PubMed Health⌕ Search

Biomedical subjects

Lars Farde

Publications and source records attributed to Lars Farde.

At least 37 records · Page 2Linked to original sources
PubMed2005

Post-mortem human brain autoradiography of the norepinephrine transporter using (S,S)-[18F]FMeNER-D2.

The binding of the norepinephrine transporter radioligand, (S,S)-[18F]FMeNER-D2, to human brain post-mortem was examined in vitro by whole hemisphere autoradiography. The rank order for the density of labelling was: locus coeruleus>>cortex approximately cerebellum approximately thalamus>caudate approximately putamen. The NET-selectivity of binding was confirmed by co-incubation with desipramine. The dual NET/SERT inhibitor duloxetine also inhibited specific binding, whereas PE2I or citalopram had no evident effect.

Adrenergic Uptake Inhibitors↗
PubMed2005

Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity.

BACKGROUND: The hypothesis that altered dopamine transmission underlies hyperactive-inattentive behavior in children with attention-deficit/hyperactivity disorder (ADHD) is based on genetic studies and the efficacy of psychostimulants. Most of previous positron emission tomography (PET) and single photon emission tomography (SPET) studies have shown altered binding of dopamine markers in the basal ganglia. Yet, the functional role of the neurochemical disturbances are poorly understood. The purpose of our study was to examine dopamine transporter (DAT) and dopamine D2 receptor (D2R) binding in adolescents with ADHD and to search for its relationship with cognitive functions as well as locomotor hyperactivity. METHODS: Twelve adolescents with ADHD and 10 young adults were examined with PET using the selective radioligands [11C]PE2I and [11C]raclopride, indexing DAT and D2R density. The simplified reference tissue model was used to calculate binding potential (BP) values. Attention and motor behavior were investigated with a continuous performance task (CPT) and motion measurements. RESULTS: The BP value for [11C]PE2I and [11C]raclopride in the striatum of children with ADHD did not differ from that of the young adult control subjects. In the midbrain, however, the BP values for DAT were significantly lower (16%; p = .03) in children with ADHD. Dopamine D2 receptor binding in the right caudate nucleus correlated significantly with increased motor activity (r = .70, p = .01). CONCLUSIONS: The lower BP values for DAT in the midbrain suggest that dopamine signaling in subjects with ADHD is altered. Altered dopamine signaling might have a causal relationship to motor hyperactivity and might be considered as a potential endophenotype of ADHD.

Adolescent↗
PubMed2005

N-oxide analogs of WAY-100635: new high affinity 5-HT(1A) receptor antagonists.

WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-desmethyl derivative DWAY 2 are well-known high affinity 5-HT(1A) receptor antagonists, which when labeled with carbon-11 (beta+; t(1/2) = 20.4 min) in the carbonyl group are effective radioligands for imaging brain 5-HT(1A) receptors with positron emission tomography (PET). In a search for new 5-HT(1A) antagonists with different pharmacokinetic and metabolic properties, the pyridinyl N-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3, in which the pyridinyl ring of 1 was oxidized to the pyridinyl N-oxide, was prepared via nucleophilic substitution of 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethylamine on 2-chloropyridine-N-oxide followed by acylation with cyclohexanecarbonyl chloride. 6Cl-NOWAY 4, a more lipophilic (pyridinyl-6)-chloro derivative of 3, was prepared by treating 1-(2-methoxyphenyl)-4-(2-(2-(6-bromo)aminopyridinyl-N-oxide)ethyl)piperazine with cyclohexanecarbonyl chloride for acylation and concomitant chloro for bromo substitution. NEWWAY 5, in which the 2-hydroxy-phenyl group of 2 is replaced with a 2-pyridinyl N-oxide group with the intention of mimicking the topology of 2, was prepared in five steps from 2-(chloroacetylamino)pyridine. N-Oxides 3-5 were found to be high affinity antagonists at 5-HT(1A) receptors, with 3 having the highest affinity and a Ki value (0.22 nM) comparable to that of 1 (0.17 nM). By calculation the lipophilicity of 3 (LogP = 1.87) is lower than that of 1 by 1.25 LogP units while TLC and reverse phase HPLC indicate that 3 has slightly lower lipophilicity than 1. On the basis of these encouraging findings, the N-oxide 3 was selected for labeling with carbon-11 in its carbonyl group and for evaluation as a radioligand with PET. After intravenous injection of [carbonyl-11C]3 into cynomolgus monkey there was very low uptake of radioactivity into brain and no PET image of brain 5-HT(1A) receptors was obtained. Either 3 inadequately penetrates the blood-brain barrier or it is excluded from brain by an active efflux mechanism. Rapid deacylation of 3 was not apparent in vivo; in cynomolgus monkey plasma radioactive metabolites of [carbonyl-11C]3 appeared less rapidly than from the radioligands [carbonyl-11C]1 and [carbonyl-11C]2, which are known to be primarily metabolized by deacylation. Ligand 3 may have value as a new pharmacological tool, but not as a radioligand for brain imaging.

