TY - JOUR
T1 - Endogenous dopamine release in the human brain as a pharmacodynamic biomarker
T2 - evaluation of the new GPR139 agonist TAK-041 with [11C]PHNO PET
AU - Rabiner, Eugenii A.
AU - Uz, Tolga
AU - Mansur, Ayla
AU - Brown, Terry
AU - Chen, Grace
AU - Wu, Jingtao
AU - Atienza, Joy
AU - Schwarz, Adam J.
AU - Yin, Wei
AU - Lewis, Yvonne
AU - Searle, Graham E.
AU - Dennison, Jeremy M.T.J.
AU - Passchier, Jan
AU - Gunn, Roger N.
AU - Tauscher, Johannes
N1 - Funding Information:
All studies were funded by the sponsor, Takeda Pharmaceutical Company Ltd. Editorial assistance in formatting, proofreading and copy editing was provided by Oxford PharmaGenesis, Oxford, UK.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/10/21
Y1 - 2021/10/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85117504612&partnerID=8YFLogxK
U2 - 10.1038/s41386-021-01204-1
DO - 10.1038/s41386-021-01204-1
M3 - Article
AN - SCOPUS:85117504612
SN - 0893-133X
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
ER -