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Unexpectedly high affinity of a novel histamine H3receptor antagonist, GSK239512,in vivoin human brain, determined using PET

S Ashworth, A Berges, E A Rabiner, A A Wilson, R A Comley, R Y K Lai, R Boardley, G Searle, R N Gunn, M Laruelle, V J Cunningham
2014 British Journal of Pharmacology  
BACKGROUND AND PURPOSE This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H3 receptors  ...  CONCLUSIONS AND IMPLICATIONS The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in  ...  Sharon Ashworth, Alienor Berges, Eugenii Rabiner, Robert Comley, Robert Lai, Rebecca Boardley, Graham Searle, Roger Gunn, Marc Laruelle and Vincent Cunningham were all GSK employees at the time the study  ... 
doi:10.1111/bph.12505 pmid:24670146 pmcid:PMC3952801 fatcat:fzogiu5pyve23iskkvrmi3kx2q

Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ-opioid receptor occupancy

Lars-Erik Broksoe Kyhl, Shen Li, Kirstine Ullitz Faerch, Birgitte Soegaard, Frank Larsen, Johan Areberg
2016 British Journal of Clinical Pharmacology  
AIMS The aims of this study were to develop a population pharmacokinetic (PK) model to describe the PK of nalmefene in healthy subjects and to relate the exposure of nalmefene to the μ-opioid receptor  ...  occupancy by simulations in the target population.  ...  Lundbeck A/S for this analysis and there are no other relationships or activities that could appear to have influenced the submitted work.  ... 
doi:10.1111/bcp.12805 pmid:26483076 pmcid:PMC4833148 fatcat:ruojmdzkrvgwhgek2xky2bsnxm

An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects

Igor Grachev, Miroslava Doder, David Brooks, Rainer Hinz
2014 Journal of Diagnostic Imaging in Therapy  
In this study we demonstrated the importance of PET imaging for establishing PK-PD relationships and utilizing this tool in confirming proof-of-target and dose guidance for Phase 2/3 clinical trials.  ...  A 5 mg dose, administered BID, was estimated to provide ≥50% receptor occupancy in approximately 75% of the population for the majority of waking hours (12 hours/day).  ...  Cunningham for help with the imaging data analysis, and Amol Tendolkar for help with PK-PD modeling. Drs.  ... 
doi:10.17229/jdit.2014-0712-002 fatcat:dyw5s4nqgjhmpkvi6xpxylteem

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease

Suzanne Reeves, Emma McLachlan, Julie Bertrand, Fabrizia D'Antonio, Stuart Brownings, Akshay Nair, Suki Greaves, Alan Smith, David Taylor, Joel Dunn, Paul Marsden, Robert Kessler (+1 others)
2017 Brain  
Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus.  ...  ; NLME = Non-linear mixed effects modelling; Caverage = Average steady state exposure across the dosage interval (24 hours); EPS = Extrapyramidal side effects; PK = Pharmacokinetic. 3 Abstract Antipsychotic  ...  ., 2004) , who modelled the non-linear occupancy curve for [ 18 F]desmethoxyfallypride, and whose estimates for amisulpride blood concentration required to achieve 60% occupancy in caudate (119ng/ml) and  ... 
doi:10.1093/brain/aww359 pmid:28334978 fatcat:sv6agjdcpjdp3b3gfolprd6pdi

Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 1, a pharmacokinetic/pharmacodynamic comparison with paroxetine in healthy men

Sue Wilson, Astrid-Maria Højer, Jeppe Buchberg, Johan Areberg, David J Nutt
2015 Journal of Psychopharmacology  
This was a randomised, doubleblind, four-way crossover, placebo-controlled, multiple-dose study in 24 healthy young men.  ...  In the pharmacokinetic/pharmacodynamics analysis significant relationships were found between REM onset latency and time spent in REM sleep and vortioxetine/paroxetine exposure.  ...  The relationship, if any, between C av,sleep and the main PSG parameters was investigated by non-linear mixed effect analysis using an E max or a simple linear model.  ... 
doi:10.1177/0269881115599387 pmid:26253622 pmcid:PMC4579403 fatcat:rn7mkkusqrbibg4aotikzirefu