Animals↗
PubMed2005

The role of the striatal dopamine transporter in cognitive aging.

We examined the relationship of age-related losses of striatal dopamine transporter (DAT) density to age-related deficits in episodic memory and executive functioning in a group of subjects (n = 12) ranging from 34 to 81 years of age. The radioligand [(11)C]beta-CIT-FE was used to determine DAT binding in caudate and putamen. Results showed clear age-related losses of striatal DAT binding from early to late adulthood, and a marked deterioration in episodic memory (word and figure recall, face recognition) and executive functioning (visual working memory, verbal fluency) with advancing age. Most importantly, the age-related cognitive deficits were mediated by reductions in DAT binding, whereas DAT binding added systematic cognitive variance after controlling for age. Further, interindividual differences in DAT binding were related to performance in a test of crystallized intelligence (the Information subtest from the Wechsler Adult Intelligence Scale-Revised) that showed no reliable age variation. These results suggest that DAT binding is a powerful mediator of age-related cognitive changes as well as of cognitive functioning in general. The findings were discussed relative to the view that the frontostriatal network is critically involved in multiple cognitive functions.

Adult↗
PubMed2005

Regional reductions in serotonin 1A receptor binding in juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is classified as primarily generalized epilepsy and as such is assumed to lack an anatomic substrate. Although neurochemical abnormalities are probable, few studies have investigated whether they exist in JME. Animal data and the high incidence of myoclonic seizures in serotonin-intoxicated patients suggest that the serotonin system may be disturbed in JME. OBJECTIVE: To test the hypothesis that JME is associated with a disturbed serotonin system and that this disturbance could be reflected in altered serotonin 1A receptor binding. DESIGN: The serotonin 1A receptor binding potential (BP) was measured with positron emission tomography and serotonin 1A receptor antagonist carbonyl-carbon 11-WAY-100635. The BP was calculated using a reference tissue model in several limbic and neocortical regions and the raphe nuclei. SETTING: Epilepsy clinics of the Karolinska University Hospital, Stockholm, Sweden. PATIENTS: Eleven patients with JME and 11 controls were studied. MAIN OUTCOME MEASURE: Serotonin 1A receptor BP calculated in a set of volumes of interest. RESULTS: The patients with JME showed a reduced BP in the dorsolateral prefrontal cortex, raphe nuclei, and hippocampus. CONCLUSIONS: The observed reductions in serotonin 1A receptor BP suggest that the serotonin system is affected in JME. Although the data give no definitive information about underlying mechanisms, they provide a strong argument for the view that not all brain regions are homogeneously involved in this condition, further questioning the current classification of primarily generalized epilepsy.

Adult↗
PubMed2005

A preliminary PET evaluation of the new dopamine D2 receptor agonist [11C]MNPA in cynomolgus monkey.

This study describes the preliminary positron emission tomography (PET) evaluation of a dopamine D(2)-like receptor agonist, (R)-2-(11)CH(3)O-N-n-propylnorapomorphine ([(11)C]MNPA), as a potential new radioligand for in vivo imaging of the high-affinity state of the dopamine D(2) receptor (D(2)R). MNPA is a selective D(2)-like receptor agonist with a high affinity (K(i)=0.17 nM). [(11)C]MNPA was successfully synthesized by direct O-methylation of (R)-2-hydroxy-NPA using [(11)C]methyl iodide and was evaluated in cynomolgus monkeys. This study included baseline PET experiments and a pretreatment study using unlabeled raclopride (1 mg/kg). High uptake of radioactivity was seen in regions known to contain high D(2)R, with a maximum striatum-to-cerebellum ratio of 2.23+/-0.21 at 78 min and a maximum thalamus-to-cerebellum ratio of 1.37+/-0.06 at 72 min. The pretreatment study demonstrated high specific binding to D(2)R by reducing the striatum-to-cerebellum ratio to 1.26 at 78 min. This preliminary study indicates that the dopamine agonist [(11)C]MNPA has potential as an agonist radioligand for the D(2)-like receptor and has potential for examination of the high-affinity state of the D(2)R in human subjects and patients with neuropsychiatric disorders.

