Search PubMed⌕ Search

Biomedical subjects

C Halldin

Publications and source records attributed to C Halldin.

At least 199 records · Page 11Linked to original sources
PubMed1990

Syntheses of [123I]-, [125I]- and unlabelled (S)-3-iodo-5,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]salicylamide (NCQ 298), selective ligands for the study of dopamine D-2 receptors.

The salicylamide NCQ 298, (S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylami de (4), binds with a high affinity and selectivity to central dopamine D-2 receptors. In the present paper the synthesis of NCQ 298 and the efficient labelling both with 123I and 125I are described. The unlabelled NCQ 298 was synthesized by iodination of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,5,6-trimethoxybenzamide followed by demethylation with boron tribromide, which produced 4 and the regioisomer 5 in a ratio of 82:18. The two isomeric salicylamides were separated by radial chromatography and tested for their abilities to inhibit the binding of [3H]raclopride to rat striatal membranes in vitro in relation to some representative salicylamides. The 5,6-dimethoxysalicylamide 4 (NCQ 298) was found to be considerably more active than the corresponding 6-methoxysalicylamide 10 (FLA 961 or IBZM). The radioligands [123I]NCQ 298 and [125I]NCQ 298 were prepared in a carrier-free form from the corresponding desiodo compound by the chloramine-T protocol and isolated by semipreparative HPLC. The total radiochemical yields of [123I]NCQ 298 and [125I]NCQ 298 (based on [123I]- and [125I]iodide and decay-corrected) were 88% and 93%, respectively, with a radiochemical purity of greater than 99%. [125I]NCQ 298 will be studied to evaluate its potential as a radioligand in studies requiring a high specific activity, selectivity and high potency to label dopamine D-2 receptors. [123I]NCQ 298 has potential as a radioligand for the in vivo examination of central dopamine D-2 receptors in human brain by Single Photon Emission Computed Tomography (SPECT).

Animals↗
PubMed1989

Localization of monoamine oxidase B in human brain by autoradiographical use of 11C-labelled L-deprenyl.

11C-labelled L-deprenyl in vitro autoradiography was used to study the regional distribution of MAO-B in human brain. 80 microns thick cryosections from two human brains, a 67 years old female and a 58 years old male, were taken on tape/paper and transferred on to a gelatinized glass plate. The sections were then incubated with 34 and 54 nM 11C-L-deprenyl for 15 min and exposed to a film sensitive to high energy radiation for 2 hours. The autoradiograms obtained were analyzed by computerized densiotometry. High 11C-deprenyl binding was found in the caudate nucleus, putamen, thalamus, substantia nigra, medial and lateral geniculate bodies, hippocampus and periaqueductal gray. Moderate to low binding was observed in cerebral cortex. Cerebral cortex and white matter showed the lowest binding. The autoradiographic technique described proved to be a fast and reliable method to investigate the topographic localization of MAO-B in large cryosections of human brain.

Aged↗
PubMed1989

11C-labelling of dimethylphenethylamine in two different positions and biodistribution studies.

Dimethylphenethylamine (DMPA), a substrate for the B-form of the monoamine oxidase enzyme (MAO, EC 1.4.3.4), was labelled with 11C in two different positions; in the methyl group (M-DMPA) and in the phenethyl group (P-DMPA). M-DMPA was prepared by N-alkylation of methylphenethylamine with [11C]methyl iodide and P-DMPA was prepared by N-alkylation of dimethylamine with [1-11C]phenethyl iodide. The radiochemical yields were 30-35% (M-DMPA) and 10% (P-DMPA), based on [11C]carbon dioxide, with overall synthesis times of 30-35 min (M-DMPA) and 50 min (P-DMPA). The compounds were isolated by semi-preparative HPLC and the radiochemical purity was in both cases greater than 99%. The biodistributions of 11C-labelled M-DMPA [correction of M-DPMA] and P-DMPA were studied in rat brain by dissection and in the brain of a Rhesus monkey by positron emission tomography (PET).

