Biomedical subjects

Christer Halldin

Publications and source records attributed to Christer Halldin.

At least 19 recordsLinked to original sources

PubMed2007

PET measurement of serotonin transporter occupancy: a comparison of escitalopram and citalopram.

The selective serotonin reuptake inhibitor (SSRI) citalopram (R,S-citalopram) is a racemic compound of two enantiomers. On the basis of in-vitro studies, inhibition of the human serotonin transporter (5-HTT) is achieved by the S-enantiomer (S-citalopram or escitalopram). The aim of the present PET study was to compare 5-HTT occupancy after single equimolar doses (with respect to S-enantiomer) in humans in vivo using R,S-citalopram (20 mg) and S-citalopram (10 mg) using PET and the radioligand [(11)C]MADAM. The design was a single-dose, double-blind, two-way crossover study in eight healthy male subjects. The 5-HTT binding potential at baseline and after single doses of study drugs was used to calculate 5-HTT occupancy in seven brain regions. Serum concentrations of the study drugs were determined in order to calculate the apparent inhibition constant (K(i),(app)), a secondary parameter of interest for the comparison. In all brain regions examined, occupancy was numerically higher after treatment with R,S-citalopram [66+/-19% to 78+/-17% (mean+/-s.d.) depending on the region] than after S-citalopram (59+/-15% to 69+/-13%; overall comparison: F=14.8, d.f.=1, 90, p<0.001). In line with this the apparent inhibition constant was significantly lower for R,S-citalopram than for S-citalopram (overall comparison: F=6.7, d.f.=1, 90, p<0.05). The small but significant difference in occupancy and K(i),(app) found between R,S-citalopram and S-citalopram suggests that not only S-citalopram but also R-citalopram to some degree occupies the 5-HTT in the human brain in vivo.

Adult↗

PubMed2007

[11C]LBT-999: a suitable radioligand for investigation of extra-striatal dopamine transporter with PET.

A new tropane derivative, (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999), was evaluated in baboons as a carbon-11 radioligand for studies of the dopamine transporter (DAT) using positron emission tomography (PET). Brain uptake was high in the striatum (17 and 13% ID/100 mL tissue in the putamen and the caudate, respectively), moderate in the midbrain and thalamus (5 and 3% ID/100 mL tissue, respectively), and low in the cortex and cerebellum (2% ID/100 mL tissue) at 30 min post injection. The striatum-to-cerebellum ratio was high (30 at 110 min post injection). Specific binding was completely blocked following pretreatment with the DAT antagonists GBR12909 (5 mg/kg i.v.) or PE2I (1 mg/kg i.v.). The [(11)C]LBT-999 uptake was decreased by these antagonists in the putamen (-79 and -92%, respectively), caudate (-80 and -91%, respectively), midbrain (-73 and -78%, respectively), and thalamus (-34 and -46%, respectively). The serotonin transporter (SERT) antagonist citalopram (5 mg/kg i.v.) or the norepinephrine transporter antagonist maprotiline (5 mg/kg i.v.) had no effect on LBT specific binding. Pharmacological challenge with PE2I (1 mg/kg i.v.) induced a rapid and almost complete decrease of the specific binding in the putamen (-97%), caudate (-96%), midbrain (-96%), and thalamus (-81%), confirming the reversibility of [(11)C]LBT-999 binding. The high brain uptake of [(11)C]LBT-999 together with its low nonspecific binding (reflected by the very high brain structure-to-cerebellum ratio) indicate that this radiotracer is an excellent candidate for in vivo quantification of the DAT, especially in extrastriatal structures, such as the midbrain.

Animals↗

PubMed2006

Dopamine D2 receptor binding in drug-naïve patients with schizophrenia examined with raclopride-C11 and positron emission tomography.