Animals↗
PubMed2005

Quantification of 11C-MADAM binding to the serotonin transporter in the human brain.

UNLABELLED: (11)C-N,N-Dimethyl-2-(2-amino-4-methylphenylthio)benzylamine ((11)C-MADAM) is a newly synthesized radioligand with high selectivity and specificity for the serotonin transporter (5-HTT) in a monkey model. The purpose of this study in humans was to examine the suitability and potential of (11)C-MADAM for quantitative PET studies of 5-HTT in applied clinical studies on the pathophysiology and treatment of neuropsychiatric disorders. METHODS: PET examination was performed on each of 9 male subjects after intravenous injection of (11)C-MADAM with high specific radioactivity. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. A metabolite-corrected arterial input function was used in kinetic 2- and 3-compartment analyses. Cerebellum was used as the reference region in a cross-validation of 6 reference tissue approaches. RESULTS: The highest radioactivity concentration was detected in the raphe nuclei, followed consecutively by the striatum, hippocampal complex, cingulate cortex, neocortex, and cerebellum. The time-activity curve for the fraction of unchanged (11)C-MADAM in plasma was best described by a sigmoid function. After 50 min, the fraction was 40%. The labeled metabolites were more polar than the mother compound. The compartment model approaches converged, and could describe the time-activity curves in all regions. The total volume of distribution (V(t)) was similar to the regional distribution volumes obtained by the linear graphic analysis. The binding potentials (BPs) for 6 different approaches yielded similar values in all regions but the raphe nuclei, where the 2 equilibrium methods provided lower values. CONCLUSION: The regional binding distribution of (11)C-MADAM is consistent with postmortem data acquired with (3)H-MADAM as well as with that of other reference ligands in vitro. The time-activity curves were well described by current major quantitative approaches. The suitability of the cerebellum as a reference region for nonspecific (11)C-MADAM binding could be confirmed, thus paving the way for experimentally less demanding approaches, such as the simplified reference tissue model, for applied clinical studies.

Adult↗
PubMed2004

[11C]vinpocetine: a prospective peripheral benzodiazepine receptor ligand for primate PET studies.

Vinpocetine, a synthetic derivative of the Vinca minor alkaloid vincamine, is a widely used drug in neurological practice. We tested the hypothesis that vinpocetine binds to peripheral benzodiazepine binding sites (PBBS) and is therefore a potential ligand of PBBS. Positron emission tomography (PET) measurements in two cynomolgous monkeys showed that pretreatment with vinpocetine markedly reduced the brain uptake of [11C]PK11195, a known PBBS radioligand. On the other hand, whereas pretreatment with PK11195 increased the brain uptake of [11C]vinpocetine due to the blockade of PBBS in the periphery, it significantly reduced the binding potential (BP) values of [11C]vinpocetine in the whole brain and in individual brain structures to PK11195. These findings indicate that, whereas the two ligands have different affinities to PBBS, vinpocetine is a potent ligand of PBBS, which in turn suggests that the pharmacological activity of vinpocetine may involve the regulation of glial functions.

Animals↗
PubMed2004

A cross-validation study on the relationship between central D2 receptor occupancy and serum perphenazine concentration.

RATIONALE: There is a need for laboratory measures to guide clinical treatment with antipsychotic drugs. For serum concentration of the classical antipsychotic drug perphenzine an optimal therapeutic interval has been identified between 2 and 6 nmol/l. Positron emission tomography (PET) studies have suggested an optimal interval in central dopamine D2 receptor occupancy of between 65 and 80%. OBJECTIVES: The aim of the present cross-validation study in clinically stable schizophrenic patients was to examine the relationship between the optimal interval in central D2 receptor occupancy and the therapeutic window for serum perphenazine concentration. METHODS: Six patients who had responded to maintenance treatment with perphenazine decanoate were examined with PET and [11C]raclopride during steady-state conditions. Blood sampling was carried out for minimum serum perphenazine concentration and during the PET examination. RESULTS. The serum perphenazine concentration was between 1.8 and 9 nmol/l and the D2 receptor occupancy varied between 66 and 82%. The relationship between central receptor occupancy and serum drug concentration was curvilinear. Mild extrapyramidal symptoms were present in the patient with the highest D2 receptor occupancy. CONCLUSIONS. The previously suggested therapeutic window in serum perphenazine concentration is in good agreement with the optimal interval suggested for central D2 receptor occupancy. Serum concentrations at low dose levels may therefore serve as a useful tool in clinical monitoring of antipsychotic drug treatment.

