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An evaluation of the brain distribution of [11C]GSK1034702, a muscarinic-1 (M1) positive allosteric modulator in the living human brain using positron emission tomography

Overview of attention for article published in EJNMMI Research, December 2014
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  • Among the highest-scoring outputs from this source (#12 of 138)
  • Above-average Attention Score compared to outputs of the same age (62nd percentile)
  • High Attention Score compared to outputs of the same age and source (80th percentile)

Mentioned by

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2 tweeters

Citations

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11 Dimensions

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39 Mendeley
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Title
An evaluation of the brain distribution of [11C]GSK1034702, a muscarinic-1 (M1) positive allosteric modulator in the living human brain using positron emission tomography
Published in
EJNMMI Research, December 2014
DOI 10.1186/s13550-014-0066-y
Pubmed ID
Authors

Khanum Ridler, Vincent Cunningham, Mickael Huiban, Laurent Martarello, Sabina Pampols-Maso, Jan Passchier, Roger N Gunn, Graham Searle, Anissa Abi-Dargham, Mark Slifstein, Jeanette Watson, Marc Laruelle, Eugenii A Rabiner

Abstract

The ability to quantify the capacity of a central nervous system (CNS) drug to cross the human blood-brain barrier (BBB) provides valuable information for de-risking drug development of new molecules. Here, we present a study, where a suitable positron emission tomography (PET) ligand was not available for the evaluation of a potent muscarinic acetylcholine receptor type-1 (M1) allosteric agonist (GSK1034702) in the primate and human brain. Hence, direct radiolabelling of the novel molecule was performed and PET measurements were obtained and combined with in vitro equilibrium dialysis assays to enable assessment of BBB transport and estimation of the free brain concentration of GSK1034702 in vivo. GSK1034702 was radiolabelled with (11)C, and the brain distribution of [(11)C]GSK1034702 was investigated in two anaesthetised baboons and four healthy male humans. In humans, PET scans were performed (following intravenous injection of [(11)C]GSK1034702) at baseline and after a single oral 5-mg dose of GSK1034702. The in vitro brain and plasma protein binding of GSK1034702 was determined across a range of species using equilibrium dialysis. The distribution of [(11)C]GSK1034702 in the primate brain was homogenous and the whole brain partition coefficient (V T) was 3.97. In contrast, there was mild regional heterogeneity for GSK1034702 in the human brain. Human whole brain V T estimates (4.9) were in broad agreement with primate V T and the f P/f ND ratio (3.97 and 2.63, respectively), consistent with transport by passive diffusion across the BBB. In primate and human PET studies designed to evaluate the transport of a novel M1 allosteric agonist (GSK1034702) across the BBB, we have demonstrated good brain uptake and BBB passage consistent with passive diffusion or active influx. These studies discharged some of the perceived development risks for GSK1034702 and provided information to progress the molecule into the next stage of clinical development. Clinical trial details: 'Brain Uptake of GSK1034702: a Positron Emission Tomography (PET) Scan Study.'; clinicaltrial.gov identifier: NCT00937846 .

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 39 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 39 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 13 33%
Student > Ph. D. Student 7 18%
Student > Master 6 15%
Professor 3 8%
Other 2 5%
Other 4 10%
Unknown 4 10%
Readers by discipline Count As %
Medicine and Dentistry 9 23%
Chemistry 9 23%
Agricultural and Biological Sciences 4 10%
Neuroscience 3 8%
Environmental Science 3 8%
Other 4 10%
Unknown 7 18%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 28 June 2015.
All research outputs
#2,192,288
of 5,285,691 outputs
Outputs from EJNMMI Research
#12
of 138 outputs
Outputs of similar age
#65,279
of 182,655 outputs
Outputs of similar age from EJNMMI Research
#4
of 21 outputs
Altmetric has tracked 5,285,691 research outputs across all sources so far. This one has received more attention than most of these and is in the 56th percentile.
So far Altmetric has tracked 138 research outputs from this source. They receive a mean Attention Score of 1.1. This one has done particularly well, scoring higher than 90% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 182,655 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 62% of its contemporaries.
We're also able to compare this research output to 21 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 80% of its contemporaries.