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J Nucl Med. 2015 Dec;56(12):1901-9. doi: 10.2967/jnumed.115.162743. Epub 2015 Sep 17.

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.

Author information

1
GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, United Kingdom Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom Christine.A.Parker@gsk.com.
2
Imanova Ltd., Imperial College London, London, United Kingdom Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom.
3
Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom Imanova Ltd., Imperial College London, London, United Kingdom Department of Engineering Science, University of Oxford, Oxford, United Kingdom.
4
Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
5
AbbVie, Translational Imaging, Integrated Science and Technology, North Chicago, Illinois.
6
Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
7
GlaxoSmithKline, Neuroscience Therapy Area Unit, Stevenage, United Kingdom.
8
Research Imaging Centre, CAMH, and Department of Psychiatry, University of Toronto, Toronto, Canada.
9
Intra-Cellular Therapies Inc., New York, New York; and.
10
School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.

Abstract

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.

KEYWORDS:

11C-GSK215083; 5HT6; Alzheimer’s disease; SB742457; human kinetic modeling

PMID:
26383152
DOI:
10.2967/jnumed.115.162743
[Indexed for MEDLINE]
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