Adult↗
PubMed2004

PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain.

(S,S)-2-(alpha-(2-Fluoromethoxyphenoxy)benzyl)morpholine ((S,S)-FMeNER) was found to be a selective high-affinity ligand for the norepinephrine transporter (NET). (S,S)-FMeNER) was labeled with fluorine-18 (t1/2 = 109.8 min) by O-fluoromethylation of desfluoromethoxy-(S,S)-FMeNER with [18F]bromofluoromethane. An analog, di-deuterated in the fluoromethoxy group ((S,S)-FMeNER-D2), was similarly labeled with di-deutero-[18F]bromofluoromethane. These two new radioligands were obtained in radiochemical purities greater than 98% and with specific radioactivities ranging from 111-185 GBq/micromol at the end of synthesis (75 min). After intravenous injection of (S,S)-[18F]FMeNER into cynomolgus monkey, PET examination with the head in the field of view revealed skull-bound radioactivity, contaminating images of the brain, and indicated fast defluorination of the radioligand. Defluorination was much reduced in similar PET experiments with (S,S)-[18F]FMeNER-D2. Ratios of radioactivity in the lower brainstem, mesencephalon, thalamus, and temporal cortex to striatum obtained with (S,S)-[18F]FMeNER-D2 at 160 min after i.v. injection were 1.5, 1.6, 1.3, and 1.5, respectively. In another PET experiment, pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the radioactivity ratios in all examined regions to near unity (e.g., to a ratio of 1.03 in mesencephalon). Labeled metabolites of (S,S)-[18F]FMeNER-D2 or (S,S)-[18F]FMeNER found in plasma were all more polar than the parent radioligand. In vitro autoradiography of (S,S)-[18F]FMeNER-D2 on post-mortem human brain cryosections furthermore showed specific binding to NET in the locus coeruleus and thalamus. (S,S)-[18F]FMeNER-D2 is the first useful radiofluorinated ligand for imaging brain NET in monkey in vivo and is superior to (S,S)-[11C]MeNER because a specific binding peak equilibrium is obtained during the PET experiment at a lower noise level.

Animals↗
PubMed2004

Joint explorative analysis of neuroreceptor subsystems in the human brain: application to receptor-transporter correlation using PET data.

Positron emission tomography (PET) has proved to be a highly successful technique in the qualitative and quantitative exploration of the human brain's neurotransmitter-receptor systems. In recent years, the number of PET radioligands, targeted to different neuroreceptor systems of the human brain, has increased considerably. This development paves the way for a simultaneous analysis of different receptor systems and subsystems in the same individual. The detailed exploration of the versatility of neuroreceptor systems requires novel technical approaches, capable of operating on huge parametric image datasets. An initial step of such explorative data processing and analysis should be the development of novel exploratory data-mining tools to gain insight into the "structure" of complex multi-individual, multi-receptor data sets. For practical reasons, a possible and feasible starting point of multi-receptor research can be the analysis of the pre- and post-synaptic binding sites of the same neurotransmitter. In the present study, we propose an unsupervised, unbiased data-mining tool for this task and demonstrate its usefulness by using quantitative receptor maps, obtained with positron emission tomography, from five healthy subjects on (pre-synaptic) serotonin transporters (5-HTT or SERT) and (post-synaptic) 5-HT(1A) receptors. Major components of the proposed technique include the projection of the input receptor maps to a feature space, the quasi-clustering and classification of projected data (neighbourhood formation), trans-individual analysis of neighbourhood properties (trajectory analysis), and the back-projection of the results of trajectory analysis to normal space (creation of multi-receptor maps). The resulting multi-receptor maps suggest that complex relationships and tendencies in the relationship between pre- and post-synaptic transporter-receptor systems can be revealed and classified by using this method. As an example, we demonstrate the regional correlation of the serotonin transporter-receptor systems. These parameter-specific multi-receptor maps can usefully guide the researchers in their endeavour to formulate models of multi-receptor interactions and changes in the human brain.

