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ABSTRACT: In vivo characterization of the brain pharmacokinetics of novel compounds provides important information for drug development decisions involving dose selection and the determination of administration regimes. In this context, the compound-target affinity is the key parameter to be estimated. However, if compounds exhibit a dynamic lag between plasma and target bound concentrations leading to pharmacological hysteresis, care needs to be taken to ensure the appropriate modeling approach is used so that the system is characterized correctly and that the resultant estimates of affinity are correct. This work focuses on characterizing different pharmacokinetic models that relate the plasma concentration to positron emission tomography outcomes measurements (e.g., volume of distribution and target occupancy) and their performance in estimating the true in vivo affinity. Measured (histamine H3 receptor antagonist-GSK189254) and simulated data sets enabled the investigation of different modeling approaches. An indirect pharmacokinetic-receptor occupancy model was identified as a suitable model for the calculation of affinity when a compound exhibits pharmacological hysteresis.Journal of Cerebral Blood Flow & Metabolism advance online publication, 6 February 2013; doi:10.1038/jcbfm.2012.208.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2013; · 5.46 Impact Factor
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Andri C Tziortzi,
Suzanne N Haber,
Graham E Searle,
Charalampos Tsoumpas,
Christopher J Long,
Paul Shotbolt,
Gwenaelle Douaud,
Saad Jbabdi,
Timothy E J Behrens, Eugenii A Rabiner,
Mark Jenkinson,
Roger N Gunn
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ABSTRACT: The striatum acts in conjunction with the cortex to control and execute functions that are impaired by abnormal dopamine neurotransmission in disorders such as Parkinson's and schizophrenia. To date, in vivo quantification of striatal dopamine has been restricted to structure-based striatal subdivisions. Here, we present a multimodal imaging approach that quantifies the endogenous dopamine release following the administration of d-amphetamine in the functional subdivisions of the striatum of healthy humans with [(11)C]PHNO and [(11)C]Raclopride positron emission tomography ligands. Using connectivity-based (CB) parcellation, we subdivided the striatum into functional subregions based on striato-cortical anatomical connectivity information derived from diffusion magnetic resonance imaging (MRI) and probabilistic tractography. Our parcellation showed that the functional organization of the striatum was spatially coherent across individuals, congruent with primate data and previous diffusion MRI studies, with distinctive and overlapping networks. d-amphetamine induced the highest dopamine release in the limbic followed by the sensory, motor, and executive areas. The data suggest that the relative regional proportions of D2-like receptors are unlikely to be responsible for this regional dopamine release pattern. Notably, the homogeneity of dopamine release was significantly higher within the CB functional subdivisions in comparison with the structural subdivisions. These results support an association between local levels of dopamine release and cortical connectivity fingerprints.
Cerebral Cortex 01/2013; · 6.54 Impact Factor
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ABSTRACT: The D(2)/D(3) agonist radioligand [(11)C]-(+)-PHNO is currently the most suitable D(3) imaging agent available, despite its limited selectivity for the D(3) over the D(2). Given the collocation of D(2) and D(3) receptors, and generally higher densities of D(2), the separation of D(2) and D(3) information from [(11)C]-(+)-PHNO PET data is somewhat complex. This complexity is compounded by recent data suggesting that [(11)C]-(+)-PHNO PET scans might be routinely performed in non-tracer conditions (with respect to D(3) receptors), and that the cerebellum (used as a reference region) might manifest some displaceable binding signal. Here we present the modelling and analysis of data from two human studies which employed an adequate dose range of selective D(3) antagonists (GSK598809 and GSK618334) to interrogate the [(11)C]-(+)-PHNO PET signal. Models describing the changes observed in the PET volume of distribution (V(T)) and binding potential (BP(ND)) were used to identify and quantify a [(11)C]-(+)-PHNO mass dose effect at the D(3), and displaceable signal in the cerebellum, as well as providing refined estimates of regional D(3) fractions of [(11)C]-(+)-PHNO BP(ND). The dose of (+)-PHNO required to occupy half of the available D(3) receptors (ED(50)(PHNO,D3)) was estimated as 40 ng/kg, and the cerebellum BP(ND) was estimated as 0.40. These findings confirm that [(11)C]-(+)-PHNO human PET studies are in fact routinely performed under non-tracer conditions. This suggests that (+)-PHNO injection masses should be minimised and tightly controlled in order to mitigate the mass dose effect. The specific binding detected in the cerebellum was modest but could have a significant effect, for example on estimates of D(3) potency in drug occupancy studies. A range of methods for the analysis of future [(11)C]-(+)-PHNO data, incorporating models for the effects quantified here, were developed and evaluated. The comparisons and conclusions drawn from these can inform the design and analysis of future PET studies with [(11)C]-(+)-PHNO.
