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Biomedical subjects

L Farde

Publications and source records attributed to L Farde.

196 records · Page 11Linked to original sources
PubMed1987

PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride.

Tracer doses of 11C-SCH 23390 and 11C-raclopride, selective D1-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with 11C-SCH 23390, but not 11C-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of 11C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or cis(Z)-flupentixol decanoate. 11C-SCH 23390 binding was slightly reduced in both the cortex and the putamen after treatment with cis(Z)-flupentixol decanoate but not after sulpiride. The results indicate that clinical antipsychotic drug treatment with sulpiride and cis(Z)-flupentixol decanoate causes a substantial blockade of D2-dopamine receptors in the basal ganglia but has only a minor effect on D1-dopamine receptors.

Adult↗
PubMed1987

Use of graphical techniques for error evaluation.

Anatomic localization in functional (such as PET) imaging often requires a structural (such as CT or NMRI) study of the brain in the same plane. Some neuropsychiatric conditions make it difficult for a patient to hold his/her head immobile even when a rigid head holder is used. We studied the effect of tilt of the anatomic reference image, in this instance CT, relative to the functional image, here PET, on the quantification of receptor ligand concentration in anatomically defined regions of the brain.

Computer Graphics↗
PubMed1987

Muscle biopsy findings, conduction velocity and refractory period of single motor nerve fibres in schizophrenia.

Eight untreated and eight neuroleptic treated male schizophrenic patients were studied. Light and electron microscopical analysis of muscle biopsies from the anterior tibial muscle showed a spectrum of pathological changes without significant quantitative or qualitative differences between the two groups. The changes included atrophic fibres, central nuclei, "moth-eaten fibres", "ring fibres", fibre splitting and subsarcolemmal and intermyofibrillar glycogen droplets. Electrophysiological investigation of single motor unit properties showed impaired peripheral impulse propagation in both patient groups while the conduction velocity and the refractory period of single motor nerve fibres were within the same range as in healthy subjects. In conclusion there are neuromuscular abnormalities in schizophrenic patients which cannot be attributed to medication or drug abuse.

Adult↗
PubMed1987

Neurotransmitter receptor imaging in Alzheimer's disease.

Recent developments in positron emission tomography and ligand binding techniques have allowed the visualization of regional metabolism and neuroreceptor distributions in the living human brain. For dopamine-D 2 and benzodiazepine receptors it has also been possible to determine neuroreceptor characteristics such as Bmax and Kd by performing in vivo saturation analysis of ligand binding to the receptors. Using 11-C raclopride and 11-C-Ro 15-1788 as ligands for dopamine-D 2 and benzodiazepine receptors respectively we have determined Bmax and Kd-values in healthy volunteers and patients with various types of neuropsychiatric disorders. These ligands were also used in order to determine the degree of receptor occupancy in psychiatric patients treated with different types of drugs interfering with these neuroreceptors. We have administered 11-C-deoxy-glucose, 11-C-raclopride and 11-C-Ro 15-1788 to patients with Alzheimer's disease in order to examine possible alterations of glucose utilization and neuroreceptor distribution and quantities in these patients. The preliminary results indicate that this approach may be useful for the analysis of degenerative alterations of neuron populations and neuroreceptor systems in Alzheimer's disease.

Alzheimer Disease↗
PubMed1986

Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET.

D2 dopamine receptors in the putamen of living human subjects were characterized by using the selective, high-affinity D2 dopamine receptor antagonist carbon-11-labeled raclopride and positron emission tomography. Experiments in four healthy men demonstrated saturability of [11C]raclopride binding to an apparently homogeneous population of sites with Hill coefficients close to unity. In the normal putamen, maximum binding ranged from 12 to 17 picomoles per cubic centimeter and dissociation constants from 3.4 to 4.7 nanomolar. Maximum binding for human putamen at autopsy was 15 picomoles per cubic centimeter. Studies of [11C]raclopride binding indicate that clinically effective doses of chemically distinct neuroleptic drugs result in 85 to 90 percent occupancy of D2 dopamine receptors in the putamen of schizophrenic patients.

Adult↗
PubMed1986

Preparation of 11C-labelled SCH 23390 for the in vivo study of dopamine D-1 receptors using positron emission tomography.

