PubMed Health⌕ Search

Biomedical subjects

L Farde

Publications and source records attributed to L Farde.

At least 109 records · Page 6Linked to original sources
PubMed1996

Characterization of the radioactive metabolites of the 5-HT1A receptor radioligand, [O-methyl-11C]WAY-100635, in monkey and human plasma by HPLC: comparison of the behaviour of an identified radioactive metabolite with parent radioligand in monkey using PET.

N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), labelled in the O-methyl group with carbon-11 (t1/2 = 20.4 min), is a promising radioligand for application with positron emission tomography (PET) to the study of 5-HT1A receptors in living human brain. An understanding of the metabolism of this new radioligand is crucial to the development of a biomathematical model for the interpretation of the kinetics of radioactivity uptake in brain in terms of receptor-binding parameters. After intravenous injection of [O-methyl-11C]WAY-100635 into humans, radioactivity was found to clear rapidly from blood and plasma. By using established methods for the analysis of radioactivity in plasma, it was found that intravenously injected [O-methyl-11C]WAY-100635 is rapidly metabolised to more polar radioactive compounds in a cynomolgus monkey and in humans. Thus, at 60 min postinjection, parent radioligand represented 40% and 5% of the radioactivity in monkey and human plasma, respectively. In monkey and human, one of the radioactive metabolites was identified as the descyclohexanecarbonyl analogue of the parent radioligand, namely [O-methyl-11C]WAY-100634. This compound is known to have high affinity for 5-HT1A receptors and alpha 1-adrenoceptors. In a PET experiment it was demonstrated that, after IV injection of [O-methyl-11C]WAY-100634 into a cynomolgus monkey, radioactivity was avidly taken up by brain. Uptake of radioactivity was higher in 5-HT1A receptor-rich frontal cortex than in cerebellum, which is devoid of 5-HT1A receptors. Polar radioactive metabolites appeared in plasma. The results suggest that the use of WAY-100635 labelled with carbon-11 in its cyclohexanecarbonyl moiety may provide enhanced signal contrast in PET studies and a possibility to develop a simple biomathematical model for regional brain radioactivity uptake.

Animals↗
PubMed1996

Preparation of [76Br]FLB 457 and [76Br]FLB 463 for examination of striatal and extrastriatal dopamine D-2 receptors with PET.

Both FLB 457 and FLB 463, two substituted benzamides with high affinity for the dopamine D-2 receptors, were labeled with bromine-76 for PET investigations. [76Br]FLB 457 was prepared by electrophilic substitution of the tributyltin precursor. The radiochemical yield was 80%. [76Br]FLB 463 was prepared by a direct electrophilic substitution enhanced by the hydroxyl group of the debromo analogue, with a total radiochemical yield of 50%. Radiochemical and chemical purity values of the radioligands as analyzed by radio-TLC and HPLC were > 99%, and the specific radioactivity was -40 GBq/mumol. During PET examinations of [76Br]FLB 457 and [76Br]FLB 463 binding in baboons there was a rapid and high uptake in the striatum. The striatal radioactivity concentration reached a plateau 1 h postinjection (p.i.). The striatum-to-cerebellum radioactivity concentration ratio increased from 11 at 1 h p.i., to 28 at 4 h p.i. for [76Br]FLB 457, owing to a continuous wash-out from the cerebellum. For [76Br]FLB 463 the corresponding value increased from 10 to 19.5. [76Br]FLB 457 has in contrast to [76Br]FLB 463 a high uptake in thalamic structures and has therefore an additional potential as a radioligand for PET examination of extrastriatal dopamine D-2 receptors in the living human brain.

Animals↗
PubMed1996

11C- and 76Br-labelled NNC 22-0010, selective dopamine D1 receptor radioligands for PET.