NeuroImage 11/2012; · 5.89 Impact Factor
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Manolo Mugnaini,
Laura Iavarone,
Palmina Cavallini,
Cristiana Griffante,
Beatrice Oliosi,
Chiara Savoia,
John Beaver, Eugenii A Rabiner,
Fabrizio Micheli,
Christian Heidbreder,
Anne Andorn,
Emilio Merlo Pich,
Massimo Bani
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ABSTRACT: Selective dopamine D(3) receptor (D(3)R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D(3)R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D(3)Rs (O(D(3))(R)) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [(125)I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7OH-PIPAT) autoradiography and [(11)C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D(3)Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between O(D(3))(R) and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and O(D(3))(R) at every time point, and 100% effect at O(D(3))(R) values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of O(D(3))(R), transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O(D(3))(R) is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D(3)R antagonist for the treatment of substance-use disorders.Neuropsychopharmacology advance online publication, 12 September 2012; doi:10.1038/npp.2012.171.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2012; · 6.99 Impact Factor
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Alessandro Colasanti,
Graham E Searle,
Christopher J Long,
Samuel P Hill,
Richard R Reiley,
Darren Quelch,
David Erritzoe,
Andri C Tziortzi,
Laurence J Reed,
Anne R Lingford-Hughes,
Adam D Waldman,
Koen R J Schruers,
Paul M Matthews,
Roger N Gunn,
David J Nutt, Eugenii A Rabiner
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ABSTRACT: We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in the living human brain by evaluating the effects of amphetamine administration on [(11)C]carfentanil binding with positron emission tomography (PET).
Twelve healthy male volunteers underwent [(11)C]carfentanil PET before and 3 hours after a single oral dose of d-amphetamine (either a "high" dose, .5 mg/kg, or a sub-pharmacological "ultra-low" dose, 1.25 mg total dose or approximately .017 mg/kg). Reductions in [(11)C]carfentanil binding from baseline to post-amphetamine scans (ΔBP(ND)) after the "high" and "ultra-low" amphetamine doses were assessed in 10 regions of interest.
[(11)C]carfentanil binding was reduced after the "high" but not the "ultra-low" amphetamine dose in the frontal cortex, putamen, caudate, thalamus, anterior cingulate, and insula.
Our findings indicate that oral amphetamine administration induces endogenous opioid release in different areas of human brain, including basal ganglia, frontal cortex areas, and thalamus. The combination of an amphetamine challenge and [(11)C]carfentanil PET is a practical and robust method to probe the opioid system in the living human brain.
Biological psychiatry 03/2012; 72(5):371-7. · 8.93 Impact Factor
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ABSTRACT: Carbon-11-labelled positron emission tomography (PET) tracers commonly used in biomedical research expose subjects to ionising radiation. Dosimetry is the measurement of radiation dose, but also commonly refers to the estimation of health risk associated with ionising radiation. This review describes radiation dosimetry of carbon-11-labelled molecules in the context of current PET research and the most widely used regulatory guidelines.
A MEDLINE literature search returned 42 articles; 32 of these were based on human PET data dealing with radiation dosimetry of carbon-11 molecules. Radiation burden expressed as effective dose and maximum absorbed organ dose was compared between tracers.
All but one of the carbon-11-labelled PET tracers have an effective dose under 9 μSv/MBq, with a mean of 5.9 μSv/MBq. Data show that serial PET scans in a single subject are feasible for the majority of radiotracers.
