Imaging cortical dopamine D1 receptors using [11C]NNC112 and ketanserin blockade of the 5-HT2A receptors

[¹¹C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D₁ receptor (R) over the 5-HT_2A R in vitro, has shown lower selectivity in vivo, hampering measurement of D₁ R in the cortex. [¹¹C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [¹¹C]NNC112 in vivo D₁ R selectivity, and (2) develop a feasible methodology for imaging cortical D₁ R without contamination by 5-HT_2A R. Seven healthy volunteers underwent [¹¹C]NNC112 PET scans at baseline and after a 5-HT_2A R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BP_ND change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BP_ND in the cortical (∼30%) and limbic regions (∼20%) but not in the striatum, which contains a much lower amount of 5-HT_2A R. Therefore, ketanserin allows D₁ R signal to be detected by [¹¹C]NNC112 PET without significant 5-HT_2A R contamination. These data confirm the presence of a significant 5-HT_2A R contribution to cortical [¹¹C]NNC112 signal, and call for caution in the interpretation of published [¹¹C]NNC112 PET findings on cortical D₁ R in humans. In the absence of more selective ligands, [¹¹C]NNC112 PET with ketanserin can be used for cortical D₁ R imaging in vivo.     

COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET

A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [11C]NNC112. We compared [11C]NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [11C]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [11C]NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia.     

Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: a [(11)C]WAY-100635 PET investigation in healthy volunteers

OBJECTIVE: The authors investigated the relationship between anxiety--a facet of the Revised NEO Personality Inventory dimension of neuroticism--and serotonin 5-HT(1A) receptor binding potential. METHOD: Positron emission tomography with [(11)C]WAY-100635 was used to estimate regional 5-HT(1A) binding potential in 19 healthy volunteers who completed the Revised NEO Personality Inventory. Correlation coefficients were calculated to determine the degree of association between 5-HT(1A) binding potential and personality inventory measures. RESULTS: There was a significant negative correlation between 5-HT(1A) binding potential and anxiety in four regions: the dorsolateral prefrontal cortex, anterior cingulate cortex, parietal cortex, and occipital cortex. CONCLUSIONS: The inverse relationship between 5-HT(1A) receptor binding potential and anxiety is consistent with 1) animal models that have shown higher anxiety in mice lacking 5-HT(1A) receptors and 2) clinical trial data that have demonstrated antianxiety properties of partial 5-HT(1A) agonists.     

Direct activation by dopamine of recombinant human 5-HT1A receptors: comparison with human 5-HT2C and 5-HT3 receptors

The effects of dopamine (DA) on the function of human 5-HT1A receptors expressed in Xenopus oocytes and CHO-K1 cells were investigated. In addition, the effect of DA on the activation of three different types of human 5-HT receptors (5-HT1A, 5-HT2C, and 5-HT3) were studied comparatively in Xenopus oocyte expression system. Application of 5-HT or DA in oocytes coexpressing 5-HT1A receptors and G-protein-activated inwardly rectifying potassium channels (GIRK1) induced inward currents with respective EC50 values of 4.2 nM and 11.2 microM. Maximal responses induced by DA were 85 +/- 4% of maximal 5-HT currents and DA responses were blocked by the specific 5-HT1A antagonist, WAY-100635 (50 nM). In CHO-K1 cells expressing 5-HT1A receptors, 5-HT and DA inhibited the specific binding of selective antagonist [3H]-8-OH-DPAT with IC50 values of 10.2 nM and 1.4 microM, and both 5-HT and DA inhibited the forskolin-induced accumulation of cAMP. In oocytes expressing 5-HT2C receptors, 5-HT and DA induced inward currents with respective EC50 values of 6.2 nM and 67.7 microM. Magnitudes of maximal DA induced currents were 42 +/- 3% of maximal 5-HT responses and blocked by the 5-HT2 antagonist, piperazine (1 microM). In oocytes expressing 5-HT3 receptors, 5-HT and DA induced fast inward currents with respective EC50 values of 2.1 microM and 266.3 microM. Maximal DA induced currents were 37 +/- 3% of maximal 5-HT responses and blocked the specific 5-HT3 antagonist LY-278584 (0.1 microM). Comparison of the potencies and efficacies of 5-HT and DA indicated that the relative potency of DA increased in the order of 5-HT3 > 5-HT1A > 5-HT2C, and relative efficacy increased in the order of 5-HT1A > 5-HT2C > 5-HT3. These results suggest that although DA activates different subtypes of human 5-HT receptors directly, the potency and efficacy of the binding site varies significantly among different receptors.     