NNC 22-0010 is a new dopamine antagonist with a high affinity and selectivity for D1 receptors in vitro. NNC 22-0010 has both an N-methyl group and a bromine, which allows radiolabelling with either 11C or 76Br. We labelled [11C]NNC 22-0010 by N-methylation of the free base of the secondary amine with [11C]methyl iodide in a total radiochemical yield of 40%. The total synthesis time was 30 min. The specific radioactivity at time of injection of the radioligand was 48 to 55 GBq/mumol. The [76Br]NNC 22-0010 was synthesized from the iodine precursor by an exchange reaction with 76Br using a Cu(+)-assisted nucleophilic substitution reaction. The radiochemical yield was 60% after purification. Specific radioactivity at time of injection of the radioligand was 6 to 20 GBq/mumol. In PET experiments with [11C]NNC 22-0010 and [76Br]NNC 22-0010 there was a rapid uptake of radioactivity in the monkey brain. The striatum-to-cerebellum ratio was 2-2.5 after 1 h. Binding in the striatum was displaced by SCH 23390, whereas binding in the cerebellum was not reduced. Metabolite studies showed that 1 h after injection about 20% of the radioactivity in plasma represented unchanged radioligand. This value was on the same level for at least 6 h. The results indicate that radiolabelled NNC 22-0010 has potential for imaging dopamine D1 receptors selectively in the human brain.

Animals↗
PubMed1995

No elevated D2 dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and [11C]N-methylspiperone.

The dopamine hypothesis of schizophrenia received strong support when a two- to three-fold elevation of D2 receptor densities was demonstrated by positron emission tomography (PET) and [11C]N-methylspiperone ([11C]NMSP). In the present study, the reproducibility of this finding was examined by application of a similar method in seven normal comparison subjects and seven neuroleptic-naive schizophrenic patients examined by PET before and after administration of haloperidol, 7.5 mg. After haloperidol, the specific binding of [11C]NMSP was reduced by 80-90%, resulting in a signal-to-noise ratio that was unfavorably low for reliable quantification. No significant difference was found between normal subjects and patients in a descriptive analysis of the time-activity curves or in a nonequilibrium graphical determination of D2 receptor densities in the basal ganglia. The results are consistent with those of a previous quantitative PET study of [11C]raclopride binding, which showed normal densities of D2 receptors in the striatum of neuroleptic-naive schizophrenic patients.

Adult↗
PubMed1995

Lipophilic metabolite of [123I]beta-CIT in human plasma may obstruct quantitation of the dopamine transporter.

I-123 or C-11 labelled 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane (beta-CIT) is a recently developed radioligand for the study of dopamine and serotonin reuptake sites in humans with single photon emission tomography (SPET) or positron emission tomography (PET). Determination of the radioligand metabolite pattern is fundamental for a quantitative analysis of radioligand binding. The metabolism of [123I]beta-CIT was determined by a gradient HPLC method in plasma samples of six human subjects. Two metabolites of [123I]beta-CIT were found, a polar and a lipophilic. At 4 h after [123I]beta-CIT injection the percentages of parent compound and polar and lipophilic metabolites were 23 +/- 3% (mean +/- SD), 33 +/- 11%, and 44 +/- 8%, respectively. The lipophilic metabolite might pass the blood-brain barrier and account for a fraction of free and nonspecifically bound radioactivity in brain. The existence of a lipophilic metabolite of [123I]beta-CIT may obstruct the use of simple ratio methods for quantitation of the dopamine transporter in brain.

Adult↗
PubMed1995

Variability in D2-dopamine receptor density and affinity: a PET study with [11C]raclopride in man.

The variability of D2-dopamine receptor binding parameters in man was determined using Positron Emission Tomography (PET) and [11C]raclopride. A saturation analysis based on five PET-experiments was performed in each of ten men and ten women. The mean density of D2-dopamine receptors (Bmax) was 28 +/- 6.9 pmol/ml (mean +/- S.D.) and the apparent affinity (Kdapp) 9.1 +/- 1.9 pmol/ml. The Hill coefficient was in all subjects close to unity (nH: 0.999 +/- 0.020), thereby indicating binding to a homogeneous class of receptors. No significant differences between males and females were found in Bmax or Kdapp. The interindividual difference in Bmax was statistically significant (alpha = 0.01). The difference in Kdapp was not significant. Upregulation of the receptor density (Bmax) has been widely discussed as a mechanism for increased dopaminergic neurotransmission in schizophrenia. This study indicates that receptor density varies considerably in a group of healthy subjects.

Adult↗
PubMed1995

Oral administration of NNC 756--a placebo controlled PET study of D1-dopamine receptor occupancy and pharmacodynamics in man.