Adult↗
PubMed2004

Positron emission tomographic evaluation of the putative dopamine-D3 receptor ligand, [11C]RGH-1756 in the monkey brain.

The dopamine-D3 receptor is of special interest due to its postulated role in the pathophysiology and treatment of schizophrenia and Parkinson's Disease. Increasing evidences support the assumption that the D3 receptors are occupied to a high degree by dopamine at physiological conditions. Research on the functional role of the D3 receptors in brain has however been hampered by the lack of D3 selective ligands. In the present Positron Emission Tomography (PET) study the binding of the novel, putative dopamine-D3 receptor ligand, [11C]RGH-1756 was characterized in the cynomolgus monkey brain. [11C]RGH-1756 was rather homogenously distributed in brain and the regional binding potential (BP) values ranged between 0.17 and 0.48. Pretreatment with unlabelled RGH-1756 decreased radioligand binding to the level of the cerebellum in most brain areas. The regional BP values were lower after intravenous injection of a higher mass of RGH-1756, indicating saturable binding of [11C]RGH-1756. The D2/D3 antagonist raclopride partly inhibited the binding of [11C]RGH-1756 in several brain areas, including the striatum, mesencephalon and neocortex, whereas the 5HT(1A) antagonist WAY-100635 had no evident effect on [11C]RGH-1756 binding. Despite the promising binding characteristics of RGH-1756 in vitro the present PET-study indicates that [11C]RGH-1756 provides a low signal for specific binding to the D3 receptor in vivo. One explanation is that the favorable binding characteristics of RGH-1756 in vitro are not manifested in vivo. Alternatively, the results may support the hypothesis that the dopamine-D3 receptors are indeed occupied to a high extent by dopamine in vivo and thus not available for radioligand binding.

Animals↗
PubMed2004

Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET.

Dopaminergic neurotransmission in extrastriatal regions may play a crucial role in the pathophysiology and treatment of neuropsychiatric disorders. The high-affinity radioligands [(11)C]FLB 457, [(123)I]epidepride, and [(18)F]fallypride are now used in clinical studies to measure these low-density receptor populations in vivo. However, a single determination of the regional binding potential (BP) does not differentiate receptor density (B(max)) from the apparent affinity (K(D)). In this positron emission tomography (PET) study, we measured extrastriatal dopamine D2 receptor density (B(max)) and apparent affinity (K(D)) in 10 healthy subjects using an in vivo saturation approach. Each subject participated in two to three PET measurements with different specific radioactivity of [(11)C]FLB 457. The commonly used simplified reference tissue model (SRTM) was used in a comparison of BP values with the B(max) values obtained from the saturation analysis. The calculated regional receptor density values were of the same magnitude (0.33-1.68 nM) and showed the same rank order as reported from postmortem studies, that is, in descending order thalamus, lateral temporal cortex, anterior cinguli, and frontal cortex. The affinity ranged from 0.27 to 0.43 nM, that is, approximately 10-20 times the value found in vitro (20 pM). The area under the cerebellar time activity curve (TAC) was slightly lower (11 +/- 8%, mean +/- SD, P = 0.004, n = 10) after injection of low as compared with high specific radioactivity, indicating sensitivity to the minute density of dopamine D2 receptors in the this region. The results of the present study support that dopamine D2 receptor density and affinity can be differentiated in low-density regions using a saturation approach. There was a significant (P < 0.001) correlation between the binding potential calculated with SRTM and the receptor density (B(max)), which supports the use of BP in clinical studies where differentiation of B(max) and K(D) is not required. In such studies, the mass of FLB 457 has to be less than 0.5 microg injected to avoid a mass effect of the radioligand itself.

Autoradiography↗
PubMed2004

New alpha(1)-adrenoceptor antagonists derived from the antipsychotic sertindole - carbon-11 labelling and pet examination of brain uptake in the cynomolgus monkey.