Animals↗
PubMed1989

On-line synthesis of [11C]nitroalkanes.

The on-line synthesis of 1-11C-labelled nitroalkanes [nitromethane (I), nitroethane (II) and nitropropane (III)], from their corresponding 1-11C-labelled alkyl iodides, by use of a heated silver nitrite column is described. The radiochemical yields of I, II and III were of the order of 40-70%, based on the corresponding [1-11C]alkyl iodides. The total radiochemical yields, starting from [11C]carbon dioxide, were of the order of 25-55% with an overall synthesis time of 8-15 min.

Alkanes↗
PubMed1989

Synthesis of [11C]sodium thiocyanate for in vivo studies of anion kinetics using positron emission tomography (PET).

Sodium thiocyanate (NaSCN) was labelled with carbon-11 for in vivo studies of anion kinetics using positron emission tomography (PET). The synthesis was complete in 35 min from end of bombardment using [11C]ammonium cyanide as the labelled precursor. [11C]NaSCN was produced by the reaction of [11C]sodium cyanide with elemental sulfur and subsequently separated by semi-preparative high performance liquid chromatography (HPLC). Radiochemical yields (isolated) were of the order of 25%. The specific activity was 18 GBq/mmol and the radiochemical purity better than 99%. A PET study performed in a healthy volunteer showed distribution of [11C]SCN- to areas corresponding to cortical fluid spaces known to be accessible to inorganic ions such as Cl-. An accumulation of the tracer was observed during the 70 min investigation, indicating at least three compartments of distribution.

Anions↗
PubMed1989

Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET--a comparison to the equilibrium analysis.

[11C]Raclopride binding to central D2-dopamine receptors in humans has previously been examined by positron emission tomography (PET). Based on the rapid occurrence of binding equilibrium, a saturation analysis has been developed for the determination of receptor density (Bmax) and affinity (Kd). For analysis of PET measurements obtained with other ligands, a kinetic three-compartment model has been used. In the present study, the brain uptake of [11C]raclopride was analyzed further by applying both a kinetic and an equilibrium analysis to data obtained from four PET experiments in each of three healthy subjects. First regional CBV was determined. In the second and third experiment, [11C]-raclopride with high and low specific activity was used. In a fourth experiment, the [11C]raclopride enantiomer [11C]FLB472 was used to examine the concentration of free radioligand and nonspecific binding in brain. Radio-activity in arterial blood was measured using an automated blood sampling system. Bmax and Kd values for [11C]raclopride binding could be determined also with the kinetic analysis. As expected theoretically, those values were similar to those obtained with the equilibrium analysis. In addition, the kinetic analysis allowed separate determination of the association and dissociation rate constants, kon and koff, respectively. Examination of [11C]raclopride and [11C]FLB472 uptake in brain regions devoid of specific D2-dopamine receptor binding indicated a fourth compartment in which uptake was reversible, nonstereoselective, and nonsaturable in the dose range studied.

Adult↗
PubMed1989

Clinical melperone treatment blocks D2-dopamine receptors in the human brain as determined by PET.

Positron emission tomography and 11-C-labelled raclopride was used to determine central D2-dopamine receptor occupancy in three melperone treated patients. Treatment with melperone in daily doses of 250 and 300 mg for 3 to 6 weeks, resulted in a receptor occupancy above 70%. Thus, clinical doses of melperone as we previously demonstrated for several classical neuroleptics cause a substantial D2-dopamine receptor blockade in the human brain in vivo.

Adult↗
PubMed1988

Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs.

Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy was found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.

Adult↗
PubMed1988

Stereoselective binding of 11C-raclopride in living human brain--a search for extrastriatal central D2-dopamine receptors by PET.