The aim was to test the dopamine hypothesis of schizophrenia in a further analysis of D(2)-like dopamine binding using the radioligand [(11)C]raclopride and high resolution 3-dimensional (3D) PET. Eighteen drug-naive patients with schizophrenia and seventeen control subjects were examined. The D(2) binding potential (BP) in the putamen, the caudate and the thalamus was calculated using the simplified reference tissue model. The volume of regions of interest was controlled for by MRI. Symptoms were rated with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). No significant group differences were found for D(2) BP in the putamen or in the caudate and there was no significant hemispheric difference for any region. In the right thalamus the D(2) BP was significantly lower in patients as compared to control subjects, whereas a numerical difference did not reach statistical significance for the left thalamus. There was no significant correlation between D(2) BP and total PANSS score in any region. There was a highly significant age effect in the caudate and in the putamen, but not in the thalamus. In this relatively large PET study of exclusively drug-naive schizophrenic patients, a lower D(2) BP in the right thalamus was found in the patient group. This finding is in agreement with two previous studies in Sweden and in Japan using the high-affinity radioligand [(11)C]FLB 457 and provide further support for a role of dopamine in the thalamus related to the pathophysiology of schizophrenia.

Adolescent↗

PubMed2006

Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [11C]PE2I.

PURPOSE: We aimed to determine the composition of radioactivity in rat brain after intravenous administration of the dopamine transporter radioligand, [(11)C]PE2I. METHODS: PET time-activity curves (TACs) and regional brain distribution ex vivo were measured using no-carrier-added [(11)C]PE2I. Carrier-added [(11)C]PE2I was administered to identify metabolites with high-performance liquid radiochromatography (RC) or RC with mass spectrometry (LC-MS and MS-MS). The stability of [(11)C]PE2I was assessed in rat brain homogenates. RESULTS: After peak brain uptake of no-carrier-added [(11)C]PE2I, there was differential washout rate from striata and cerebellum. Thirty minutes after injection, [(11)C]PE2I represented 10.9 +/- 2.9% of the radioactivity in plasma, 67.1 +/- 11.0% in cerebellum, and 92.5 +/- 3.2% in striata, and was accompanied by two less lipophilic radiometabolites. [(11)C]PE2I was stable in rat brain homogenate for at least 1 h at 37 degrees C. LC-MS identified hydroxylated PE2I (1) (m/z 442) and carboxyl-desmethyl-PE2I (2) (m/z 456) in brain. MS-MS of 1 gave an m/z 442-->424 transition due to H(2)O elimination, so verifying the presence of a benzyl alcohol group. Metabolite 2 was the benzoic acid derivative. Ratios of ex vivo measurements of [(11)C]PE2I, [(11)C]1, and [(11)C]2 in striata to their cognates in cerebellum were 6.1 +/- 3.4, 3.7 +/- 2.2 and 1.33 +/- 0.38, respectively, showing binding selectivity of metabolite [(11)C]1 to striata. CONCLUSION: Radiometabolites [(11)C]1 and [(11)C]2 were characterized as the 4-hydroxymethyl and 4-carboxyl analogs of [(11)C]PE2I, respectively. The presence of the pharmacologically active [(11)C]1 and the inactive [(11)C]2 is a serious impediment to successful biomathematical analysis.

Animals↗

PubMed2006

A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria.

The cause of premenstrual dysphoric disorder (PMDD) is largely unknown. It has been hypothesized that normal ovarian function triggers PMDD-related biochemical events within the brain and that serotonin plays an important role. In the present study, positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635 were used to examine serotonin 5-HT(1A) receptors in a control group of women and in a group of women with PMDD. Two PET examinations were performed in each subject, one before (follicular phase) and one after ovulation (luteal phase). Each subject's menstrual cycle was confirmed by ultrasonography of the ovaries as well as with hormone levels in blood and urine. The 5-HT(1A) binding potential was measured in six regions of interest and calculated according to the simplified reference tissue model. In the raphe nuclei, the 5-HT(1A) binding potential changed from the follicular to the luteal phase of the menstrual cycle in asymptomatic controls. In women with PMDD, the observed change between phases was significantly smaller. The results are in concordance with previously reported challenge studies of 5-HT(1A) receptor-mediated effects indicating different serotonergic responses between women with PMDD and controls. The study principally provides new support, in vivo, for a serotonergic dysregulation in women with PMDD.

