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

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 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. 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. 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

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

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 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. 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. 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

Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study

We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [11C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model. The administration of GSK356278 reduced [11C](R)-rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 46 ± 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development

Prediction of repeat-dose occupancy from single-dose data:characterisation of the relationship between plasma pharmacokinetics and brain target occupancy

Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [(11)C]DASB ([(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC(50)=2.62±0.93 ng/mL) was significantly better (P<0.05) than that from the direct model (OC(50)=2.29±1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD