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

Author(s):  
Eugenii A. Rabiner ◽  
Tolga Uz ◽  
Ayla Mansur ◽  
Terry Brown ◽  
Grace Chen ◽  
...  

AbstractThe 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.

NeuroImage ◽  
2001 ◽  
Vol 13 (6) ◽  
pp. 1172
Author(s):  
Ines K. Goerendt ◽  
Cristina Messa ◽  
Andrew D. Lawrence ◽  
Paola Piccini ◽  
Paul M. Grasby ◽  
...  

NeuroImage ◽  
1998 ◽  
Vol 7 (4) ◽  
pp. A51 ◽  
Author(s):  
M.J. Koepp ◽  
R.N. Gunn ◽  
A.D. Lawrence ◽  
V.J. Cunningham ◽  
A. Dagher ◽  
...  

1990 ◽  
Vol 528 (1) ◽  
pp. 80-82 ◽  
Author(s):  
Kenichi Kashihara ◽  
Takashi Hamamura ◽  
Kazuya Okumura ◽  
Saburo Otsuki

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