Central alpha(1)-adrenergic receptors are potential targets for recently developed antipsychotic drugs. Two new 11C labeled potent and selective alpha(1)-adrenoceptor antagonists, 1- [2- [4-[1-(4-fluorophenyl)-5-(2-[(11)C]methyl-tetrazol-5-yl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-imidazolidin-2-one ([(11)C]2) and 1- [2- [4-[1-(4-fluorophenyl)-5-(1-[(11)C]methyl-(1,2,3-triazol-4-yl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-imidazolidin-2-one ([(11)C]3) were prepared and evaluated for imaging of central alpha(1)-adrenergic receptors in the cynomolgus monkey brain. For both compounds, the total brain radioactivity was only about 0.6% of the radioactivity injected i.v. There was no evident binding in regions known to contain alpha(1)-adrenoceptors. This observation suggests that the affinity of the radioligands in primates in vivo is not sufficient to provide a signal for specific binding that can be differentiated from the background. In addition, active efflux by P-glycoprotein may be responsible for the low total brain-uptake of the two radioligands. Both compounds showed a highly polarised and verapamile sensitive transport across monolayers of Caco-2 cells. The total brain-uptake of [(3)H]2 was 6 times higher in mdr1a(-/-) knock-out mice lacking the gene encoding P-glycoprotein compared to wild type mice. Pretreatment of one monkey with Cyclosporin A (15 mg/kg) resulted in 40% higher brain uptake for [(11)C]3 when compared with baseline. These observations support the view that efflux by P-glycoprotein can be of quantitative importance for the total brain-uptake of some PET radioligands.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Low dopamine d(2) receptor binding in subregions of the thalamus in schizophrenia.

OBJECTIVE: Several structural and functional brain imaging studies have pointed to a disturbance of thalamic subnuclei in patients with schizophrenia. The dopamine hypothesis of schizophrenia has, however, not been thoroughly examined in terms of this complex structure, which has connections with most brain regions of central interest in schizophrenia research. The aim of the present study was to examine dopamine D(2) receptor binding in subregions of the thalamus in patients with schizophrenia. METHOD: The authors used positron emission tomography and the radioligand [(11)C]FLB457 to examine dopamine D(2) receptor binding in thalamic subregions of 10 drug-naive patients with schizophrenia. Binding potential was calculated by the reference tissue method and used as an index for dopamine D(2) receptor binding. Comparisons were made with 19 healthy subjects. Subregions of interest were defined on individual magnetic resonance images using a percentage-based operational approach. Clinical symptoms were rated by using the Brief Psychiatric Rating Scale (BPRS). RESULTS: The [(11)C]FLB457 binding potential was lower in the central medial and posterior subregions of the thalamus in patients with schizophrenia. At a functional level, there was a significant negative correlation between binding potential and BPRS positive symptom scores. CONCLUSIONS: The subregions with low D(2) receptor binding comprise primarily the dorsomedial nucleus and pulvinar, two important components in circuitries previously suggested in the pathophysiology of schizophrenia. Aberrant dopaminergic neurotransmission in thalamic subregions might be a mechanism underlying positive symptoms in schizophrenia.

Adult↗
PubMed2003

Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET.

Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT(4)) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT(4) receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT(4) receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT(4) receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [(123)I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT(4) receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT(4) receptor antagonist, SB 204070, at 20 min before [(123)I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176 min after radioligand injection. These findings show that [(123)I]SB 207710 is an effective radioligand for imaging brain 5-HT(4) receptors in vivo.

Animals↗
PubMed2003

NURR1 promoter polymorphisms: Parkinson's disease, schizophrenia, and personality traits.

We have previously identified mutations in exon three in NURR1 (NR4A2) in two patients with schizophrenia (SZ) and one patient with bipolar disease with psychotic symptoms. In the present study we analyzed the promoter region of NURR1 and identified five polymorphic sites: three were found to be in strong linkage disequilibrium with a previously identified polymorphic site in the sixth intron. One polymorphism of this haplotype and the two other independent polymorphisms were investigated for their possible association with SZ and Parkinson's disease (PD) by comparing their frequencies in a Swedish material consisting of 134 subjects with SZ and 207 matched controls and 108 subjects with PD and 125 matched controls. Exon 1 was also investigated in our Parkinson and control material but no variances were found. The distributions of the two most informative polymorphisms in the promoter were investigated in an American material as well consisting of 141 subjects with SZ and 139 matched controls. Furthermore, the identified markers were screened for association with putative endophenotypes of SZ in the Swedish material. The distribution of sequence variants among the Swedish controls matched for SZ was investigated with regard to personality. No significant genotype or allelic association of the three sequence variants with SZ or PD was found. Several comparisons regarding endophenotypes or personality indicated association at the 5% confidence level, although correction for multiple testing rendered none of these findings significant. We conclude that the identified polymorphic sites in the human NURR1 are unlikely to be involved in conferring susceptibility for SZ or PD in our patient material.

Adult↗