Adult↗

PubMed2006

Synthesis of 11C-labelled (R)-OHDMI and CFMME and their evaluation as candidate radioligands for imaging central norepinephrine transporters with PET.

(R)-1-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-3-methylamino-propan-2-ol ((R)-OHDMI) and (S,S)-1-cyclopentyl-2-(5-fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-ethanol (CFMME) were synthesized and found to be potent inhibitors of norepinephrine reuptake. Each was labelled efficiently in its methyl group with carbon-11 (t(1/2)=20.4 min) as a prospective radioligand for imaging brain norepinephrine transporters (NET) with positron emission tomography (PET). The uptake and distribution of radioactivity in brain following intravenous injection of each radioligand into cynomolgus monkey was examined in vivo with PET. After injection of (R)-[(11)C]OHDMI, the maximal whole brain uptake of radioactivity was very low (1.1% of injected dose; I.D.). For occipital cortex, thalamus, lower brainstem, mesencephalon and cerebellum, radioactivity ratios to striatum at 93 min after radioligand injection were 1.35, 1.35, 1.2, 1.2 and 1.0, respectively. After injection of [(11)C]CFMME, radioactivity readily entered brain (3.5% I.D.). Ratios of radioactivity to cerebellum at 93 min for thalamus, occipital cortex, region of locus coeruleus, mesencephalon and striatum were 1.35, 1.3, 1.3, 1.2 and 1.2, respectively. Radioactive metabolites in plasma were measured by radio-HPLC. (R)-[(11)C]OHDMI represented 75% of plasma radioactivity at 4 min after injection and 6% at 30 min. After injection of [(11)C]CFMME, 84% of the radioactivity in plasma represented parent at 4 min and 20% at 30 min. Since the two new hydroxylated radioligands provide only modest regional differentiation in brain uptake and form potentially troublesome lipophilic radioactive metabolites, they are concluded to be inferior to existing radioligands, such as (S,S)-[(11)C]MeNER, (S,S)-[(18)F]FMeNER-D(2) and (S,S)-[(18)F]FRB-D(4), for the study of brain NETs with PET in vivo.

Animals↗

PubMed2006

Synthesis of 3H-labeled N-(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(4-methylphenyl)nortropane (PE2I) and its interaction with mice striatal membrane fragments.

PE2I is a high-affinity dopamine transporter (DA(T)) ligand that exhibits high selectivity for the DA(T) over the serotonin (5-HT(T)) and norephinephrine transporter (NE(T)) making its carbon-11 and iodine-125 labeled forms very useful for quantification of DA(T) binding sites in vivo. In this paper, we reported the synthesis of tritium-labeled PE2I, as well as improvements in the preparation of its acid precursor and PE2I itself with significant improvement in the total yield compared to previously published results. The new radioligand was evaluated as a tool for assessing DA(T) binding sites in vitro. The radioligand binding to mice striatal membranes demonstrated a homogeneous population of DA(T) binding sites with the K(d) value 9 nM.

Animals↗

PubMed2006

Measurement of serotonin transporter binding with PET and [11C]MADAM: a test-retest reproducibility study.

