Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C]PHNO PET

Eugenii A Rabiner,Grace Chen,Wei Yin,Jingtao Wu,Roger N Gunn,Joy Atienza,Tolga Uz,Terry Brown,Johannes Tauscher,Jan Passchier,Adam J Schwarz,Graham E Searle,Jeremy M T J Dennison,Yvonne Lewis,Ayla Mansur

doi:10.1038/s41386-021-01204-1

Abstract

The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041). GPR139 agonism is a novel candidate mechanism for the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction. Ten healthy volunteers underwent [11C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). One of the post-d-amphetamine scans for each subject was preceded by a single oral dose of TAK-041 (20 mg in five; 40 mg in the other five participants). D-amphetamine induced a significant decrease in [11C]PHNO binding potential relative to the non-displaceable component (BPND) in all regions examined (16–28%), consistent with increased synaptic dopamine release. Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BPND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BPND was generally higher after the 40 mg than the 20 mg TAK-041 dose, with the difference between doses reaching statistical significance in the putamen. Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [11C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development.

Highlights

Positron emission tomography (PET) studies have become an essential component of early-phase development for novel smallmolecule pharmaceuticals targeting the central nervous system (CNS)
The aim of this study was to evaluate the effects of TAK-041, a novel G-protein-coupled receptor 139 (GPR139) agonist, on AMPH-induced dopamine release in the CNS, and indirectly comment on its brain penetration and target engagement
We have demonstrated a dose-dependent modulation of dopamine release in the human brain by TAK-041

Summary

Introduction

Positron emission tomography (PET) studies have become an essential component of early-phase development for novel smallmolecule pharmaceuticals targeting the central nervous system (CNS). These PET studies typically use a radioligand specific for the molecular target in question and relate changes in target occupancy, as measured with PET at several time points subsequent to a single oral dose of the drug under investigation, to drug concentration in the plasma at the time of the PET scans Such a study helps to confirm brain penetration and central target engagement and, together with proper modelling approaches, provides a rational basis for drug-dosing schedules in future clinical trials. Data derived from such studies can establish the time–exposure–occupancy relationship for a novel compound [1, 2], enabling the selection of a relevant dose range, thereby significantly increasing efficiency, reducing time and cost, and increasing the probability of success of subsequent clinical trials. This approach uses a PET radioligand that is sensitive to the concentration of an endogenous neurotransmitter to detect changes in endogenous neurotransmitter levels induced by the novel pharmaceutical

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