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

Haruhi Mizushima, Kazuya Kinoshita, Koji Abe, Hitoshi Ishizuka, Yasuhiko Yamada
2007 Biological and Pharmaceutical Bulletin  
correlations between the receptor occupancies and the PD/safety parameters would be useful to optimize the dose regimen and formulation. 19) In the studies, positron emission tomography (PET) 14, 15)  ...  PET studies have an advantage in that they can measure the receptor occupancy directly, however, the synthesis of the positron emission substrate and the system of detection are sometimes impediments to  ...  The results of the analysis using the linear inhibitory model, which did not improve the fitting between the effect and the receptor occupancy, compared to the inhibitory effect E max model (data not shown  ... 
doi:10.1248/bpb.30.955 pmid:17473442 fatcat:ug76vcxga5h4dl7lgckffhow2u

Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat

Yin Cheong Wong, Trayana Ilkova, Rob C. van Wijk, Robin Hartman, Elizabeth C.M. de Lange
2018 European Journal of Pharmaceutical Sciences  
; k on , drug association rate to the receptor; PET, positron emission tomography; PK, pharmacokinetics; RO, receptor occupancy  ...  It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans.  ...  We would like to thank Yumi Yamamoto for providing suggestions to the PK model and Dirk-Jan van den Berg for assisting LC − MS analysis of the animal samples.  ... 
doi:10.1016/j.ejps.2017.10.031 pmid:29106979 fatcat:y5aeinll4ndcfbvxtflzy5egr4

Therapeutic D2/3 receptor occupancies and response with low amisulpride blood concentrations in very late-onset schizophrenia-like psychosis (VLOSLP)

Suzanne Reeves, Kate Eggleston, Elizabeth Cort, Emma McLachlan, Stuart Brownings, Akshay Nair, Suki Greaves, Alan Smith, Joel Dunn, Paul Marsden, Robert Kessler, David Taylor (+2 others)
2017 International Journal of Geriatric Psychiatry  
This study aimed to investigate blood drug concentration, D2/3 receptor occupancy, and outcome in VLOSLP during open amisulpride prescribing, and compare this with Alzheimer's disease (AD).  ...  imaging was used to estimate D2/3 receptor occupancy.  ...  Small sample size meant that it was not possible to fully characterise the non-linear PK-occupancy curve in VLOSLP.  ... 
doi:10.1002/gps.4758 pmid:28643852 fatcat:eocm6hlpabgxvckydh27spen3y

Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746

Jean-Dominique Gallezot, Beata Planeta, Nabeel Nabulsi, Donna Palumbo, Xiaoxi Li, Jing Liu, Carolyn Rowinski, Kristin Chidsey, David Labaree, Jim Ropchan, Shu-Fei Lin, Aarti Sawant-Basak (+4 others)
2016 Journal of Cerebral Blood Flow and Metabolism  
We developed a method to (1) estimate the in vivo dissociation constant K d of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy  ...  This method was applied in a study of healthy human subjects with the histamine H 3 receptor radioligand [ 11 C]GSK189254 to measure the PK-occupancy relationship of the H 3 antagonist PF-03654746.  ...  XL contributed to interpretation of data and statistical analysis. JL contributed to PK analysis and interpretation of data.  ... 
doi:10.1177/0271678x16650697 pmid:27207170 pmcid:PMC5363483 fatcat:vnuwaf3isre5tnxzl7on4kgat4

Pharmacokinetics and time-course of D2 receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients

AM Catafau, MM Penengo, G. Nucci, S. Bullich, I. Corripio, E. Parellada, C. García-Ribera, R. Gomeni, E. Merlo-Pich
2008 Journal of Psychopharmacology  
The 123 I-IBZM SPECT measured D 2 receptor occupancy (D 2 RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still  ...  The aims of this study were: 1) To define the relationship between striatal D 2 receptor occupancy (D 2 RO) and plasma concentration (C P ) in stabilized schizophrenic patients on clinically relevant doses  ...  Medical Department from GlaxoSmithKline Spain, particularly Juan Lahuerta and Luis Guardiola-Gómez for their support and all the patients who participated in this study.  ... 
doi:10.1177/0269881107083810 pmid:18308793 fatcat:wtziyas4andtnoqymnat3nn7cm