[(11)C]MADAM, or [(11)C]N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine, is a radioligand suitable for positron emission tomography (PET) studies of the serotonin transporter (5-HTT) in man. The purpose of this study was to examine the test-retest reproducibility using a design tailored for future applied studies. Nine healthy male subjects were examined with PET and [(11)C]MADAM under baseline conditions at two occasions 4-8 weeks apart. The subjects participated in a Phase 1 trial to which the present study was an addendum. Eight regions of interest were studied, including frontal cortex, hippocampal complex, and the raphe nuclei. All regions, but the raphe nuclei, were defined on MR-images to which the PET-images were coregistered using SPM2. Binding potentials were calculated using the simplified reference tissue model, with cerebellum as reference region. Test-retest data were calculated from the binding potentials, and included binding potential (BP) quotient, BP difference, and the intraclass correlation coefficient. The quotient was about one in all regions, and the mean difference varied between 0 and 11%. The intraclass correlation coefficient varied between 0.96 and 0.51 in the raphe nuclei and averaged bilateral regions. [(11)C]MADAM was shown to have good to excellent reliability in measurements of 5-HTT binding in brain regions of interest in research on psychiatric disorders.

Adult↗

PubMed2006

Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2.

RATIONALE: Atomoxetine is a potent and selective norepinephrine transporter (NET) reuptake inhibitor acting as a nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). Previous positron emission tomography (PET) studies had failed to demonstrate the feasibility of measuring a dose-dependent and saturable NET occupancy in human brain using [11C]MeNER. OBJECTIVES: To determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[18F]FMeNER-D2 in nonhuman primate brain. METHODS: A total of eight PET measurements were performed in two cynomolgus monkeys. Each monkey was examined four times with PET: under baseline conditions and after steady-state infusion with 0.03, 0.06, or 0.12 mg/kg/h of atomoxetine. A prolonged intravenous (i.v.) infusion design was developed rather than an i.v. bolus to better mimic an oral absorption profile and to reach plasma steady state. RESULTS: During baseline conditions, (S,S)-[18F]FMeNER-D2 uptake was highest in the locus coeruleus, thalamus, mesencephalon, and the cingulate gyrus, whereas the radioactivity in the caudate was low. Peak equilibrium measurements were achieved using (S,S)-[18F]FMeNER-D2 in contrast to the previously reported data for [11C]MeNER. After administration of atomoxetine, a dose-dependent occupancy from 38 to 82% was observed for various brain regions known to contain high densities of NET. CONCLUSIONS: This is the first in vivo PET study to successfully demonstrate the ability to measure a dose-dependent change in NET occupancy in brain using (S,S)-[18F]FMeNER-D2. Furthermore, an asymptotic relationship between N-desmethylatomoxetine plasma concentration and NET occupancy was established. In total, these data encourage further PET studies using (S,S)-[18F]FMeNER-D2 in humans.

Adrenergic Uptake Inhibitors↗

PubMed2006

A comparison of recent parametric neuroreceptor mapping approaches based on measurements with the high affinity PET radioligands [11C]FLB 457 and [11C]WAY 100635.

In positron emission tomography (PET) studies, the detailed mapping of neuroreceptor binding is a trade-off between parametric accuracy and spatial precision. Logan's graphical approach is a straightforward way to quickly obtain binding potential values at the voxel level but it has been shown to have a noise-dependent negative bias. More recently suggested approaches claim to improve parametric accuracy with retained spatial resolution. In the present study, we used PET measurements on regional D2 dopamine and 5-HT1A serotonin receptor binding in man to compare binding potential (BP) estimates of six different parametric imaging approaches to the traditional Logan ROI-based approach which was used as a "gold standard". The parametric imaging approaches included Logan's reference tissue graphical analysis (PILogan), its version recently modified by Varga and Szabo (PIVarga), two versions of the wavelet-based approach, Gunn's basis function method (BFM) and Gunn et al.'s recent compartmental theory-based approach employing basis pursuit strategy for kinetic modeling (called DEPICT). Applicability for practical purposes in basic and clinical research was also considered. The results indicate that the PILogan and PIVarga approaches fail to recover the correct values, the wavelet-based approaches overcome the noise susceptibility of the Logan fit with generally good recovery of BP values, and BFM and DEPICT seem to produce values with a bias dependent on receptor density. Further investigations on this bias and other phenomena revealed fundamental issues regarding the use of BFM and DEPICT on noisy voxel-wise data. In conclusion, the wavelet-based approaches seem to provide the most valid and reliable estimates across regions with a wide range of receptor densities. Furthermore, the results support the use of receptor parametric imaging in applied studies in basic or clinical research.

