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 (VT) was 3.97. In contrast, there was mild regional heterogeneity for GSK1034702 in the human brain. Human whole brain VT estimates (4.9) were in broad agreement with primate VT and the fP/fND 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 http://clinicaltrials.gov/show/NCT00937846.
Ridler, K., Cunningham, V., Huiban, M., Martarello, L., Pampols-Maso, S., Passchier, J., … Rabiner, E. A. (2014). 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. EJNMMI Research, 4(1). https://doi.org/10.1186/s13550-014-0066-y