Characterization of in vivo pharmacokinetic properties of the dopamine D1 receptor agonist DAR-0100A in nonhuman primates using PET with [11C] NNC112 and [11C] raclopride

DAR-0100A, the active enantiomer of dihydrexidine, is a potent dopamine D1 agonist under investigation for treatment of cognitive impairment and negative symptoms of schizophrenia. We measured the dose–occupancy relationship for DAR-0100A at D1 receptors using positron emission tomography (PET) imaging in baboons with [¹¹C] NNC112 and its binding to D2 with [¹¹C] raclopride. Two baboons were scanned with [¹¹C] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [¹¹C] raclopride at baseline and after one dose of DAR-0100A. Occupancy (ΔBP_ND) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and ΔBP_ND. ΔBP_ND was larger in the striatum than in the cortex, consistent with reports showing that 25% of [¹¹C] NNC112 BP_ND in the cortex is attributed to 5-HT_2A. Plasma EC₅₀ estimates ranged from 150 to 550 ng/mL according to the constraints on the model. There was no detectable effect of DAR-0100A on [¹¹C] raclopride BP_ND. These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [¹¹C] NNC112 PET and binding of DAR-0100A to D2 will be negligible. This is the first demonstration with PET of a significant occupancy by a full D1 agonist in vivo.     

PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756

NNC 756 ((+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine) is a new high affinity dopamine (DA) D1 receptor antagonist. Labeled with C-11, it has been used as a PET radiotracer to visualize D1 receptors both in striatal and extrastriatal areas, such as the prefrontal cortex. The goal of this study was to evaluate several methods for derivation of D1 receptor binding potential (BP) with [11C]NNC 756 in baboons, and to use these methods to assess the vulnerability of [11C]NNC 756 binding to competition by endogenous DA. A three-compartment model provided a good fit to PET data acquired following a single bolus injection. BP values obtained with this analysis were in good agreement with values derived from in vitro studies. BP values measured following injection of the potent DA releaser amphetamine (1 mg/kg, n=2) were similar to values measured under control conditions. Kinetic parameters derived from single bolus experiments were used to design a bolus plus continuous infusion administration protocol aimed at achieving a state of sustained binding equilibrium. Injection of amphetamine during sustained equilibrium did not affect [11C]NNC 756 binding. Similar results were observed with another D1 radiotracer, [11C]SCH 23390. Doses of amphetamine used in this study are known to reduce by 20-40% the binding potential of several D2 receptors radiotracers. Therefore, the absence of displacement of [11C]NNC 756 by an endogenous DA surge may indicate important differences between D1 and D2 receptors in vivo, such as differences in proportion of high affinity states not occupied by DA at baseline. These findings may also imply that a simple binding competition model is inadequate to account for the effects of manipulation of endogenous DA levels on the in vivo binding of radiolabeled antagonists.     

In vivo occupation of dopamine D1, D2 and serotonin (5-HT)2A receptors by sertindole in the rat brain.

OBJECTIVE: To determine the in vivo occupation of dopamine D1, D2 and serotonin (5-HT)2A receptors by novel antipsychotic agent sertindole using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist at these receptor sites. DESIGN: Animal study. INTERVENTIONS: Intraperitoneal administration to Wistar rats of 1 of 4 test compounds: a control compound of 0.15% tartaric acid, or a compound of either sertindole (0.5 mg/kg or 2.0 mg/kg) or clozapine (20 mg/kg) dissolved in 0.15% tartaric acid 1 hour before intraperitoneal administration of EEDQ (8 mg/kg) or ethanol/water solution. RESULTS: Sertindole exhibited little or no effect on D1 and D2 binding sites in vivo. On the other hand, sertindole occupied 5-HT2A receptors more extensively and firmly than EEDQ. This study indicates that sertindole is characterized by high occupancy of 5-HT2A receptors and by low or minimum occupancy of D1 and D2 receptors. CONCLUSIONS: These characteristics are very similar to atypical antipsychotic agents such as clozapine. Sertindole's low liability to cause extrapyramidal side effects (EPS) may be related to greater long-term binding for 5-HT2A receptors relative to D2 receptors.     

Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility.