Although differing in approach, the two most widely used regulatory frameworks (those in the USA and the EU) do not differ substantially with regard to the maximum allowable injected activity per PET study. The predictive validity of animal dosimetry models is critically discussed in relation to human dosimetry. Finally, empirical PET data are related to human dose estimates based on homogenous distribution, generic models and maximum cumulated activities. Despite the contribution of these models to general risk estimation, human dosimetry studies are recommended where continued use of a new PET tracer is foreseen.
Nuclear Medicine and Biology 02/2012; 39(2):305-14. · 3.02 Impact Factor
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Christine A Parker,
Roger N Gunn, Eugenii A Rabiner,
Mark Slifstein,
Robert Comley,
Cristian Salinas,
Christopher N Johnson,
Steen Jakobsen,
Sylvain Houle,
Marc Laruelle,
Vincent J Cunningham,
Laurent Martarello
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ABSTRACT: The development of a PET radioligand for imaging 5-hydroxytryptamine (5-HT) 6 receptors in the brain would, for the first time, enable in vivo imaging of this target along with assessment of its involvement in disease pathophysiology. In addition, such a tool would assist in the development of novel drugs targeting the 5-HT6 receptor.
On the basis of in vitro data, GSK215083 was identified as a promising 5-HT6 radioligand candidate and was radiolabeled with (11)C via methylation. The in vivo properties of (11)C-GSK215083 were evaluated first in pigs (to investigate brain penetration and specific binding), second in nonhuman primates (to confirm brain penetration, specific binding, selectivity, and kinetics), and third in human subjects (to confirm brain penetration and biodistribution).
(11)C-GSK215083 readily entered the brain in all 3 species, leading to a heterogeneous distribution (striatum > cortex > cerebellum) consistent with reported 5-HT6 receptor densities and distribution determined by tissue-section autoradiography in preclinical species and humans. In vivo saturation studies using escalating doses of GSK215083 in primates demonstrated saturable, dose-dependent binding to the 5-HT6 receptor in the striatum. Importantly, (11)C-GSK215083 also exhibited affinity for the 5-HT2A receptor; however, given the differential localization of these 2 receptors in the central nervous system, the discrete 5-HT6 binding properties of this radioligand were able to be determined.
These data demonstrate the utility of (11)C-GSK215083 as a promising PET radioligand for probing the 5-HT6 receptor in vivo in both preclinical and clinical species.
Journal of Nuclear Medicine 02/2012; 53(2):295-303. · 6.38 Impact Factor
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ABSTRACT: There is growing recognition of the importance of integrating drug occupancy data acquired by positron emission tomography (PET) with the plasma pharmacokinetics of the drug, in order to establish proper dose selection in subsequent clinical trials. Here we present a study in human subjects of the occupancy of NK(1) receptors achieved following different doses of casopitant, a selective NK(1) antagonist.
Two PET scans were carried out in each of eight human subjects, with the PET radioligand [(11)C]GR205171, a high-affinity and selective NK(1) receptor antagonist. The first scan was under baseline conditions and the second 24 h after a single oral dose of casopitant (2-120 mg). Arterial blood was collected throughout the scans for determination of plasma and whole blood input functions. Venous blood samples were taken prior to and following oral dosing up to 24 h for a pharmacokinetic study of casopitant concentration in plasma.
It was first necessary to establish a suitable kinetic model for the estimation of [(11)C]GR205171 NK(1) receptor binding parameters in human brain tissue. A three-tissue compartment model with simultaneous estimation of multiple regions sharing common variables across regions was found suitable for the analysis. Because of the injected cold mass of the tracer and the high affinity of [(11)C]GR205171 a correction for tracer occupancy effects was also incorporated into the analysis. We then developed a pharmacokinetic-receptor occupancy (PK-RO) model of the relationship between casopitant plasma concentrations and receptor binding, using a population approach.
These results indicate that after chronic dosing, casopitant can achieve a degree of NK(1) receptor occupancy higher than those that have previously been tested in studies of clinical depression.