Algorithms↗

PubMed2006

Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding.

Clinical observations support a central role of the dopamine system in restless legs syndrome (RLS) but previous imaging studies of striatal dopamine D2-receptors have yielded inconclusive results. Extrastriatal dopaminergic function has hitherto not been investigated. Sixteen RLS patients naïve to dopaminergic drugs and sixteen matched control subjects were examined with PET. [11C]Raclopride and [11C]FLB 457 were used to estimate D2-receptor availability in striatum and extrastriatal regions, respectively. Examinations were performed both in the morning (starting between 10:00 and 12:00 h) and evening (starting at 18:00 h). Measures were taken to monitor and control for head movement during data acquisition. In the striatum, patients had significantly higher [11C]raclopride binding potential (BP) values than controls. In extrastriatal regions, [11C]FLB 457 BP was higher in patients than controls, and in the regional analysis the difference was statistically significant in subregions of thalamus and the anterior cingulate cortex. The diurnal variability in BP with [11C]FLB 457 and [11C]raclopride was within the previously reported test-retest reproducibility for both radioligands. The study supports involvement of the dopamine system in both striatal and extrastriatal brain regions in the pathophysiology of RLS. The brain regions where differences in D2-receptor binding were shown are implicated in the regulation of affective and motivational aspects of sensory processing, suggesting a possible pathway for sensory symptoms in RLS. Increased D2-receptor availability in RLS may correspond to higher receptor densities or lower levels of endogenous dopamine. Both interpretations are consistent with the hypothesis of hypoactive dopaminergic neurotransmission in RLS, as increased receptor levels can be owing to receptor upregulation in response to low levels of endogenous dopamine. The results do not support variations in dopamine D2-receptor availability as a correlate to the diurnal rhythm of RLS symptoms.

Adult↗

PubMed2006

Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors.

11C-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([11C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([11C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [11C]5 and [11C]6 display high affinity for the NET in vitro (Ki = 0.94 and 0.68 nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT.

Amines↗

PubMed2006

Search for correlations between serotonin 5-HT1A receptor expression and cognitive functions--a strategy in translational psychopharmacology.

RATIONALE: Animal studies and studies of human aging have suggested that the serotonin 5-HT1A receptor may serve as a biomarker for cognitive functioning and a target for pharmacological treatment of cognitive deficits. OBJECTIVES: The purpose of this positron emission tomography (PET) study was to search for relationships between interindividual variability in serotonin 5-HT1A receptor binding potential (BP) and cognitive functioning. MATERIALS AND METHODS: Twenty-four male control subjects, age 20-55 years, were examined with [11C]WAY100635 PET and a battery of cognitive tests. 5-HT1A receptor binding potential were calculated for the raphe nuclei, the hippocampus and the neocortex. Correlation coefficients between BP and cognitive performance were obtained for each region. RESULTS: There was a severalfold of variability in 5-HT1A BP between individuals. We found no significant correlation between regional [11C]WAY100635 binding and cognitive performance. CONCLUSIONS: The results do not provide support for involvement of the 5-HT1A receptor in cognitive functioning in man and question the predictive validity of some currently used animal models in translational neuroscience.

Adult↗

PubMed2006

Quantitative analyses of regional [11C]PE2I binding to the dopamine transporter in the human brain: a PET study.