The selective D2-dopamine receptor antagonist raclopride and its pharmacologically inactive (R)-enantiomer FLB472 were labelled with 11C and used in a study with positron emission tomography to examine the stereoselectivity of 11C-raclopride binding to central D2-dopamine receptors in three healthy men. After the injection of 11C-raclopride, there was a high accumulation of radioactivity in the dopamine-rich basal ganglia, whereas after the injection of 11C-FLB472 there was no such accumulation of radioactivity. Thus, the binding of 11C-raclopride is stereoselective. Distribution ratios [radioactivity in a brain region/"free" (not protein-bound) radioactivity in plasma] were calculated for the two enantiomers to study regional differences in the accumulation of radioactivity. The distribution ratios in white matter were similar for the two enantiomers. In the putamen, a three to four-fold higher distribution ratio was found for 11C-raclopride than for 11C-FLB472, reflecting the presence of specific binding of 11C-raclopride binding to D2-dopamine receptors in the basal ganglia. In the temporal and frontal cortices the distribution ratios were, however, only a few per cent higher for 11C-raclopride than for 11C-FLB472, indicating that if D2-dopamine receptors are present in the human neocortex, then their density is indeed very low.

Adult↗
PubMed1988

11C-labelling of Ro 15-1788 in two different positions, and also 11C-labelling of its main metabolite Ro 15-3890, for PET studies of benzodiazepine receptors.

The benzodiazepine receptor antagonist Ro 15-1788 has been labelled with 11C in two different positions [( methyl-11C]Ro 15-1788 (I) and [ethyl-11C]Ro 15-1788 (II]. Product I was prepared by N-alkylation of the desmethyl compound (Ro 15-5528) with [11C]methyl iodide and product II was prepared by esterification of the desethyl compound (Ro 15-3890) with [11C]ethyl iodide. Ro 15-3890, the main metabolic product of Ro 15-1788, was labelled by two synthetic routes. In route A, [methyl-11C]Ro 15-3890 (III) was prepared by N-alkylation of the corresponding desmethyl compound (Ro 15-6877) with [11C]methyl iodide. In route B, III was prepared by a subsequent hydrolysis of I. The radiochemical yields were on the order of 15-60% (EOB) with an overall synthesis time of 40-50 min. Compounds I, II and III were isolated by semi-preparative HPLC and the radiochemical purity was in all cases greater than 99%.

Carbon Radioisotopes↗
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

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

The Bücherer-Strecker synthesis of D- and L-(1-11C)tyrosine and the in vivo study of L-(1-11C)tyrosine in human brain using positron emission tomography.

The synthesis of D- and L-(1-11C)tyrosine, starting with 11C-cyanide, is reported. DL-(1-11C)Tyrosine was prepared by the Bücherer-Strecker reaction, from carrier added 11C-cyanide with an incorporation of 80% in 20 min. The isolation of the pure D- and L-amino acid isomers from the enantiomeric mixture was accomplished within 15 min by preparative HPLC using a chiral stationary phase and a phosphate buffer as the mobile phase. Typically, the total synthesis time was 50 min (including purification) from end of trapping of 11C-cyanide, with a radiochemical yield of D- and L-amino acid of 40%-60%. The D- and L-(1-11C)tyrosine were both obtained optically pure, with a carrier added specific activity of 0.3-0.5 Ci/mmol and a radiochemical purity better than 99%. The 11C labelled L-tyrosine was used in an in vivo study in the human brain using positron emission tomography (PET).

Brain↗
PubMed1987

Turnover of brain monoamine oxidase measured in vivo by positron emission tomography using L-[11C]deprenyl.

The distribution of carbon-11-labeled L-deprenyl, an irreversible inhibitor of monoamine oxidase type B (MAO-B), was determined in the baboon brain by positron emission tomography. The irreversible blood-to-brain transfer constant (influx constant, Ki) was measured using a complete metabolite-corrected arterial plasma concentration curve. This influx constant was used as a measure of functional enzyme activity for sequential determinations of MAO-B recovery following a single high dose of unlabeled L-deprenyl. The half-life for turnover of MAO-B was thus determined to be 30 days. Using appropriate irreversible inhibitors, this procedure should be generally useful for determining enzyme turnover rates in any organ in vivo and can be applied to some human studies as well.

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↗