NNC 756 is a new benzazepine with high affinity and selectivity for D1-dopamine receptors. In a double-blind, placebo controlled, cross-over study, positron emission tomography and the radioligand [11C]SCH 23390 were used to determine central D1-dopamine receptor occupancy after a single oral dose of 80 mg NNC 756 in three healthy men. NNC 756 induced 75, 66 and 47% occupancy of D1-dopamine receptors in the putamen of at 1.5 h after drug administration and 46, 36 and 24% after 7.5 h. There was a hyperbolic relationship between the occupancy values and the serum concentrations. The Ki value for the hyperbola was 6.4 ng/ml (+/- SD 1.4). The occupancy at 1.5 h is on the same level as that shown to induce effects in animal models for prediction of antipsychotic effect. Restlessness (akathisia) appeared in two subjects and nausea in one subject at time of peak drug concentration in serum. The oral dose level of 80 mg should be appropriate to investigate the potential antipsychotic effect of NNC 756.

Administration, Oral↗
PubMed1995

Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man.

SCH 39166 is the first selective D1-dopamine receptor antagonist developed for clinical trials in schizophrenia. SCH 39166 was evaluated as a radioligand for PET, labeled with 11C, and as a D1-dopamine receptor antagonist after single oral doses in healthy men. After intravenous injection of [11C]SCH 39166 distribution of radioactivity in brain grossly reflected D1-dopamine receptor density. The putamen to cerebellum ratio at equilibrium was low (1.54 +/- 0.18 SD), which makes [11C]SCH 39166 less suitable as a radioligand for applied PET studies. Saturability of specific binding was demonstrated after IV injection of [11C]SCH 39166 with low specific radioactivity. Stereospecificity of binding was examined using the stereoisomer [11C]SCH 39165. D1-Receptor occupancy was demonstrated with [11C]SCH 39166 2 h after administration of single oral doses of unlabeled SCH 39166 to each of three healthy subjects (25, 100 and 400 mg). There was a substantial reduction of specific [11C]SCH 39166 uptake in the putamen after all doses. Single oral doses of 100 mg induced approximately 70% D1-dopamine receptor occupancy in the basal ganglia, which should be sufficient to investigate the antipsychotic potential of D1-dopamine receptor antagonism in clinical studies.

Adult↗
PubMed1995

Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients.

SCH 39166 is the first selective D1 dopamine receptor antagonist developed for the treatment of schizophrenic patients. To examine potential antipsychotic effect, tolerability and safety, SCH 39166 was given orally to 17 acutely ill drug free schizophrenic patients (DSMIIIR) in an open 4-week study. Doses were escalated from 10 to 100 mg b.i.d. according to a fixed schedule over 17 days and remained at 100 mg b.i.d. for another 11 days. The drug was withdrawn prematurely in ten patients because of deterioration or refusal to take SCH 39166. In the nine patients participating for more than 2 weeks, none had an apparent reduction of BPRS or CGI scores. Side effects were agitation, akathisia and emesis in single patients. After withdrawal of SCH 39166 of the patients improved when treated with classical neuroleptics or clozapine. The result of the study does not support the prediction that selective D1 dopamine receptor antagonism will produce antipsychotic effects in schizophrenia.

Adult↗
PubMed1995

Effect of clozapine and risperidone on 5-HT2 and D2-dopamine receptor binding in the post-mortem human brain. An autoradiographic study.

Effects of the antipsychotics risperidone and clozapine on 5-HT2 and D2-dopamine receptor binding were examined using [3H]N-methylspiperone ([3H]NMSP) and in vitro receptor autoradiography on human whole hemisphere cryosections. The 5-HT2 receptor antagonist ketanserin and the D2-dopamine receptor antagonist raclopride were used as references. [3H]NMSP binding was observed in caudate nucleus, putamen, and cerebral cortex indicating binding to D2-dopamine and 5-HT2 receptors. Risperidone and clozapine counteracted the binding to both receptor types. This was in contrast to raclopride, which selectively blocked the D2-dopamine receptors in the basal ganglia, and ketanserin, which selectively blocked the 5-HT2 receptors in the cerebral cortex. Risperidone (100 nM and 10 microM) blocked up to 90% of [3H]NMSP binding to both receptor types, whereas the blocking capacity of clozapine (10 microM) was lower (approximately 60%). The lack of total blockade of D2-dopamine receptors is in line with results obtained in with [11C]raclopride and positron emission tomography studies of clozapine treated human subjects. However, autoradiographic studies of clozapine competition of [3H]raclopride binding show total displacement of the binding at high clozapine concentrations, thus contradicting the PET results with [11C]raclopride, as well as the autoradiographic results obtained with [3H]NMSP. In conclusion it can be stated that pharmacological concentrations of the two drugs clozapine and risperidone block a large proportion of D2-dopamine receptors and 5-HT2 receptors in the human brain. Moreover, the study shows the usefulness of human whole hemisphere autoradiography for the study of interaction of drugs with different central neurotransmitter receptors.

