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J E Litton

Publications and source records attributed to J E Litton.

18 recordsLinked to original sources
PubMed1998

Regional increases in [11C]flumazenil binding after epilepsy surgery.

INTRODUCTION: Animal experiments suggest that epileptic seizures alter the expression of mRNA for neuro-receptors. PET measurements with [11C]flumazenil show that patients with partial seizures have a reduced density of benzodiazepine (BZ) receptors in the epileptogenic regions (ER) and some of the target areas for seizure activity, the so called projection areas. Recent data suggest that the degree of BZ receptor reduction in ER is correlated to seizure frequency. We therefore hypothesized that seizure activity can alter the BZ receptor binding, and that some of these changes could normalize when the seizures disappeared. METHODS: In 4 patients whose seizures were generated by mesial temporal lobe structures, BZ receptor density was measured with [11C]flumazenil PET before, and 1 year after the epilepsy surgery and cessation of seizures. By use of a computerized anatomical brain atlas the same regions were analyzed in both PET scans, and the results related to data from 7 healthy controls. RESULTS: Presurgical PET scans showed reductions in BZ receptor density in the epileptogenic region and some of its primary projection areas. Other cortical regions had normal values. Postsurgically, the calculated BZ receptor density normalized (29+/-17% increase) in several of the affected projection areas, whereas the values in other cortical regions remained unaltered. CONCLUSION: Regional reductions in BZ receptor density may be dynamic and related to seizures. The present preliminary observations encourage further studies on seizure-related changes in regional receptor binding in humans.

Adult↗
PubMed1997

Improved receptor analysis in PET using a priori information from in vitro binding assays.

An accurate determination of non-specific binding is required for the analysis of in vitro and in vivo receptor binding data. For some radioligands the non-specific binding is of the same magnitude as the specific binding. Furthermore, in vitro measurements have shown that the non-specific binding can be different in different brain regions. If this is the case in a PET study for determining Bmax and Kd, a correction for the non-specific binding has to be applied. The aim of the present communication is to present a means for determining corrected Bmax and Kd with Scatchard analysis using in vitro binding studies. The influence of non-specific binding on the free and specifically bound radioligand is expressed with the aid of a correction factor, which can be calculated from measurable quantities. Introduction of the corrected free and specifically bound radioligand should give binding parameters closer to reality than previously obtained results.

Animals↗
PubMed1994

PET-determination of benzodiazepine receptor binding in studies on alcoholism.

Positron Emission Tomography (PET) and the radioligand [11C]flumazenil were used to examine benzodiazepine (BZ) receptor binding in the human brain. In a first study of healthy males acute ingestion of alcohol did not alter total radioactivity uptake or specific [11C]flumazenil binding in the neocortex or cerebellum. In a second study [11C]flumazenil binding was determined in 5 healthy male controls and 5 chronic alcohol dependent men using a saturation procedure with two PET experiments. Mean values for BZ-receptor density and affinity were similar in the two groups but the Bmax variance for the alcohol dependents was significantly larger (p < 0.05) for all regions. The present studies do not support the view that alcohol affects central BZ receptor binding in man.

Adult↗
PubMed1994

Saturation analysis in PET--analysis of errors due to imperfect reference regions.

In the determination of specific binding in receptor binding techniques in vitro as well as in vivo, determination of the nonspecific binding as well as the free component is of crucial importance. If a low proportion of specific binding is included when determining the nonspecific binding, relatively large errors may be obtained. In the present study, benzodiazepine (BZ) receptor binding in the human brain was determined in vivo using position emission tomography (PET) by applying a saturation procedure using [11C]flumazenil as an example of this problem. Analysis of the errors in Bmax and KD obtained using Scatchard analysis in PET was performed using a priori information from in vitro [3H]flumazenil binding in the pons, used normally as a reference region in BZ receptor binding studies. Even if the density of BZ receptors in the reference region pons is only 2% compared to that in the frontal cortex, this small proportion of specific binding sites will result in a 10% error in the Bmax and KD values. Simulation of a number of Scatchard plots was performed at varying ratios between the nonspecific and the specific binding.