To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient (k3/k4). Both kinetic and graphic analyses provided BP and k3/k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k3/k4 by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90+/-0.06 (mean +/- SD of 12 regions) and 0.84+/-0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72+/-0.17 and 0.58+/-0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor density.     

Intrastriatal serotonin 5-HT2 receptors mediate dopamine D1-induced hyperlocomotion in 6-hydroxydopamine-lesioned rats

Striatal dopamine (DA) and serotonin (5-HT) functions are altered following DA denervation. Previous research indicates that intrastriatal coadministration of D1 and 5-HT2 receptor agonists synergistically increase locomotor behavior in DA-depleted rats. In the present study, we examined whether striatal 5-HT2 mechanisms also account for supersensitive D1-mediated locomotor behavior following DA denervation. Adult male Sprague-Dawley rats were subjected to bilateral striatal cannulation and then received either intracerebroventricular (i.c.v.) or intrastriatal 6-hydroxydopamine (6-OHDA; 200 microg or 20 microg/side, respectively). After at least 3 weeks, i.c.v.-lesioned rats received intrastriatal infusions of the 5-HT2 receptor antagonist ritanserin (2.0 microg/side) or its vehicle (DMSO) followed by systemic SKF 82958, a D1 agonist (1.0 mg/kg, i.p.) and locomotor activity was monitored. In another experiment, intrastriatal sham and 6-OHDA-lesioned rats received bilateral intrastriatal infusions of ritanserin (2.0 microg/side) or its vehicle (DMSO) followed by intrastriatal infusions of SKF 82958 (5.0 microg/side) or vehicle (0.9% saline). Rats with DA loss demonstrated supersensitive locomotor responses to both systemic and intrastriatal SKF 82958. Ritanserin pretreatment blunted systemic SKF 82958-induced hyperlocomotion and returned intrastriatal D1-mediated hyperactivity to sham lesion levels. The results of this study suggest that striatal 5-HT2 receptors contribute to D1-mediated hyperkinesias resulting from DA loss and suggest a pharmacological target for the alleviation of dyskinesia that can develop with continued DA replacement therapy.     

Age and sex effects on 5-HT4 receptors in the human brain: a [11C]SB207145 PET study

Experimental studies indicate that the 5-HT₄ receptor activation influence cognitive function, affective symptoms, and the development of Alzheimer''s disease (AD). The prevalence of AD increases with aging, and women have a higher predisposition to both AD and affective disorders than men. This study aimed to investigate sex and age effects on 5-HT₄ receptor-binding potentials in striatum, the limbic system, and neocortex. Positron-emission tomographic scans were conducted using the radioligand [¹¹C]SB207145 in a cohort of 30 healthy subjects (mean age 44 years; range 20 to 86 years; 14 men and 16 women). The output parameter, BP_ND, was modeled using the simplified reference tissue model, and partial volume correction was performed with the Muller–Gartner method. A decline with age of 1% per decade was found only in striatum. Women had a 13% lower 5-HT₄ receptor binding in the limbic system. The lower limbic 5-HT₄ receptor binding in women supports a role for 5-HT₄ receptors in the sex-specific differences in emotional control and might contribute to the higher prevalence of affective diseases and AD in women. The relatively stable 5-HT₄ receptor binding with aging contrasts others in subtypes of receptors, which generally decrease with aging.     

Effects of aging on 5-HT(1A) receptors and their functional response to 5-HT(1a) agonist in the living brain: PET study with [carbonyl-(11)C]WAY-100635 in conscious monkeys.

Age-related changes in the serotonin 5-HT(1A) receptors in the living brains of conscious young (5.9 +/- 1.8 years old) and aged (19.0 +/- 3.3 years old) monkeys (Macaca mulatta) were evaluated by [carbonyl-(11)C]WAY-100635 and high-resolution positron emission tomography (PET). The regional distribution pattern of [carbonyl-(11)C]WAY-100635 at 60-91 min postinjection was the highest in the cingulate gyrus and hippocampus, high in the frontal and temporal cortices, lower in the occipital cortex, striatum, thalamus, and raphe nuclei, and lowest in the cerebellum in both young and aged monkeys. Graphical Logan plot analysis with metabolite-corrected plasma radioactivity as an input function into the brain was applied to evaluate 5-HT(1A) receptor binding in vivo. Significant age-related decreases in 5-HT(1A) receptor binding were observed only in the frontal and temporal cortices. In the hippocampus, although 5-HT(1A) receptor binding indicated no significant age-related changes, it showed an inverse correlation with individual cortisol levels in plasma. When the 5-HT(1A) receptor agonist 8-OH-DPAT was administered intravenously at a dose of 0.1, 0.3, or 1 mg/kg 30 min after tracer injection, binding of [carbonyl-(11)C]WAY-100635 was displaced in both age groups in a dose-dependent manner. However, the degree of displacement was more marked in young than in aged monkeys. These observations demonstrated the usefulness of [carbonyl-(11)C]WAY-100635 as an indicator of the age-related changes in cortical 5-HT(1A) receptors measured noninvasively by PET. In addition, these observations suggested that the age-related impairment of 5-HT(1A) receptor responses to 8-OH-DPAT might be related to the reduced efficacy of antidepressant therapy in elderly patients with depression.     

