Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Neuropsychopharmacology (New York, N.Y.), 2022-06, Vol.47 (7), p.1405-1412

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2022

Quelle

Open access e-journals list

Beschreibungen/Notizen

• 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 [ C]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 [ C]PHNO binding potential relative to the non-displaceable component (BP ) 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 BP in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BP 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. [ C]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.