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K Någren

Publications and source records attributed to K Någren.

87 records · Page 5Linked to original sources
PubMed1990

PET demonstrates different behaviour of striatal dopamine D-1 and D-2 receptors in early Parkinson's disease.

Striatal dopamine D-1 receptor binding was investigated in vivo with positron emission tomography (PET) in five patients with early Parkinson's disease using [11C]-SCH 23390. All patients had predominantly unilateral symptoms and showed a significant reduction in the accumulation of [18F]-6-F-DOPA in the striatum contralateral to the symptoms. None of the patients had received any antiparkinsonian medication. The striatal and cerebellar radioactivity was measured and corresponding striatum/cerebellum ratios were counted. The mean striatum/cerebellum ratio of [11C]-SCH 23390 binding was symmetric between the hemispheres. By contrast, the striatum/cerebellum ratio of [11C]raclopride binding, labelling dopamine D-2 receptors, was increased significantly in the hemisphere contralateral to the symptoms as compared with the opposite hemisphere. Thus, the present results show that the behaviour of striatal D-1 and D-2 receptors is different in early Parkinson's disease.

Adult↗
PubMed1990

Positron emission tomography demonstrates dopamine D2 receptor supersensitivity in the striatum of patients with early Parkinson's disease.

Striatal dopamine D2 receptor binding was studied in vivo with positron emission tomography in seven patients with early Parkinson's disease using [11C]-raclopride. The patients had unilateral symptoms and none of them had received levodopa treatment. The accumulation of [11C]-raclopride in the striatum was rapid and reached a steady state at approximately 40 min after injection. The binding of [11C]-raclopride was measured in the striatum and cerebellum: The total striatal radioactivity in both hemispheres was counted and the respective striatum/cerebellum ratios were calculated. The striatum/cerebellum ratio of [11C]-raclopride binding was significantly (p less than 0.01) increased in the hemisphere contralateral to the parkinsonian symptoms as compared with the opposite hemisphere. Thus, this study demonstrates that there is denervation supersensitivity in dopamine D2 receptor binding in early Parkinson's disease.

Adult↗
PubMed1990

Synthesis of compounds of interest for positron emission tomography with particular reference to synthetic strategies for 11C labeling.

The future impact of positron emission tomography in clinical and basic sciences will be closely related to further developments of detector systems with regard to sensitivity and resolution, but probably even more with respect to developments in the synthesis of relevant labeled tracer molecules. Among the interesting radionuclides, 11C is of special interest since it is a radionuclide of an element, carbon, frequently occurring in the biosystem. In this paper some of the recent progress within the field of using the short-lived radionuclide 11C with a half-life of 20.4 min is presented. The paper deals with synthetic strategies which have been applied starting from simple one-carbon precursors like 11C carbon dioxide. In these strategies the development of reliable methods for production of one-carbon and multiple-carbon precursors, as well as multiple-carbon difunctional precursors, is important. Some examples are discussed. Labeled precursors can be applied conventional types of organic synthesis, in enzyme catalyzed reactions, or by using a combination of these. The synthesis of interesting 11C labeled receptor ligands and amino acids such as alanine, valine, phenylalanine, DOPA, tryptophan, 5-hydroxytryptophan, 2-methyltyrosine and some neuropeptides are presented.

Carbon Radioisotopes↗
PubMed1989

The diabetic heart: a porcine model evaluated with positron emission tomography using 1-11C-palmitate and 3-11C-pyruvate.

The potential value of positron emission tomography (PET) in evaluating the myocardial energy metabolism was studied in two previously healthy mini-pigs before, during and after the induction of non-insulin dependent diabetes with alloxan. The distribution and kinetics of radioactivity derived from trace amounts of 11C-pyruvate and 1-11C-palmitate were followed in different sections of the myocardium. The early distribution of both tracers was similar even after the development of diabetes. The elimination of 11C-pyruvate derived radioactivity was slower in the diabetic heart. The rate of beta-oxidation was also decreased as suggested by the elimination curve of 11C-palmitate and the incorporation of 11C-palmitate into the triglyceride and phospholipid pool of the myocardium was increased in the diabetic animals. The results are consistent with previous observations using other techniques. Positron emission tomography offers the opportunity to characterize regional tissue metabolism quantitatively in vivo. This method may become a powerful tool in studying myocardial metabolism and the metabolic basis for the cardiac dysfunction in diabetes mellitus.

