in the brain. In order to study the cerebral binding sites of THA in vivo, we labeled a close derivative of THA with carbon 11 for positron emission tomography (PET) analysis. We report the biodistribution of this compound, 1,2,3,4-tetrahydro-9-[ 11C]methylaminoacridine ([ 11C]MTHA), in the rodent and describe the first PET experiments in non-human primates. The distribution of [ 11C]MTHA in baboon brain, although rather diffuse in the gray matter, showed a higher concentration in the cortex and basal ganglia than in the cerebellum and binding could be displaced (50%) by cold THA. These results suggest that [ 11C]MTHA is a promising PET ligand for the study of the cerebral binding of THA.

PET analysis of [ 11C]flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls

Benzodiazepine (BZ) receptor binding in the brain was determined in five chronic alcohol-dependent men and in five healthy male control subjects using [ 11C]flumazenil (Ro 15-1788) and positron emission tomography (PET). Magnetic resonance imaging was used to evaluate brain anatomy and pathology, and to define regions of interest in the brain. [ 11C]Flumazenil binding was quantified by applying a saturation procedure with two PET experiments, the first with high (400–3400 Ci/mmol) and the second with low (≈1 Ci/mmol) specific radioactivity. Radioactivity in the pons was taken as an estimate of free and nonspecifically bound radioligand. Equilibrium was defined to prevail when the derivative of specific binding (dC b(t)/dt) was equal to zero. The values were used in a Scatchard analysis for determination of the maximum density of binding sites ( B max ) and the equilibrium binding constant ( K d ). The mean values of B max and k d were about the same in the two groups, but the B max variance for the alcoholics was significantly greater for all regions of interest as compared with the healthy volunteers. The results may indicate that chronic alcohol consumption has multiple effects on the BZ receptor complex.

PET analysis of [c]Flumazenil binding to Benzodiazepine receptors in chronic alcohol-dependent men and healthy controls

Benzodiazepine (BZ) receptor binding in the brain was determined in five chronic alcohol-dependent men and in five healthy male control subjects using [ 11 C]flumazenil (Ro 15-1788) and positron emission tomography (PET). Magnetic resonance imaging was used to evaluate brain anatomy and pathology, and to define regions of interest in the brain. [ 11 C]Flumazenil binding was quantified by applying a saturation procedure with two PET experiments, the first with high (400–3400 Ci/mmol) and the second with low (≈1 Ci/mmol) specific radioactivity. Radioactivity in the pons was taken as an estimate of free and nonspecifically bound radioligand. Equilibrium was defined to prevail when the derivative of specific binding (dC b (t)/dt) was equal to zero. The values were used in a Scatchard analysis for determination of the maximum density of binding sites ( B max ) and the equilibrium binding constant ( K d ). The mean values of B max and k d were about the same in the two groups, but the B max variance for the alcoholics was significantly greater for all regions of interest as compared with the healthy volunteers. The results may indicate that chronic alcohol consumption has multiple effects on the BZ receptor complex.

Testing of the spatial resolution and efficiency of scintillating fiber PET modules

Two experimental positron emission tomography (PET) camera modules were constructed using (1) two 5-cm*5-cm*2.5-cm detector stacks made of parallel 0.5- and 1.0-mm-diameter scintillating fibers and (2) two 5-cm*5-cm*5-cm detector stacks made of alternating x and y layers of 0.5-and 1.0-mm diameter scintillating fibers. Each stack was viewed by Hamamatsu R2486 position sensitive photomultipliers. The time resolution of the coincidence system was 10 ns. The spatial resolution and efficiency of the PET modules was tested using an approximately 1 mu Ci 0.5-mm-diameter Na-22 source. The best results were achieved with the 1.0-mm parallel fiber stacks: 2.0-mm spatial resolution (FWHM) and 2.3% efficiency. Possibilities to improve the characteristics of this agreement and, particularly, the alternating x and y layer stacks are discussed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Stability of resting deoxyglucose metabolic values in PET studies of schizophrenia

Positron emission tomography (PET) and the deoxyglucose method were used to determine the test-retest stability of regional cerebral glucose metabolism in 8 male schizophrenic patients and 11 normal control subjects, scanned twice under baseline (resting) conditions. Normal and schizophrenic subjects showed comparable stability of regional metabolism. When the regional values were scaled to compensate for the effects of changes in whole brain metabolism, the resulting mean regional changes were reduced to about 1–2% in both groups. This study demonstrates that the baseline resting state is an appropriate reference state for schizophrenic subjects in deoxyglucose PET experiments.