Human Kinetic Modeling of the 5HT6 PET Radioligand 11C-GSK215083 and Its Utility for Determining Occupancy at Both 5HT6 and 5HT2A Receptors by SB742457 as a Potential Therapeutic Mechanism of Action in Alzheimer Disease.
J Nucl Med
; 56(12): 1901-9, 2015 Dec.
Article
em En
| MEDLINE
| ID: mdl-26383152
ABSTRACT
UNLABELLED Antagonism of 5-hydroxytrypamine-6 (5HT6) receptors is associated with procognitive effects in preclinical species, suggesting a therapeutic potential for this mechanism in Alzheimer disease (AD) and other cognitive diseases. In a phase 2 dose study, SB742457, a novel 5HT6 antagonist, showed increasing procognitive effects in patients with AD as the dose increased, with a procognitive signal in AD patients at a dose of 35 mg/d superior to the other doses tested (5 and 15 mg/d). METHODS:
In this article, we describe the quantification and pharmacologic selectivity of a new 5HT6 PET ligand ((11)C-GSK215083) in healthy volunteers and its use to measure occupancies achieved at various doses of SB742457.RESULTS:
Kinetic analysis of (11)C-GSK215083 uptake in the human brain demonstrated the multilinear model, MA2, to represent the method of choice when a blood input was available and the full tissue reference method when no input was available. Pharmacologic dissection of the in vivo (11)C-GSK215083-specific binding showed the ligand bound mostly the 5HT6 in the striatum (blocked by SB742457 but not by the selective 5-hydroxytryptamine-2A (5HT2A) antagonist ketanserin) and the 5HT2A in the frontal cortex (blocked by both ketanserin and SB742457). Repeated administration of SB742457 (3, 15, and 35 mg/d) saturated the 5HT6 receptors at all doses. In the cortex, 5HT2A receptor occupancy was 24% ± 6% (3 mg/d), 35% ± 4% (15 mg/d), and 58% ± 19% (35 mg/d; mean ± SD), suggesting a progressive engagement of 5HT2A as the dose increased.CONCLUSION:
Collectively, these data support the use of (11)C-GSK215083 as a 5HT6 clinical imaging tool and suggest that blocking both the 5HT6 and the 5HT2A receptors may be required for the optimal therapeutic action of SB742457 in AD.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
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Antagonistas da Serotonina
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Sulfonas
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Receptores de Serotonina
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Compostos Radiofarmacêuticos
/
Receptor 5-HT2A de Serotonina
/
Doença de Alzheimer
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Adult
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Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
J Nucl Med
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Reino Unido