The dopamine D-1 receptor antagonist, SCH 23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepin-7-ol), was labelled by alkylation of the desmethyl compound SCH 24518 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro-5-phenyl-1H-3-benzazepin-7- ol) with [11C]methyl iodide. A multivariate optimization method, Simplex, was employed to obtain the optimal radiochemical yield. Both straight-phase and reversed-phase preparative HPLC were investigated in the purification of [11C]SCH 23390. Reaction in acetone with subsequent straight-phase LC separation resulted in 80% radiochemical yield, based on [11C]methyl iodide, with a total synthesis time of 35-40 min and a radiochemical purity greater than 99%. The average specific activity was on the order of 11.1 GBq/mmol. The 11C-labelled SCH 23390 was used to visualize the dopamine D-1 receptor-rich areas of a monkey brain by positron emission tomography. The data obtained showed a rapid distribution of radioactivity into the brain and a conspicuous accumulation of [11C]SCH 23390 in the striatum.

Animals↗
PubMed1986

Applications of a computerized adjustable brain atlas in positron emission tomography.

A computerized brain atlas, adjustable to the patient's anatomy, has been developed. It is primarily intended for use in positron emission tomography (PET), but may also be employed in other fields utilizing neuro-imaging, such as stereotactic surgery. The atlas is based on anatomic information obtained from digitized cryosectioned cadaver brains. It can be adjusted to fit a wide range of individual brains with reasonable accuracy. The corresponding transformation is chosen so that the modified atlas agrees with a set of CT or MR images of the patient. The computerized atlas can be used to facilitate and improve the quantification and evaluation of PET data by: enabling the merging and comparison of results from different individuals or groups of individuals; serving as a vehicle in the comparison of different examinations of the same patient, thus reducing the need of reproducible fixation systems; supplying external information to be used in the image reconstruction, such as proper three-dimensional regions of interest; improving the attenuation and scatter corrections; helping to select suitable patient orientation during the PET study. By applying the inverse atlas transformation to the PET data volume it is possible to relate the PET information to the anatomy of the reference atlas. Reformatted PET data from different patients can thus be averaged, and averages from different categories of patients can be compared. The method will facilitate the identification of statistically significant differences in the PET information from different groups of patients.

Brain↗
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↗
PubMedDate not supplied

Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain.

Loss of dopamine D2-like receptors in the striatum has been associated with both normal human aging and impairment of cognitive and motor functions in the elderly. To investigate whether there are age-associated changes in dopamine D2 and D3 receptor subtypes (D2/3Rs) outside the striatum, a D2/3R selective high-affinity radioligand [11C]FLB 457 was used in positron emission tomography (PET) examinations for 24 normal healthy male subjects (age range 19-74 years). Significant age-related declines of D2/3Rs were detected in all the brain regions studied: the anterior cingulate cortex (decline of 13% per increase of a decade in age, P < 0.001). the frontal cortex (11%, P < 0.001), the lateral temporal cortex (10%, P < 0.001), the hippocampus (10%, P < 0.01), the medial temporal cortex (9%, P < 0.001), the amygdala (7%, P < 0.01), the medial thalamus (6%, P < 0.001) and the lateral thalamus (5%, P < 0.01). The rate of D2/3R decline was significantly faster in the frontal cortex as compared to the medial temporal cortex (P < 0.05, Bonferroni corrected) and as compared to the medial thalamus (P < 0.05, Bonferroni corrected). These results indicate that the previously demonstrated age-related decline in striatal dopamine D2 receptors extends to several extrastriatal regions in normal human males. Further, the rate of D2/3R decline may be faster in the frontal cortex as compared to the temporal and thalamic regions.

Adult↗
PubMedDate not supplied

PET study of the M1-agonists [11C]xanomeline and [11C]butylthio-TZTP in monkey and man.

Xanomeline, a substituted TZTP, is a new M1 selective muscarinic agonist in clinical trials for Alzheimer's disease. The brain uptake of [11C]xanomeline and the analog [11C]butylthio-TZTP was examined by positron emission tomography (PET). Radioactivity accumulated most markedly in the neocortex and the striatum. Pharmacological characterization in vitro and in cynomolgus monkeys in vivo by PET indicated specific [11C]butylthio-TZTP binding to muscarinic receptors and to sigma-1 recognition sites. More than 5% of the radioactivity was in the human brain 5 min after i.v. injection of [11C]xamomeline or [11C]butylthio-TZTP. This high brain uptake may be clinically advantageous in the sense that substituted TZTP may induce central muscarinic agonist effects at a dose level for which there is a low risk of peripheral side-effects.

Adult↗