Animals↗
PubMed1988

Comparative double-tracer whole-body autoradiography: uptake of 11C-, 18F- and 3H-labeled compounds in rat tumors.

The uptake of various labeled compounds by tumors was studied by double-tracer whole-body autoradiography (DTWBA) in rats. Each animal carried two types of tumors: mammary carcinomas and the Walker 256 carcinosarcomas. The markers used were [18F]- and [3H]fluorodeoxyglucose (glucose utilization), [3H]thymidine (cell proliferation), [11C]methionine (amino acid metabolism) and [11C]- and [3H]toremifene (estrogen-receptor-avid agents). In each experiment, the distribution of a substance labeled with short-lived radionuclide (11C or 18F) was compared with that of another substance labeled with a long-lived nuclide (3H). Quantification was done by combining computerized image analysis of the autoradiograms with liquid scintillation counting of punched tissue pieces obtained from the cryosections. The relationships between the uptakes of the various radiopharmaceuticals were recorded in tumors and normal tissues. The dynamics of [18F]fluorodeoxyglucose and [11C]methionine were determined in tumors and some selected tissues by positron emission tomography (PET). The uptake rate between fluorodeoxyglucose and thymidine in the mammary tumor was five times higher than the ratio in the Walker tumor. The corresponding figure for FDG/methionine was four times. Thymidine, compared with methionine, was twice as efficient. Thus, the mammary tumors were best imaged with FDG or thymidine. The non-steroid antiestrogen toremifene was taken up in very low amounts by these tumors. By DTWBA, experimental tumors may serve as their own control.

Animals↗
PubMed1987

Positron emission tomography (PET) in the study of dopamine receptors in the primate brain: evaluation of a kinetic model using 11C-N-methyl-spiperone.

The regional kinetics of 11C-N-methyl-spiperone (11C-NMSP) are described in the monkey brain under tracer conditions and after displacement and protection experiments. The primary aim of the study was to investigate different methodological problems associated with use of 11C-NMSP in the quantitation of receptor properties before applying the method in clinical research. Special emphasis was placed on the evaluation of different mathematical approximations of a general compartment model. Different mathematical procedures are described and the results indicate that the approximations performed are reasonable. The simplest method for obtaining a reliable measurement of the rate constant k3 (which is approximately equal to proportional to the number of receptors) and k4 (the receptor dissociation rate constant) uses the radioactivity in the cerebellum as a measure of the tissue concentration of ligand equilibrating with the receptor compartment.

Animals↗
PubMed1987

Synthesis of L- and D-[methyl-11C]methionine.

This report describes the synthesis of L- and D-[methyl-11C]methionine in pure enantiomeric forms. The compounds were prepared routinely approximately 1,000 times with less than 20 failures. Starting with carbon-11 (11C) methyl iodide, a simple one-carbon precursor produced from a one-pot or a two-pot apparatus, L- and D-[methyl-11C]methionine were prepared, respectively, with an optical purity higher than 99% in 40%-90% radiochemical yields. The total time for synthesis, starting from [11C]carbon dioxide, was 12-15 min. The crude product usually had a radiochemical purity greater than 95%. The total time for synthesis, including LC purification, was 20-30 min. The radiochemical purity of the product in each case was greater than 98%.

Carbon Radioisotopes↗
PubMed1986

Kinetics of four 11C-labelled enkephalin peptides in the brain, pituitary and plasma of rhesus monkeys.

