| 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 . |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 50% |
| Unknown | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 50% |
| Scientists | 1 | 50% |
Mendeley readers
The data shown below were compiled from readership statistics for 47 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 47 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 18 | 38% |
| Student > Ph. D. Student | 8 | 17% |
| Student > Master | 6 | 13% |
| Professor | 3 | 6% |
| Other | 2 | 4% |
| Other | 5 | 11% |
| Unknown | 5 | 11% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 11 | 23% |
| Chemistry | 11 | 23% |
| Agricultural and Biological Sciences | 5 | 11% |
| Environmental Science | 3 | 6% |
| Neuroscience | 3 | 6% |
| Other | 3 | 6% |
| Unknown | 11 | 23% |
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
#14,791,252
of 22,772,779 outputs
Outputs from EJNMMI Research
#221
of 555 outputs
Outputs of similar age
#202,310
of 359,774 outputs
Outputs of similar age from EJNMMI Research
#4
of 6 outputs
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So far Altmetric has tracked 555 research outputs from this source. They receive a mean Attention Score of 2.5. This one has gotten more attention than average, scoring higher than 55% of its peers.
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