Binding Sites↗
PubMed1993

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 (approximately 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 (dCb(t)/dt) was equal to zero. The values were used in a Scatchard analysis for determination of the maximum density of binding sites (Bmax) and the equilibrium binding constant (Kd). The mean values of Bmax and Kd were about the same in the two groups, but the Bmax 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.

Adult↗
PubMed1992

PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil.

Acute alcohol administration to rats has in preliminary studies been reported to drastically increase the binding of the benzodiazepine (BZ) receptor antagonist [3H]flumazenil (Ro 15-1788) to central BZ receptors. In the present study the effect of acute alcohol ingestion on the disposition of [11C]flumazenil in the human brain and plasma was examined by positron emission tomography (PET) in four healthy volunteers. Neocortex, cerebellum and pons (reference region) were delineated using X-ray computerized tomography (CT). Alcohol did not increase either total radioactivity uptake or specific [11C]flumazenil binding in neocortex or cerebellum. However, alcohol had a small but significant effect on [11C]flumazenil in arterial blood. After alcohol the plasma radioactivity peak was higher, more narrow and occurred earlier than in the control experiments. The present experiments contradict the view that alcohol directly affects central BZ receptor binding in man. Thus the dramatic increase of flumazenil binding in rat brain reported previously could not be observed in the human brain.

Adult↗
PubMed1992

[11C]Ro 15-4513, a ligand for visualization of benzodiazepine receptor binding. Preparation, autoradiography and positron emission tomography.

Ro 15-4513, a partial inverse agonist at the benzodiazepine (BZ) receptor site was labelled with 11C and used for in vitro autoradiography on human post mortem brain sections and for positron emission tomography (PET) on Cynomolgus monkeys. The total radiochemical yield of [11C]Ro 15-4513 was 30-40% with an overall synthesis time of 40 min. The specific radioactivity was about 1000 Ci/mmol at end of synthesis. In vitro autoradiography showed that [11C]Ro 15-4513 bound specifically predominantly in the neocortex of the human brain. Specific binding was also demonstrated in the basal ganglia and the cerebellar cortex. Flumazenil (Ro 15-1788) and clonazepam inhibited the binding in cerebral regions, but a significant proportion in the cerebellum was not inhibited by these agents. This proportion may represent alpha 6-containing BZ receptors. PET examination of [11C]Ro 15-4513 binding in Cynomolgus monkeys demonstrated high uptake of radioactivity in neocortex. The uptake of radioactivity was markedly displaced by high doses of Ro 15-4513 or clonazepam. [11C]Ro 15-4513 should be a useful ligand to examine BZ receptor characteristics in the living human brain by PET.

Animals↗
PubMed1991

Autoradiography with saturation experiments of 11C-Ro 15-1788 binding to human brain sections.

In vitro autoradiography of a 11C-labelled ligand, Ro 15-1788, was used in saturation experiments in order to quantify benzodiazepine receptor binding in whole human brain hemisphere cryo-sections. A special incubation chamber was developed with the aim of performing standardized quantitative studies with short-lived positron emitting isotopes. 11C-labelled ligand binding was studied in temporal cortex, cerebellum, white manner and pons incubated in vitro. White manner, lacking benzodiazepine receptor binding, was used as an estimated of nonspecific binding, for calculation of Saturability of binding was demonstrated in the neocortical and cerebellar regions. Radioactivity counting of incubated adjacent tissue sections was done as a control. Computerized densitometry of the autoradiograms gave similar results as the tissue counting. A comparison with in vivo saturation experiments using the same 11C-labelled ligand and positron emission tomography in healthy human subjects also gave binding characteristics of the same magnitude. The 11C-autoradiograms showed a good spatial resolution (about 180 microns). 11C-autoradiography with suitable radioligands should be a valuable technique of screening the distribution and characteristics of neuroreceptors in the human brain. This quantitative method will provide the PET investigator with preliminary binding data, and may thus supply valuable information concerning positioning in PET and concerning significant regions of interest.

Autoradiography↗
PubMed1986

The preparation of 11C-labelled fluoromethane for the study of regional cerebral blood flow using positron emission tomography.

Fluoromethane, previously labelled with 18F and used as a tracer in the measurement of regional cerebral blood flow, was 11C-labelled by the reaction of 11C-methyl iodide with tetraethylammonium fluoride. Sufficient quantities of radiotracer were prepared with a minimum amount of handling from 15 min target irradiations in the 14N(p, alpha)11C reaction. Total synthesis time was 25 min from end-of-bombardment, allowing serial blood flow measurements 30 min apart. The use of 11C-fluoromethane as a cerebral blood flow tracer in positron emission tomography is discussed.

Adult↗
PubMed1985

Preparation of 11C-labelled Raclopride, a new potent dopamine receptor antagonist: preliminary PET studies of cerebral dopamine receptors in the monkey.

A new dopamine receptor antagonist, Raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy- 6-methoxybenzamide, FLA 870) (1), has been labelled using [11C]ethyl iodide for alkylation of the nitrogen of the pyrrolidine ring in the corresponding secondary amine (5). The synthesis of 5 and an efficient method for the preparation of [11C]ethyl iodide are described. The 11C-labelled FLA 870 (1) was purified by HPLC and then used in positron emission tomography to visualize the dopamine receptor-rich areas of the monkey brain. The images obtained show selective accumulation of FLA 870 in striatum and a 10-fold separation between the binding to caudate vs cerebellum.

Animals↗
PubMed1985

Imaging of [11C]-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography.

The benzodiazepine antagonist Ro 15-1788 was labelled with [11C] and examined for possible use as ligand for PET scan studies on benzodiazepine receptors in the brain of cynomolgus monkeys and human subjects. [11C] Ro 15-1788 allowed the in vivo visualization of benzodiazepine receptor binding in cerebral and cerebellar cortical areas as well as in basal brain nuclei in PET scan images. [11C] Ro 15-1788 exhibited a high ratio of specific benzodiazepine receptor binding (cerebral cortex) to non-specific binding (pons) and the kinetics of binding should be satisfactory for quantitative clinical PET scan studies using [11C]. The in vivo binding of [11C] Ro 15-1788 in the cerebral cortex of cynomolgus monkeys and healthy human subjects was reduced by approximately 90% within 10 min after the intravenous injection of a high dose of unlabelled Ro 15-1788 (0.5 mg/kg i.v.). Different areas of the healthy human brain showed an approximately 10-fold variation in maximal [11C] Ro 15-1788 binding that corresponded to the previously known distribution of benzodiazepine receptors in these regions. The highest degree of binding was obtained in the medial occipital cerebral cortex followed by frontal cortex, cerebellum, thalamus, striatum and pons. Two psychiatric patients with anxiety syndromes who had been treated for a long time with high doses of benzodiazepines had roughly the same degree of maximal [11C] Ro 15-1788 binding in brain regions as the healthy subjects but the rate of decline of [11C] Ro 15-1788 in the brain was higher. This indicates that there is measurable competition between [11C] Ro 15-1788 binding and clinical benzodiazepine concentrations in the body fluids of psychiatric patients. The results demonstrate that [11C] Ro 15-1788 should be a valuable tool for quantitative analyses of benzodiazepine receptor characteristics and receptor occupancy in the brain of patients with neuropsychiatric disorders.

Adult↗
PubMed1985

Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography.

Two substituted benzamides, FLB 524 and raclopride, were labeled with 11C and examined for their possible use as ligands for positron emission tomography (PET)-scan studies on dopamine-2 (D-2) receptors in the brains of monkeys and healthy human subjects. Both ligands allowed the in vivo visualization of D-2 receptor binding in the corpus striatum caudate nucleus/putamen complex in PET-scan images. [11C]Raclopride showed a high ratio of specific striatal to nonspecific cerebellar binding, and the kinetics of binding of this ligand made it optimal for PET studies. The in vivo binding of [11C]raclopride in the striatum of cynomolgus monkeys was markedly reduced by displacement with haloperidol. This and previous in vitro data indicate that [11C]raclopride binds selectively to striatal D-2 dopamine receptors. In healthy human subjects, [11C]raclopride binding in the caudate nucleus/putamen was 4- to 5-fold greater than nonspecific binding in the cerebellum. In comparison with previously available ligands for PET-scan studies on central dopamine receptors in man, [11C]raclopride appears to be advantageous with regard to (i) specificity of binding to D-2 receptors, (ii) the high ratio between binding in dopamine-rich (caudate, putamen) and dopamine-poor (cerebellum) human brain regions, and (iii) rapid association and reversibility of specific binding. [11C]Raclopride should be a valuable tool for characterizing D-2 receptors in the brains of patients with neuropsychiatric disorders.

Animals↗
PubMed1984

Strategy for the measurement of regional cerebral blood flow using short-lived tracers and emission tomography.

This report describes a strategy for measurement of regional CBF that rigorously accounts for differing tracer partition coefficients and recirculation, and is convenient for use with positron emission tomography. Based on the Kety model, the measured tissue concentration can be expressed in terms of the arterial concentration, the rate constant K, and the blood flow f. The local partition coefficient may be computed as p = f/K. In our approach, maps of K and f are computed from two transverse section reconstructions. The reconstructions are based on weighted sums of projection data measured frequently during the observation period. Theoretical studies of noise propagation in the estimates of K and f were carried out as a function of tomographic count rate, total measurement time, and tracer half-life for varying input functions. These calculations predict that statistical errors in f of between 5 and 10% at a resolution of 1 cm full width at half maximum can be obtained with existing tomographs following i.v. injection. To compare theory and experiment, a series of flow studies were carried out in phantoms using a positron tomograph. These measurements demonstrate close agreement between computed flow and noise estimates and those measured in a controlled situation. This close agreement between theory and experiment as well as the low statistical errors observed suggest that this approach may be a useful tool in clinical investigation.

Cerebrovascular Circulation↗
PubMed1983

C-11-labeled glucose and its utilization in positron-emission tomography.

Carbon-11-labeled glucose was prepared photosynthetically using the green alga Scenedesmus obtusiusculus Chod. The carbohydrates were extracted from the cells with dilute HCI and the glucose was isolated and purified using high-performance liquid chromatography. The manipulations in the hot cell are described. Analysis of the material (gas liquid chromatography and HPLC) showed that the glucose obtained was radiochemically pure. The total incorporation of the 11CO2 added to the algae was 60-80%. The radiochemical yield of pure carrier-added glucose was approximately 25%, at 40 min after E.O.B. including the HPLC purification and sterile filtration. The C-11 glucose uptake in rat brain was compared with that of commercial D[U-14C]glucose, and preliminary PET studies with D-[11C]glucose in a patient with a brain infarct are presented.

Animals↗
PubMedDate not supplied

Input function in PET brain studies using MR-defined arteries.

The internal carotid arteries were drawn as region of interests (ROIs) on proton density weighted MR images. After transferring the ROIs from the MR to the PET images from the same subject, time-radioactivity curves were calculated for each ROI and the radioactivity curves were used for determination of the blood input function in dynamic brain PET studies. The method is validated by comparing measurements with those from an external on-line continuous flow-through arterial blood-sampling system.

Brain Mapping↗
PubMedDate not supplied

PET studies of glucose metabolism in patients with schizophrenia.

The hypothesis of abnormal patterns of metabolism in schizophrenia was examined in a series of six young patients with psychotic symptoms satisfying the research diagnostic criteria. After intravenous injection of 11C-glucose obtained through a photosynthetic process, the regional activity of 11C in brain was measured with a four-ring positron camera. Regions of interest were obtained from computed tomographic images. Each patient underwent a second positron emission tomographic examinations after 4-5 weeks of treatment with a neuroleptic drug. No evidence of a hypofrontal pattern was found, but after treatment there was a reduced frontal uptake on the left side compared with temporal regions. The left-right asymmetry in the lentiform nucleus was reduced after treatment.

Acute Disease↗