The kinetics of four 11C-labelled enkephalin peptides: Tyr-Gly-Gly-Phe-Met (Met-enkephalin), Tyr-D-Met-Gly-Phe-Pro-NH2 [D-Met2,Pro5)-enkephalinamide), Tyr-D-Ala-Gly-Phe-Met-NH2 (DALA) and Tyr-D-Ala-D-Ala-Phe-Met-NH2 (TAAFM) all labelled at the methyl group of methionine was studied in the Rhesus monkey. After intravenous administration, the regional kinetics in the head, lungs, liver and kidneys were followed by means of positron emission tomography (PET). The total radioactivity in blood and urine was measured and the composition of 11C-labelled peptide fragments in plasma in vivo and in vitro was analysed by liquid chromatography. With PET, an increased radioactivity was observed in the brain and pituitary over the 60-90 min investigation period after i.v. injection of the peptides. The highest radioactivities were noted for Met-enkephalin, followed by DALA and D-Met2, Pro5-enkephalinamide, while very low radioactivities were found for TAAFM. The uptake of Met-enkephalin- and DALA-derived radioactivity was of the same order as has previously been shown for morphine in the brain and considerably higher than that of D-Met2,Pro5-enkephalinamide and TAAFM, respectively. A large fraction of the brain radioactivity derived from Met-enkephalin and DALA probably emanated from [11C]methionine as indicated by plasma and urine analysis. Met-Enkephalin was rapidly eliminated from plasma in vitro with an half-life of less than two minutes, whereas DALA was stable suggesting clearance by other tissues than plasma. In conclusion, both Met-enkephalin and DALA, were rapidly hydrolyzed in vivo to [11C]methionine. [11C]Methionine was probably taken up in the brain, as the radioactivity increased with time in different brain regions as measured with PET.D-Met2,Pro5-Enkephalinamide and TAAFM were virtually stable in vivo and at least part of the radioactivity observed in the brain may have represented the intact peptide.

Animals↗
PubMed1986

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↗
PubMed1986

The synthesis of the neuropeptide Met-enkephalin and two metabolic fragments labelled with 11C in the methionine methyl group.

Starting from the corresponding N-benzyloxycarbonyl S-benzyl homocysteine peptide benzyl esters, Met-enkephalin and two metabolites, Gly-Phe-Met and Phe-Met, have been labelled with 11C for application in positron emission tomography in vivo. All labelling experiments were accomplished in high radiochemical yields within 30-40 min from start of the [11C]methyl iodide synthesis. Alkylations with this reagent were performed in liquid ammonia, using sodium to generate the free peptides with their reactive sulphide anions, essentially as previously described for [methyl-11C]methionine. The products were purified by liquid chromatography (LC) to a radiochemical purity of 98% or better.

Carbon Radioisotopes↗
PubMed1985

Protected homocysteine peptides as precursors of labelled methionine peptides. Application in preparation of methionine-enkephalin.

A synthetic scheme from N-benzyloxycarbonyl S-benzyl homocysteine peptide benzyl ester, assembled using well-established procedures in solution and purified, to the corresponding free methionine peptide, has been explored preparatively. Deprotection by sodium in liquid ammonia followed by alkylation on sulfur with methyl iodide gave, after purification by semipreparative HPLC, in the case of methionine-enkephalin a pure product in high yield. No evidence from side-reactions on tyrosine could be detected by HPLC. The scheme was primarily designed to be adaptable to the preparation of 11C-labelled methionine-enkephalin and, in particular, to exploit 11C-methyl iodide, now in routine production in our laboratory, in peptide synthesis, thus providing access to 11C-labelled enkephalins with high specific radioactivity for in vivo experiments. Applying 2H-, 3H-, 13C- or 14C-methyl iodide instead, however, this approach should be equally useful for the preparation of the corresponding peptides. Provided overalkylation by methyl iodide and fatal splitting of peptide bonds by the sodium/ammonia reagent can be avoided, the scheme should be applicable also to the synthesis of other methionine-containing peptides.

Chromatography, High Pressure Liquid↗
PubMed1984

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↗
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

[11C]methionine quantitation in cancer PET studies.

Quantitation of the uptake of positron emitting tracers in cancer patients is still unsettled. A uniform method is needed for comparison of results and for collecting a data base of tumor PET studies. We have measured the tumoral uptake of [11C]methionine in 46 cancer patients using four different methods of analysis. The accumulation of [11C]methionine at 35-40 min after the injection adjusted to the injected dose and body surface area turned out to give similar results as a more complicated method where the uptake rate of [11C]methionine from the plasma to the tumor was calculated (r = 0.92, p less than 0.0001). The results suggest that in clinical [11C]methionine PET studies, 40 min emission scanning with frequent blood sampling is unnecessary. Only a single 5 min emission scan 25-40 min after the injection is required for analysis if the accumulation is adjusted to the injected dose and body surface area.

Breast Neoplasms↗