A Positron Emission Tomography Study to Assess Binding of Lecozotan, a Novel 5-Hydroxytryptamine-1A Silent Antagonist, to Brain 5-HT1A Receptors in Healthy Young and Elderly Subjects, and in Patients With Alzheimer's Disease

Abstract

This positron emission tomography (PET) study was conducted to assess binding of lecozotan, a new potent and silent 5-hydroxytryptamine-1A (5-HT1A) antagonist being developed for the treatment of Alzheimer's disease (AD), to 5-HT1A receptors in the human brain using 11C-labeled WAY-100635. Lecozotan was administered as a single dose of 0.5, 1, or 5 mg to young subjects and 5 mg to elderly subjects and AD patients. PET measurements were performed at 3-4 time points over a 25-h period. Mean peak 5-HT1A receptor occupancy (RO) in young subjects (seen at 1 h) was 10%, 18%, and 44% for the three doses, respectively. Mean peak RO was slightly higher in elderly (63%) and AD patients (55%). An Emax pharmacokinetic/pharmacodynamic model adequately described the lecozotan plasma concentration-RO relationship. Steady-state peak RO is predicted to be approximately 70% for 5 mg q12 h (twice-daily). Results demonstrate that lecozotan binds to the human brain 5-HT1A receptors and has a maximum observed RO of 50-60% following a single dose of 5 mg in elderly subjects/AD patients.

The relation of developmental changes in brain serotonin transporter (5HTT) and 5HT1A receptor binding to emotional behavior in female rhesus monkeys: Effects of social status and 5HTT genotype

“…Drevets and colleagues (2007) replicated previous findings of reduced 5HT1A BP ND in mesiotemporal cortex and raphe in depressed male and female subjects, although, in a review of the field, noted that inconsistencies in the literature may arise from brain region-specific effects or pathophysiological heterogeneity within depressive disorders. Age, sex, and reproductive hormones are also significant factors found to affect 5HT1A BP ND (Moller et al, 2007; Raje et al, 2008; Moses-Kolko et al, 2011). …”

Measurement of the serotonin 1A receptor availability in patients with schizophrenia during treatment with the antipsychotic medication ziprasidone

“…Studies performed during treatment with non-antipsychotic 5-HT 1A antagonist or partial agonist medications consistently demonstrate in vivo occupancy at the receptor (Andree et al, 2003;Farde et al, 2000;Martinez et al, 2001b;Rabiner et al, 2000Rabiner et al, , 2002cRaje et al, 2008) while PET studies performed during treatment with non-antipsychotic drugs which act as full agonists have, in general, failed to detect significant occupancy at this receptor site (Bantick et al, 2004b;Nakayama et al, 2002;Rabiner et al, 2000Rabiner et al, , 2002c.…”

Correlating Efficacy in Rodent Cognition Models with in Vivo 5-Hydroxytryptamine1A Receptor Occupancy by a Novel Antagonist, (R)-N-(2-Methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexane Carboxamide (WAY-101405)

“…5-HT 1A receptor occupancy, at 2 h, the same time that cognitive assessments were made, was approximately 90% at doses of 1 and 3 mg/kg. We have recently demonstrated, in human patients using positron emission tomography imaging, that lecozotan can occupy up to 60% of 5-HT 1A receptors in elderly subjects and Alzheimer's disease patients (Raje et al, 2008), and clinical trials, measuring cognitive performance in similar patient populations are ongoing. The results of these studies will further increase our understanding of the role of 5-HT 1A receptors in human cognitive function.…”