PURPOSE: The dopamine transporter (DAT) is a plasma membrane protein of central interest in the pathophysiology of neuropsychiatric disorders and is known to be a target for psychostimulant drugs. [(11)C]PE2I is a new radioligand which binds selectively and with moderate affinity to central DAT, as has been demonstrated in vitro by autoradiography and in vivo by positron emission tomography (PET). The aims of the present PET study were to quantify regional [(11)C]PE2I binding to DAT in the human brain and to compare quantitative methods with regard to suitability for applied clinical studies. METHODS: One PET measurement was performed in each of eight healthy male subjects. The binding potential (BP) values were obtained by applying kinetic compartment analysis, which uses the metabolite-corrected arterial plasma curve as an input function. They were compared with the BP values quantified by two reference tissue approaches, using cerebellum as a reference region representing free and non-specific radioligand binding. RESULTS: The radioactivity concentration was highest in the striatum, lower in the midbrain and very low in the cerebellum. The regional [(11)C]PE2I binding could be interpreted by kinetic compartment models. However, the BP values in the striatum obtained by the compartment analyses were about 30% higher than the BP values obtained using reference tissue methods. We suggest that the difference may be explained by the inaccurate metabolite correction, small amounts of radioactive metabolites that could account for the presence of non-specific binding in the cerebellum and insufficient data acquisition time. CONCLUSION: The reference methods may be used to quantify [(11)C]PE2I binding in clinical studies, assuming that non-specific binding in the cerebellum does not vary between subjects and that an extended data acquisition time is employed. Moreover, the study corroborates the previous observation that [(11)C]PE2I is advantageous for PET examination of DAT binding in the midbrain, a region from which dopaminergic innervation originates and which is of central interest for the pathophysiology of several neuropsychiatric disorders.

Adult↗

PubMed2006

Synthesis and structure-activity relationships (SARs) of 1,5-diarylpyrazole cannabinoid type-1 (CB(1)) receptor ligands for potential use in molecular imaging.

Cannabinoid type-1 (CB(1)) receptor ligands, derived from the 1,5-diarylpyrazole core template of rimonabant (Acomplia), have been the focus of several studies aimed at examining structure-activity relationships (SARs). The purpose of this study was to design and synthesize a set of compounds based on the 1,5-diarylpyrazole template while focusing on the potential for discovery of CB(1) receptor radioligands that might be used as probes with in vivo molecular imaging. Each synthesized ligand was evaluated for potency as an antagonist at CB(1) and cannabinoid type-2 (CB(2)) receptors in vitro using a GTPgamma(35)S-binding assay. clog P values were calculated with Pallas 3.0. The antagonist binding affinities (K(B)) at CB(1) receptors ranged from 11 to >16,000 nM, CB(1) versus CB(2) selectivities from 0.6 to 773, and clog Ps from 3.61 to 6.25. An interesting new ligand, namely N-(piperidin-1-yl)-1-(2-bromophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxamide (9j), emerged from the synthesized set with appealing properties (K(B)=11 nM; CB(1) selectivity>773; clog P=5.85), for labeling with carbon-11 and development as a radioligand for imaging brain CB(1) receptors in vivo with positron emission tomography (PET).

Drug Design↗

PubMed2006

Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study.

RATIONALE: The D1-like dopamine receptors have been suggested to play a role in the pathophysiology and treatment of schizophrenia. Previous positron emission tomography studies have demonstrated that the atypical antipsychotic clozapine occupies D1-like dopamine receptors in the striatum in clozapine-treated patients. OBJECTIVES: The aim of the present study was to compare striatal and cortical D1-like dopamine receptor occupancy by clozapine in the primate brain. METHODS: Three monkeys were each examined three times at the same day with the radioligand (+)-[11C]NNC 112. The first measurement was at baseline conditions, the second after 1.5 mg/kg and the third after 6 mg/kg clozapine IV. To compare regional levels of nonspecific binding in brain regions, an additional monkey was examined using the inactive enantiomer (-)-[11C]NNC 112. Receptor occupancy was calculated using both the equilibrium-ratio analysis and the simplified reference tissue model. RESULTS: After 1.5 mg/kg the D1-like dopamine receptor occupancy ranged from 30 to 38% in the striatum, whereas the range was 51 to 57% in the frontal cortex. After 6.0 mg/kg the occupancy was 53 to 64% in the striatum and 63 to 83% in the frontal cortex. The differences between striatal and cortical D(1)-like receptors occupancy were between 12 and 25%. The study with (-)-[11C]NNC 112 did not show regional differences in nonspecific binding that might explain the regional differences in occupancy. CONCLUSIONS: The higher D1-like dopamine receptor occupancy in the frontal cortex may reflect a different distribution of the D1 and D5 dopamine receptor subtypes among brain regions and different affinity of clozapine for the two subtypes. The finding supports the suggestion that binding to D1-like dopamine receptors may explain clozapine's atypical drug actions.