European Journal of Nuclear Medicine 02/2012; 39(2):226-35. · 4.53 Impact Factor
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ABSTRACT: To date, ¹¹C-(R)-PK11195 has been the most widely used TSPO PET imaging probe, although it suffers from high non-specific binding and low signal to noise. A significant number of 2nd generation TSPO radioligands have been developed with higher affinity and/or lower non-specific binding, however there is substantial inter-subject variation in their affinity for the TSPO. TSPO from human tissue samples binds 2nd generation TSPO radioligands with either high affinity (high affinity binders, HABs), or low affinity (LABs) or expresses both HAB and LAB binding sites (mixed affinity binders, MABs). The expression of these different TSPO binding sites in human is encoded by the rs6971 polymorphism in the TSPO gene. Here, we use a predictive biomathematical model to estimate the in vivo performances of three of these 2nd generation radioligands (¹⁸F-PBR111, ¹¹C-PBR28, ¹¹C-DPA713) and ¹¹C-(R)-PK11195 in humans. The biomathematical model only relies on in silico, in vitro and genetic data (polymorphism frequencies in different ethnic groups) to predict the radioactivity time course in vivo. In particular, we provide estimates of the performances of these ligands in within-subject (e.g. longitudinal studies) and between-subject (e.g. disease characterisation) PET studies, with and without knowledge of the TSPO binding class. This enables an assessment of the different radioligands prior to radiolabelling or acquisition of any in vivo data. The within-subject performance was characterised in terms of the reproducibility of the in vivo binding potential (%COV[BP(ND)]) for each separate TSPO binding class in normal and diseased states (50% to 400% increase in TSPO density), whilst the between-subject performance was characterised in terms of the number of subjects required to distinguish between different populations. The results indicated that the within-subject variability for ¹⁸F-PBR111, ¹¹C-PBR28 and ¹¹C-DPA713 (0.9% to 2.2%) was significantly lower than ¹¹C-(R)-PK11195 (16% to 36%) for HABs and MABs in both normal and diseased states. For between-subject studies, sample sizes required to detect 50% differences in TSPO density with the 2nd generation tracers are approximately half that required with ¹¹C-(R)-PK11195 when binding class information is known a priori. As binding class can be identified using a simple genetic test or from peripheral blood assays, the combination of binding class information with 2nd generation TSPO imaging data should provide superior tools to investigate inflammatory processes in humans in vivo.
NeuroImage 01/2012; 60(2):902-10. · 5.89 Impact Factor
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David R Owen,
Astrid J Yeo,
Roger N Gunn,
Kijoung Song,
Graham Wadsworth,
Andrew Lewis,
Chris Rhodes,
David J Pulford,
Idriss Bennacef,
Christine A Parker,
Pamela L StJean,
Lon R Cardon,
Vincent E Mooser,
Paul M Matthews, Eugenii A Rabiner,
Justin P Rubio
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ABSTRACT: [(11)C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value=3.1 × 10(-13)). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2012; 32(1):1-5. · 5.46 Impact Factor
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Jean-Dominique Gallezot,
John D Beaver,
Roger N Gunn,
Nabeel Nabulsi,
David Weinzimmer,
Tarun Singhal,
Mark Slifstein,
Krista Fowles,
Yu-Shin Ding,
Yiyun Huang,
Marc Laruelle,
Richard E Carson, Eugenii A Rabiner
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ABSTRACT: Although [¹¹C]-(+)-PHNO has enabled quantification of the dopamine-D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). We quantified the affinity of [¹¹C]-(+)-PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [¹¹C]-(+)-PHNO administered in a bolus + infusion paradigm. Varying doses of unlabeled (+)-PHNO were coadministered on each occasion (total doses ranging from 0.09 to 5.61 μg kg⁻¹). The regional binding potential (BP(ND) ) and the corresponding doses of injected (+)-PHNO were used as inputs in a model that quantified the affinity of (+)-PHNO for the D2R and D3R, as well as the regional fractions of the [¹¹C]-(+)-PHNO signal attributable to D3R binding. (+)-PHNO in vivo affinity for the D3R (K(d)/f(ND) ~0.23-0.56 nM) was 25- to 48-fold higher than that for the D2R (K(d)/f(ND) ~11-14 nM). The tracer limits for (+)-PHNO (dose associated with D3R occupancy ~10%) were estimated at ~0.02-0.04 μg kg⁻¹ injected mass for anesthetized primate and at 0.01-0.02 μg kg⁻¹ for awake human positron emission tomography (PET) studies. Our data enabled a rational design and interpretation of future PET studies with [¹¹C]-(+)-PHNO.