Age-dependent decline of dopamine D1 receptors in human brain: A PET study

Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [¹¹C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22–74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [¹¹C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly. Synapse 30:56–61, 1998. Published 1998 Wiley-Liss, Inc.     

Differential effects of stress on [11C]raclopride and [11C]MNPA binding to striatal D2/D3 dopamine receptors: A PET study in conscious monkeys

It has been reported that stress and facilitation of dopamine neuronal system are closely related. In the present study, the effects of stress on the binding of antagonist‐based [¹¹C]raclopride and agonist‐based (R)‐2‐CH3O‐N‐n‐ propylnorapomorphine ([¹¹C]MNPA) to D₂/D₃ receptors were evaluated in the striatum of conscious monkey brain. The stress state assessed from plasma cortisol level was negatively correlated with [¹¹C]raclopride binding as expected. It was noteworthy that [¹¹C]MNPA binding exhibited a positive correlation with stress state; thus, the animals with higher cortisol levels showed higher binding to D₂/D₃ receptors. Synapse 65:84–89, 2011. © 2010 Wiley‐Liss, Inc.     

Localization of serotonin 5-HT2 receptors in living human brain by positron emission tomography using N1-([11C]-methyl)-2-Br-LSD

N1-([11C]-Methyl)-2-Br-LSD ([11C]-MBL) has been developed as a positron emission tomography (PET) imaging agent for serotonin 5-HT2 receptors. In vitro receptor binding assays with nonradioactive MBL show high-affinity binding to serotonin 5-HT2 receptors (Ki = 0.5 nM), a secondary interaction of 8-fold lower affinity with dopamine D2 receptors, and low-affinity interactions with alpha 1-adrenergic as well as serotonin 5-HT1 receptors. Intravenous injection of [11C]-MBL in a baboon led to selective labeling of cortical regions that was markedly blocked by prior administration of ketanserin, a selective 5-HT2 receptor antagonist. Clinical trials with [11C]-MBL have been conducted in seven normal human volunteers, and the regional distribution of radioactivity in the brain was distinctly serotonergic. Labeling was highest in frontal, temporal, and parietal cortex with lower levels observed in caudate and putamen. The tracer rapidly washed from the cerebellum and the low levels of activity in this brain region were used to define nonspecific binding. The maximum specificity was reached between 30 and 60 minutes postinjection when frontal cortex to cerebellum ratios ranged from 1.7 for a 52-year-old male to 2.7 for a 30-year-old male. In agreement with previous studies, a trend towards lower ratios (lower serotonin 5-HT2 receptor levels) was observed in older volunteers. These studies indicate that [11C]-MBL is a selective radioligand that can be used to monitor serotonin 5-HT2 receptor densities in vivo in most regions of the human brain.     

Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states

Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels.     

Quantification of serotonin 5-HT1A receptors in monkey brain with [11C](R)-(-)-RWAY

