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Open Access 01-12-2014 | Original research

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

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

Published in: EJNMMI Research | Issue 1/2014

Abstract

Background

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.

Methods

GSK1034702 was radiolabelled with ¹¹C, and the brain distribution of [¹¹C]GSK1034702 was investigated in two anaesthetised baboons and four healthy male humans. In humans, PET scans were performed (following intravenous injection of [¹¹C]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.

Results

The distribution of [¹¹C]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.

Conclusion

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.

Trial registration

Clinical trial details: ‘Brain Uptake of GSK1034702: a Positron Emission Tomography (PET) Scan Study.’; clinicaltrial.gov identifier: NCT00937846.

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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
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
Publication date: 01-12-2014
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2014
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-014-0066-y

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusion

Trial registration

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Trial registration

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