Dopamine D1-receptor binding in the living human brain.
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Benzazepines↗
Biomedical subjects
C Halldin
Publications and source records attributed to C Halldin.
Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET).
By means of positron emission tomography the uptake and kinetics of N-(methyl-11C)clozapine in different brain regions have been studied in Rhesus monkeys. 11C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5-12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of 11C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for 11C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.
Animals↗
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↗
A direct comparison of the brain uptake and plasma clearance of N-[11C]methylspiroperidol and [18F]N-methylspiroperidol in baboon using PET.
Serial PET studies of N-[11C]methylspiroperidol and [18F]N-methylspiroperidol were carried out in a single baboon with an intervening time period of 2 h between injection of the 11C and the 18F-labeled tracers. The kinetic patterns of uptake and egress of radioactivity in striatum and cerebellum as well as the magnitude of the uptake was very similar with the two tracers. In addition, no significant difference in clearance of total radioactivity from arterial plasma was detected. Analysis of plasma radioactivity for unchanged drug showed no significant differences in the amount of unchanged tracer at different times, although the profile of labeled metabolites was different. These results indicate that the only significant difference between the use of N-[11C]methylspiroperidol and [18F]N-methylspiroperidol for PET studies of brain dopamine receptors relate to the difference in physical half-life of the radionuclide rather than to differences in the profile of metabolically produced labeled compounds.
Animals↗
Peripheral benzodiazepine binding sites in human gliomas evaluated with positron emission tomography.
A specific ligand for peripheral type benzodiazepine receptors, Ro5-4864, was synthesised and labelled with 11C for use in positron emission tomography (PET). Four patients with suspected glioma, two patients with high grade astrocytoma and two with low grade astrocytoma, as well as one patient with meningioma were examined with PET after the administration of 200 MBq 11C-Ro5-4864. The images as well as kinetic analyses revealed lower uptake of the ligand in tumor as compared with cortical tissue. Markedly elevated uptake in the thalamus suggests a functional role of the ligand.
Benzodiazepinones↗
Selective, irreversible in vivo binding of [11C]clorgyline and [11C]-L-deprenyl in mice: potential for measurement of functional monoamine oxidase activity in brain using positron emission tomography.
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Animals↗
Radiotoxicity of 11C-methionine measured by the accumulation of DNA strand breaks in mammalian cells.
The radiotoxic effects of L-[methyl-11C] methionine were estimated by measuring the accumulation of DNA strand breaks. CHO, Chinese-hamster cells, were incubated in 11C-methionine-containing medium for 60 min at 37 degrees C. The number of unrepaired DNA strand breaks was then examined by the DNA-unwinding method. For comparison, cells were also externally irradiated under similar conditions with gamma radiation (137Cs) or positrons (11C). The relative biological effectiveness of 11C-methionine was estimated to be about 1.
Animals↗
11C-methionine kinetics in pregnant rhesus monkeys studied by positron emission tomography: a new approach to feto-maternal metabolism.
By use of Positron Emission Tomography (PET), dynamic studies of the metabolism within the feto-maternal unit can be performed using various tracers. Many compounds like amino acids, carbohydrates, fatty acids and drugs can be performed using various tracers. Many compounds like amino acids, carbohydrates, fatty acids and drugs can be labelled with 11C and used as tracers. 11C-labelled L- or D-methionine was injected intravenously into pregnant Rhesus monkeys. The distribution of the radioactivity in maternal muscles, aorta, placenta and the liver of the fetus was quantitatively estimated as a function of time. Simultaneously blood, urine and amniotic fluid samples were analyzed for 11C-activity. The distribution of 11C between the high and the low molecular fraction of plasma (MW greater than 5000) was studied after gel filtration. Both when 11C-L- and D-methionine were given, the radioactivity rapidly crossed the placenta and was accumulated in the fetal liver. In the 11C-L-methionine experiments, about 70 per cent of the radioactivity in plasma was found in the high molecular fraction one hour after injection. A greater part of 11C-D-compared to 11C-L-activity was excreted in the urine.
Amniotic Fluid↗
Discrepancies in brain tumor extent as shown by computed tomography and positron emission tomography using [68Ga]EDTA, [11C]glucose, and [11C]methionine.
A patient with an anaplastic (malignant) astrocytoma was examined with computed tomography (CT) and with positron emission tomography (PET), in the latter case using [68Ga]EDTA, [11C]glucose, and [11C]methionine. The CT examination as well as the [68Ga]EDTA study showed a small tumor located in the region of the head of the left caudate nucleus. The [11C]glucose examination showed increased uptake on the same region, as did the [11C]methionine examination, but the latter also showed a considerable uptake in the entire left thalamic region. The patient died 15 days after the [11C]methionine study and a histologic evaluation of thin sections obtained at autopsy showed excellent agreement between tumor extent and activity distribution after [11C]methionine administration. The tumor tissue seen only with [11C]methionine was histologically different from that part of the tumor observed with the other tracers. Although cytologically similar, the latter showed large necrotic areas and an ability to induce marked endothelial proliferation, whereas in the former neither necroses nor notable endothelial proliferation was seen. In this case more than 50% of the tumor would have remained radiologically imperceptible without the [11C]methionine PET examination.
Astrocytoma↗
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↗
Dynamic study of supratentorial gliomas with L-methyl-11C-methionine and positron emission tomography.
The regional kinetics of intravenously injected L-methyl-11C-methionine (11C-L-methionine) in the brain was investigated by positron emission tomography (PET) in 14 patients with gliomas. In both tumor and unaffected brain the tracer uptake reached a nearly constant level in 5 min or less. The ratio between the uptake of 11C-L-methionine by high-grade tumors and the uptake by unaffected brain was 1.9-4.8. In two cases of low-grade astrocytoma the ratio was 0.8-1.0. High uptakes of 11C-L-methionine occurred in gliomas even in the absence of blood-brain barrier defects as observed by other methods. This indicates that besides active transport of amino acid, a larger extracellular space in tumor as compared with unaffected brain tissue may also contribute to the increased uptake of 11C-L-methionine--derived radioactivity. In some patients delineation of the tumors was improved by use of PET with 11C-L-methionine as compared with computed tomography, angiography, and, in some instances, PET with 68Ga-EDTA. PET with 11C-L-methionine permits better evaluation of the tumor extent and may affect preoperative grading.
Adult↗