Synapse 12/2011; 66(6):489-500. · 2.94 Impact Factor
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ABSTRACT: Monoamine oxidase A (MAO-A) is an important target in the pathophysiology and therapeutics of major depressive disorder, aggression, and neurodegenerative conditions. We measured the effect of changes in MAO-A substrate on MAO-A binding in regions implicated in affective and neurodegenerative disease with [(11)C]-harmine positron emission tomography in healthy volunteers. Monoamine oxidase A V(T), an index of MAO-A density, was decreased (mean: 14%±9%) following tryptophan depletion in prefrontal cortex (P<0.031), and elevated (mean: 17%±11%) in striatum following carbidopa-levodopa administration (P<0.007). These findings suggest an adaptive role for MAO-A in maintaining monoamine neurotransmitter homeostasis by rapidly compensating fluctuating monoamine levels.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2011; 32(3):443-6. · 5.46 Impact Factor
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ABSTRACT: Animal research and human postmortem evidence highlight the importance of brain dopamine D3 receptor (D3R) function in multiple neuropsychiatric disorders, including addiction. Separate anatomical and functional neuroimaging findings implicate disrupted frontal cortical connectivity with distributed brain networks in processes relevant for these diseases. This potential conjunction between molecular and functional markers has not, however, been tested directly. Here, we used a novel combination of [(11)C]-(+)-PHNO positron emission tomography and resting-state functional magnetic resonance imaging in the same healthy individuals to investigate whether differences in midbrain D3R availability are associated with functional interactions between large-scale networks and regions involved in reward processing and cognition. High midbrain D3R availability was associated with reduced functional connectivity between orbitofrontal cortex (OFC) and networks implicated in cognitive control and salience processing. The opposite pattern was observed in subcortical reward circuitry and the "default mode" network, which showed greater connectivity with OFC in individuals with high D3R availability. These findings demonstrate that differential interactions between OFC and networks implicated in cognitive control and reward are associated with midbrain D3R availability, consistent with the hypothesis that dopamine D3R signaling is an important molecular pathway underlying goal-directed behavior.
Cerebral Cortex 12/2011; · 6.54 Impact Factor
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Robert A Comley,
Cristian Salinas,
Romina Mizrahi,
Irina Vitcu,
Alvina Ng,
William Hallett,
Nicholas Keat,
Alan A Wilson, Eugenii A Rabiner,
Marc Laruelle,
Sylvain Houle
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ABSTRACT: We measured the whole-body distribution of IV-injected [¹¹C]GSK215083, a new 5-HT₆ antagonist PET tracer, as a function of time in adult subjects, in order to determine the radiation exposure.
After injection with a single bolus of [¹¹C]GSK215083 (range 330-367 MBq; mean 346 MBq), PET emission data were acquired for approximately 120 min in six subjects (three males and three females). Five organs were identified as exhibiting uptake above background. For these, regions of interest were delineated on emission images, and time-activity curves (TAC) generated. Residence times were calculated as the area under the curve of the TAC, normalized to injected activities and standard values of organ volumes. Dosimetry calculations were then performed using the computer program OLINDA/EXM 1.0.
The mean effective dose averaged over both males and females (deviation) was estimated to be 7.7 ± 1.0 μSv/MBq (male 7.0 ± 0.4; female 8.5 ± 0.6). For the effective dose equivalent, the corresponding values are 7.8 ± 1.2 μSv/MBq (male 6.8 ± 0.5; female 8.9 ± 0.1). The organ receiving the highest dose was the lung, with an average equivalent dose of 25.6 ± 6.9 μSv/MBq (male 20.8 ± 5.6; female 30.4 ± 4.4).
The estimated radiation dose for [¹¹C]GSK215083 is consistent with those for other neuroreceptor ligands labeled with carbon-11. The somewhat higher dose estimate for females compared to males may reflect the difference in observed residence times and representative differences in the male and female phantoms used for dosimetry calculations. Based on conventionally accepted dose limits, [¹¹C]GSK215083 may be used for multiple PET scans in the same subject.
Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 11/2011; 14(4):517-21. · 2.47 Impact Factor
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Akila De Silva,
Victoria Salem,
Christopher J Long,
Aidan Makwana,
Rexford D Newbould, Eugenii A Rabiner,
Mohammad A Ghatei,
Stephen R Bloom,
Paul M Matthews,
John D Beaver,
Waljit S Dhillo
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ABSTRACT: Obesity is a major public health issue worldwide. Understanding how the brain controls appetite offers promising inroads toward new therapies for obesity. Peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) are coreleased postprandially and reduce appetite and inhibit food intake when administered to humans. However, the effects of GLP-1 and the ways in which PYY and GLP-1 act together to modulate brain activity in humans are unknown. Here, we have used functional MRI to determine these effects in healthy, normal-weight human subjects and compared them to those seen physiologically following a meal. We provide a demonstration that the combined administration of PYY(3-36) and GLP-1(7-36 amide) to fasted human subjects leads to similar reductions in subsequent energy intake and brain activity, as observed physiologically following feeding.
Cell metabolism 11/2011; 14(5):700-6. · 17.35 Impact Factor
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Paul Shotbolt,
Andri C Tziortzi,
Graham E Searle,
Alessandro Colasanti,
Jasper van der Aart,
Sergio Abanades,
Christophe Plisson,
Sam R Miller,
Mickael Huiban,
John D Beaver,
Roger N Gunn,
Marc Laruelle, Eugenii A Rabiner
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ABSTRACT: [(11)C]PHNO is a D(2)/D(3) agonist positron emission tomography radiotracer, with higher in vivo affinity for D(3) than for D(2) receptors. As [(11)C]-(+)-PHNO is an agonist, its in vivo binding is expected to be more affected by acute fluctuations in synaptic dopamine than that of antagonist radiotracers such as [(11)C]raclopride. In this study, the authors compared the effects of an oral dose of the dopamine releaser amphetamine (0.3 mg/kg) on in vivo binding of [(11)C]-(+)-PHNO and [(11)C]raclopride in healthy subjects, using a within-subjects, counterbalanced, open-label design. In the dorsal striatum, where the density of D(3) receptors is negligible and both tracers predominantly bind to D(2) receptors, the reduction of [(11)C]-(+)-PHNO binding potential (BP(ND)) was 1.5 times larger than that of [(11)C]raclopride. The gain in sensitivity associated with the agonist [(11)C]-(+)-PHNO implies that ∼65% of D(2) receptors are in the high-affinity state in vivo. In extrastriatal regions, where [(11)C]-(+)-PHNO predominantly binds to D(3) receptors, the amphetamine effect on [(11)C]-(+)-PHNO BP(ND) was even larger, consistent with the higher affinity of dopamine for D(3). This study indicates that [(11)C]-(+)-PHNO is superior to [(11)C]raclopride for studying acute fluctuations in synaptic dopamine in the human striatum. [(11)C]-(+)-PHNO also enables measurement of synaptic dopamine in D(3) regions.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 08/2011; 32(1):127-36. · 5.46 Impact Factor
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ABSTRACT: Human in vivo molecular imaging with positron emission tomography (PET) enables a new kind of 'precision pharmacology', able to address questions central to drug development. Biodistribution studies with drug molecules carrying positron-emitting radioisotopes can test whether a new chemical entity reaches a target tissue compartment (such as the brain) in sufficient amounts to be pharmacologically active. Competition studies, using a radioligand that binds to the target of therapeutic interest with adequate specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Tailored radiotracers can be used to measure relative rates of biological processes, while radioligands specific for tissue markers expected to change with treatment can provide specific pharmacodynamic information. Integrated application of PET and magnetic resonance imaging (MRI) methods allows molecular interactions to be related directly to anatomical or physiological changes in a tissue. Applications of imaging in early drug development can suggest approaches to patient stratification for a personalized medicine able to deliver higher value from a drug after approval. Although imaging experimental medicine adds complexity to early drug development and costs per patient are high, appropriate use can increase returns on R and D investment by improving early decision making to reduce new drug attrition in later stages. We urge that the potential value of a translational molecular imaging strategy be considered routinely and at the earliest stages of new drug development.