Padsevonil randomized phase IIa trial in treatment-resistant focal epilepsy – a translational approach

Pierandrea Muglia, Jonas Hannestad, Christian Brandt, Steven De Bruyn, Massimiliano Germani, Brigitte Lacroix, Marian Majoie, Christian Otoul, David Sciberras, Bernhard J Steinhoff, Koen Van Laere, Wim Van Paesschen (+4 others)
2020 Brain Communications  
Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models.  ...  GABAA receptor occupancy.  ...  Acknowledgements The authors express their profound gratitude to the patients who participated in the PoC trial and their families.  ... 
doi:10.1093/braincomms/fcaa183 pmid:33241213 pmcid:PMC7677606 fatcat:alnxradxezgephs63r5cujvrpy

11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195

Masato Kobayashi, Teresa Jiang, Sanjay Telu, Sami S Zoghbi, Roger N Gunn, Eugenii A Rabiner, David R Owen, Qi Guo, Victor W Pike, Robert B Innis, Masahiro Fujita
2017 Journal of Cerebral Blood Flow and Metabolism  
Unlike human studies where full receptor blockade is difficult because of possible pharmacological effects, in these monkey studies, we administered the blocking agent to cause full receptor blockade.  ...  Receptor occupancy was 31% ± 29% in HABs and 23% ± 18% in MABs.  ... 
doi:10.1177/0271678x17699223 pmid:28322082 fatcat:dt5aefwsyva73cuxz6amhb6atq

Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors

Masao Imaizumi, Emmanuelle Briard, Sami S. Zoghbi, Jonathan P. Gourley, Jinsoo Hong, Yota Fujimura, Victor W. Pike, Robert B. Innis, Masahiro Fujita
2008 NeuroImage  
The images showed no receptorfree region that could be used for reference tissue analysis. Thus, quantitation of receptor density required measurement of parent radioligand in arterial plasma.  ...  The objectives of the current study were to evaluate kinetics of brain uptake, and the influence of the peripheral binding on the arterial input function in rhesus monkey.  ...  In vitro receptor screening at all sites other than that labeled with [ 3 H]PK 11195 were performed by the NIMH Psychoactive Drug Screening Program (contract # NO1MH32004).  ... 
doi:10.1016/j.neuroimage.2007.09.063 pmid:18024084 pmcid:PMC2275117 fatcat:gy4hbqj4yjc7bow4ey3bloemvu

Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects

Magdalena Nord, Svante Nyberg, Jacob Brogren, Aurelija Jucaite, Christer Halldin, Lars Farde
2011 International Journal of Neuropsychopharmacology  
effect at lower D 2 receptor occupancy than typical antipsychotics.  ...  This study investigated if the pharmacokinetic differences translate into different time curves for central D 2 dopamine receptor occupancy.  ...  [Clinical trial registration information : Positron emission tomography (PET) study with [ 11 C]raclopride to determine central D 2 dopamine occupancy of SEROQUEL (registration identification no. : NCT00832221  ... 
doi:10.1017/s1461145711000514 pmid:21477416 pmcid:PMC3198174 fatcat:zbp5y7sq4fbmnatmc3hk7wfjza

Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABAA receptor positive allosteric modulator PF-06372865

Sarah A Nickolls, Rachel Gurrell, Guido van Amerongen, Juha Kammonen, Lishuang Cao, Adam R Brown, Clara Stead, Andy Mead, Christine Watson, Cathleen Hsu, Robert M Owen, Andy Pike (+11 others)
2018 British Journal of Pharmacology  
Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABA A receptors, have significant side effects that limit their clinical utility.  ...  PF-06372865 exhibited concentration-dependent occupancy of GABA A receptors in preclinical species.  ...  Acknowledgements The authors thank the healthy volunteers who participated in these trials.  ... 
doi:10.1111/bph.14119 pmid:29214652 fatcat:t52b7hmwwzdu7fqbfpoqz4frci
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