[11C](R)-(-)-RWAY ([11C]2, 3, 4, 5, 6, 7-hexahydro-1{4-[1[4-(2-methoxyphenyl)-piperazinyl]]-2-phenylbutyry}-1H-azepine) is a new radioligand for imaging brain 5-HT1A receptors with positron emission tomography. In [11C](R)-(-)-RWAY, the direction of the amide bond is expected to reduce metabolism by hydrolysis while allowing easy 11C-labeling at the methoxy position. The purposes of this study were to evaluate different tracer kinetic models in nonhuman primates to quantify 5-HT1A receptors with [11C](R)-(-)-RWAY and to test for the possible action of P-glycoprotein (P-gp), one of the known efflux pumps at the blood-brain barrier. The brain uptake of radioactivity from [11C](R)-(-)-RWAY into 5-HT1A receptor-rich brain regions was severalfold greater than for its antipode ([11C](S)-(+)-RWAY) and could be displaced by receptor saturating doses of the selective 5-HT1A antagonist, WAY-100635. Pretreatment with tariquidar, a potent inhibitor of P-gp, increased brain uptake of [11C](R)-(-)-RWAY about 1.5-fold and the plasma free fraction about 1.8-fold. Thus, the effect of tariquidar on brain uptake may have been caused by displacement of the radioligand binding to plasma proteins. Mathematical modeling showed that the estimated values of regional binding potential were correlated strongly between two-tissue compartment model and multilinear reference tissue model, and thus, supported the use of the cerebellum as a reference region.     

No change in [(11) C]CUMI-101 binding to 5-HT(1A) receptors after intravenous citalopram in human

The main objective of this study was to determine the sensitivity of [¹¹C]CUMI‐101 to citalopram challenge aiming at increasing extracellular 5‐HT. CUMI‐101 has agonistic properties in human embryonic kidney 293 cells transfected with human recombinant 5‐HT_1A receptors (Hendry et al. [2011] Nucl Med Biol 38:273–277; Kumar et al. [2006] J Med Chem 49:125–134) and has previously been demonstrated to be sensitive to bolus citalopram in monkeys (Milak et al. [2011] J Cereb Blood Flow Metab 31:243–249). We studied six healthy individuals. Two PET‐scans were performed on the same day in each individual before and after constant infusion of citalopram (0.15 mg/kg). The imaging data were analyzed using two tissue compartment kinetic modeling with metabolite corrected arterial input and Simplified Reference Tissue Modeling using cerebellum as a reference region. There was no significant difference in regional distribution volume or non‐displaceable binding potential values before and after citalopram infusion. The mean receptor occupancy was 0.03 (range ?0.14 to 0.17). Our data imply that [¹¹C]CUMI‐101 binding is not sensitive to citalopram infusion in humans. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

Striatal dopamine D2 receptors in tardive dyskinesia: PET study.

The dopamine D2 receptors were investigated in vivo in eight neuroleptic-free patients with persistent tardive dyskinesia using positron emission tomography and 76Br-bromospiperone. The striatal receptor density, estimated by the striatum/cerebellum radioligand concentration ratio, was not elevated in patients as compared with age-matched controls but was positively correlated with the severity of orofacial dyskinesia assessed with the Abnormal Involuntary Movement Rating Scale. These results indicate that tardive dyskinesia is associated with normal levels of striatal D2 receptors but the severity of orofacial movements may depend on the relative density of striatal D2 receptors.     

A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone

OBJECTIVE: Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT(2) receptors compared with dopamine D(2) receptors in vitro. The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography (PET) study. METHOD: The authors conducted a PET study to evaluate D(2) occupancy (using [(11)C]raclopride) and 5-HT(2) occupancy (using [(18)F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12-16 hours after the last dose. RESULTS: The mean 5-HT(2) receptor occupancy was significantly higher than the mean D(2) receptor occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT(2) receptor occupancy was almost four times lower than that for D(2) receptor occupancy. CONCLUSIONS: These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT(2) than D(2) receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies. The relatively high D(2) receptor occupancy, even at trough plasma levels, suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine. Since ziprasidone plasma levels show significant (more than twofold) variation within a single dose cycle, studies that are aimed at peak plasma levels (6 hours after the last dose) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone.     

D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride

Several groups have reported increased densities of D2 dopamine receptors in the basal ganglia of schizophrenic brains postmortem. The significance of this finding has been questioned, since an upregulation of receptor number may be a neuronal response to neuroleptic drug treatment. We have used positron emission tomography and [11C]raclopride to examine central D2 dopamine receptor binding in 20 healthy subjects and 18 newly admitted, young, neuroleptic-naive patients with schizophrenia. An in vivo saturation procedure was applied for quantitative determination of D2 dopamine receptor density (Bmax) and affinity (Kd). When the two groups were compared, no significant difference in Bmax or Kd values was found in the putamen or the caudate nucleus. The hypothesis of generally elevated central D2 dopamine receptor densities in schizophrenia was thus not supported by the present findings. In the patients but not in the healthy controls, significantly higher densities were found in the left than in the right putamen but not in the caudate nucleus.