British Journal of Clinical Pharmacology 08/2011; 73(2):175-86. · 2.96 Impact Factor
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Christophe Plisson,
Cristian Salinas,
David Weinzimmer,
David Labaree,
Shu-Fei Lin,
Yu-Shin Ding,
Steen Jakobsen,
Paul W Smith,
Kawanishi Eiji,
Richard E Carson,
Roger N Gunn, Eugenii A Rabiner
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ABSTRACT: The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [(11)C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET.
A procedure was developed for labeling MP-10 with carbon-11. [(11)C]MP-10 was evaluated in vivo both in the pig and baboon brain.
Alkylation of the corresponding desmethyl compound with [(11)C]methyl iodide produced [(11)C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [(11)C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1-2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [(11)C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [(11)C]MP-10 were slower, reaching peak tissue concentrations at 30-60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [(11)C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V(T)) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP(ND)) as the outcome measure of specific binding. Quantification of [(11)C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP(ND) estimates consistent with those obtained by the two-tissue compartment model.
We demonstrated that [(11)C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET.
Nuclear Medicine and Biology 08/2011; 38(6):875-84. · 3.02 Impact Factor
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ABSTRACT: 5-Hydroxytryptamine (5-HT or serotonin) is an important neurotransmitter for a number of brain functions and widely distributed throughout the brain. Physiological and pharmacological relationship between 5-HT1A receptors and serotonin transporter (5-HTT) in the regulation of 5-HT neurotransmission has now been documented. A relationship between 5-HT1A receptors and 5-HTT is also suggested by the pathophysiology of depression and the mechanism of action of antidepressants. We have scanned 42 healthy adults with both [11C] WAY-100635 and [11C] DASB to investigate the anatomical co-distribution of multiple serotonergic markers. We hypothesized that lower 5-HTT densities in the dorsal raphe nucleus (DRN) and limbic regions will be accompanied by lower 5-HT1A receptor density in the same regions, contributing to the 5-HT1A receptor desensitization. In addition, variations in DRN 5-HT1A receptor density can theoretically influence the density and/or function of other serotonin receptor subtypes and the 5-HTT consequent to changes in serotonergic tone. In a comparatively large sample of volunteers, we have shown that the relationship between 5-HT1A and 5-HTT PET indices was complex. We were unable to demonstrate robust, intra-regional relationships between 5-HT1A and 5-HTT densities. Inter-regionally, DRN 5-HT1A receptors were related to cortical (temporal and frontal regions) and paralimbic (insula), but not limbic 5-HTT. This latter finding may reflect differences in 5-HT tone between individuals, and highlights probable substrates sensitive to variations in DRN 5-HT function.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2011; 36(11):2258-65. · 6.99 Impact Factor
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Roger N Gunn,
Venkatesha Murthy,
Ana M Catafau,
Graham Searle,
Santiago Bullich,
Mark Slifstein,
Daniele Ouellet,
Stefano Zamuner,
Raul Herance,
Cristian Salinas,
Ricardo Pardo-Lozano, Eugenii A Rabiner,
Magi Farre,
Marc Laruelle
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ABSTRACT: The current interest in developing Glycine transporter Type 1 (GlyT-1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT-1 PET molecular imaging tool to aid drug development and dose selection. We report on [(11) C]GSK931145 as a novel GlyT-1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma-occupancy relationship of the GlyT-1 inhibitor GSK1018921. Human PET studies were performed to determine the test-retest reproducibility of [(11) C]GSK931145 and the plasma-occupancy relationship of GSK1018921. [(11) C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction (f(P) : 0.8 vs. 8%) and delivery (K(1) : 0.025 vs. 0.126 ml cm(-3) min(-1) ) were significantly lower in humans. Test-retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(V(T) ): 29-38%), but was improved using a pseudo reference tissue model (VAR(BP(ND) ): 16-23%). GSK1018921 EC(50) estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively.
Synapse 06/2011; 65(12):1319-32. · 2.94 Impact Factor