Adult↗
PubMed1995

PET imaging of neuroreceptors in schizophrenia.

Among the brain imaging techniques developed during the past two decades positron emission tomography has the highest sensitivity, allowing the analysis of specific neurotransmitter mechanisms in the living human brain. By using a combination of selective ligands labelled with positron emitting isotopes, D1 and D2 dopamine, serotonin 5HT2 and benzodiazepine receptors were examined in schizophrenic patients (DSM-IIIR) and healthy control subjects. With this technique receptor populations could be excellently visualized and quantified with regard to number and binding characteristics in several brain regions. The characteristics of total D1 and D2 dopamine receptor populations in the caudate and putamen did not differ significantly in young drug naive schizophrenic patients and age matched control subjects. On the other hand, there was a highly significant reduction of the D1 signal in high intensity regions of the basal ganglia when [11C]SCH 23390, a selective D1 dopamine receptor antagonist, was used. These results suggest the possibility of a reduced D1 dopamine receptor density in the patch compartment of the basal ganglia in schizophrenia. For 5HT2 and benzodiazepine receptors no major alteration of receptor characteristics was observed in several neocortical and limbic brain regions.

Humans↗
PubMed1995

Synthesis and binding properties of [3H]NNC 12-0781, a new radioligand for the dopamine reuptake system.

The tritiated dopamine reuptake inhibitor [3H]NNC 12-0781 ([1-[2-(bis(4-fluorophenyl)-methoxy)-ethyl]-4-(3-(2-furanyl)-2,3-[3H] - propyl)-piperazine) was radiolabelled in one step starting from 1-[2-(bis(4-fluorophenyl)-methoxy)-ethyl]-4-(3-(2-furanyl)-2-propenyl)- piperazine, using tritium gas and PdO as catalyst. The radiochemical purity of [3H]NNC 12-0781 was higher than 99% after HPLC purification with a specific radioactivity of 21 Ci/mmol. [3H]NNC 12-0781 bound specifically to rat striatum in vitro at +4 degrees C with a Kd of 1.76 nM and Bmax of 587 fmol/mg tissue. The nonspecific binding was about 10% at Kd. At +37 degrees C no acceptable binding was observed. The association of [3H]NNC 12-0781 thus has the characteristics of a radioligand for the dopamine transporter in vitro at +4 degrees C.

Animals↗
PubMed1995

[O-methyl-11C]beta-CIT-FP, a potential radioligand for quantitation of the dopamine transporter: preparation, autoradiography, metabolite studies, and positron emission tomography examinations.

beta-CIT-FP [N-(3-fluoropropyl)-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane] is a cocaine analogue with a high affinity for the dopamine transporter. [O-methyl-11C]beta-CIT-FP ([11C]beta-CIT-FP) was prepared by O-alkylation of the free acid with [11C]methyl iodide. The total radiochemical yield of [11C]beta-CIT-FP was 50 to 60% with an overall synthesis time of 30 min. The radiochemical purity was > 99%, and the specific radioactivity at time of injection was about 37 GBq/mumol (1000 Ci/mmol). Autoradiographic examination of [11C]beta-CIT-FP binding in human brain postmortem demonstrated specific binding in the caudate nucleus and putamen. Positron emission tomography (PET) examination of [11C]beta-CIT-FP in a Cynomolgus monkey demonstrated accumulation in the striatum with a striatum-to-cerebellum ratio of about 8 after 60 min. Equilibrium in the striatum was attained within 70 to 90 min. The radioactivity ratios of thalamus/cerebellum and neocortex/cerebellum were about 2 and 1.5, respectively. In a displacement experiment, radioactivity in the striatum but not in the cerebellum was reduced after injection of beta-CIT, indicating that striatal radioactivity following injection of [11C]beta-CIT-FP is associated with dopamine transporter sites and that the binding is reversible. The fraction of the total radioactivity in plasma representing [11C]beta-CIT-FP determined by high-performance liquid chromatography (HPLC) was 84% at 15 min and 50% at 95 min. [11C]beta-CIT-FP should be a useful PET radioligand for the quantitation of dopamine transporters in the human brain in vivo.

Animals↗