Animals↗

PubMed2006

Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride.

PET measurements of stimulant-induced dopamine (DA) release are typically performed with antagonist radioligands that bind to both the high- and low-affinity state of the receptor. In contrast, an agonist radioligand binds preferentially to the high-affinity state and is expected to have greater sensitivity to DA, which is the endogenous agonist. [(11)C]MNPA, (R)-2-CH(3)O-N-n-propylnorapomorphine (MNPA), is a D(2) agonist radioligand with subnanomolar affinity to the D(2) receptor. The aim of the present study is to assess and compare the sensitivity of the agonist radioligand [(11)C]MNPA and antagonist radioligand [(11)C]raclopride to synaptic DA levels. Four cynomolgus monkeys were examined with [(11)C]MNPA and [(11)C]raclopride (16 PET measurements with each tracer) at baseline and after pretreatment with various doses of amphetamine. The effect of amphetamine was calculated by the change in binding potential (BP) analyzed with the multilinear reference tissue model (MRTM2). Amphetamine caused a reduction in [(11)C]MNPA BP of 4% at 0.1, 23% at 0.2, 25% at 0.5, and 46% at 1.0 mg/kg. [(11)C]Raclopride BP was reduced to a lesser extent by 2% at 0.1, 16% at 0.2, 15% at 0.5, and 23% at 1.0 mg/kg. The data were used to estimate the in vivo percentage of high-affinity state receptors to be approximately 60%. These results demonstrate that [(11)C]MNPA is more sensitive than [(11)C]raclopride to displacement by endogenous DA, and that it may provide additional information about the functional state of the D(2) receptor in illnesses such as schizophrenia and Parkinson's disease.

Amphetamine↗

PubMed2005

Pharmacological characterization of (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999) as a highly promising fluorinated ligand for the dopamine transporter.

In the aim to develop an efficient fluorinated probe for positron emission tomography (PET) exploration of the dopamine transporter (DAT), we studied several in vitro and in vivo characteristics of the phenyltropane derivative (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999). In vitro on rat striatal membrane, [(3)H]LBT-999 bound to a single site with a K(d) of 9 nM, B(max) of 17 pmol/mg protein, and a very high selectivity for the DAT [IC(50) for 1-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) and (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)nortropane (PE2I): 2.4 and 18 nM, respectively; IC(50) for paroxetine, citalopram, N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine, nisoxetine, and desipramine >1 muM]. In vitro on post-mortem human brain sections, LBT-999 bound with high intensity to the caudate-putamen, weakly to the thalamus, and not in the neocortex and cerebellum. This binding was totally abolished in the presence of PE2I. Ex vivo cerebral biodistribution of [(11)C]LBT-999 in rats showed striatum/cerebellum radioactivity ratios of 18 and 25 at 30 and 60 min postinjection, respectively. This accumulation was strongly prevented by preinjection of GBR 12909, whereas paroxetine and nisoxetine had no effect. An in vivo kinetic PET study in three baboons showed a fast and very high uptake in the striatum, with a plateau at 30 min postinjection and a maximal putamen/cerebellum ratio of 30. Taken together, these findings demonstrate that LBT-999 is a highly promising agent for in vivo exploration of the DAT. This probe is currently labeled with (18)F for further characterizations.

Animals↗