Positron emission tomographic analysis of dose-dependent NAD-299 binding to 5-hydroxytryptamine-1A receptors in the human brain.
BACKGROUND
The serotonin 5-HT(1A) receptor has been ascribed a putative role in the pathophysiology and drug treatment of depression. NAD-299 (generic name robalzotan) is a new potential antidepressant with high affinity and selectivity for the 5-HT(1A) receptor.


OBJECTIVE
The aim of this positron emission tomography (PET) study was to examine the extent and time-course of 5-HT(1A) occupancy by NAD-299 in the human brain, in relation to plasma concentration after escalating single oral doses.


METHODS
Five healthy male subjects received one or more single oral doses of NAD-299 (0.5, 2.5 and 10 mg) in aqueous solution under fasting conditions. Total and unbound (after ultrafiltration) plasma concentrations of NAD-299 were determined by liquid chromatography-mass spectrometry (LC-MC), over a tentative dosage interval of 8 h. Regional 5-HT(1A) receptor occupancy in brain was calculated by the simplified reference tissue model using the radioligand [ carbonyl-(11)C]WAY-100635.


RESULTS
After the 10 mg dose, occupancy was high in the raphe (62-85%) and neocortical regions (68-75%) at time for C(max), but had declined considerably (17-44%) at 7 h after dose intake.


CONCLUSIONS
This study confirmed that the new selective 5-HT(1A) antagonist NAD-299 occupies 5-HT(1A) receptors in the living human brain in a dose-dependent manner following oral dosage. The curvilinear relationship between NAD-299 drug concentration and 5-HT(1A) receptor occupancy was established and can be used for dose selection in subsequent clinical patient studies.
Andrée
Bengt
B
Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska Hospital, 171 76, Stockholm, Sweden. bengt.andree@ks.se
Hedman
Ann
A
Thorberg
Seth-Olav
SO
Nilsson
Dag
D
Halldin
Christer
C
Farde
Lars
L
D000328:Adult; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology*; D001578:Benzopyrans / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology; D014055:Tomography, Emission-Computed
D000928:Antidepressive Agents; D001578:Benzopyrans; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C108607:robalzotan