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

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.

A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System

“…Up to now, specific and validated PET radioligands for use in humans have been developed for the receptors 5-HT 1A R, 5-HT 1B R, 5-HT 2A R, and 5-HT 4 R and for 5-HTT (Paterson and Kornum, 2013). A radioligand for the 5-HT 6 receptor has been validated in humans (Parker et al, 2012), but was not included here because it also has high affinity to the 5-HT 2A receptor (Parker et al, 2015).…”

Characterization and Reliability of [18F]2FNQ1P in Cynomolgus Monkeys as a PET Radiotracer for Serotonin 5-HT6 Receptors

“…ICC ranged from 0.16 in the raphe to 0.97 in the prefrontal cortex. Of note, [ 18 F]2FNQ1P exhibited BP ND less than 1 as other serotonergic tracers ([ 18 F]MPPF and [ 11 C]GSK215083), which are used for in vivo imaging in both animals and humans studies (Yamamoto et al, 2013; Parker et al, 2015; Ballanger et al, 2016). …”

“…So BP ND is linked to the available receptor density and the affinity of the radioligand for its specific receptor. As previous data from Parker and collaborators (Parker et al, 2012, 2015) support the use of the cerebellum as a region of reference for high affinity 5-HT 6 R ligands, the cerebellum (excluding vermis) was used as the reference area for both models. Regional parametric values were obtained by modeling the mean regional kinetics, extracted in the native PET spaces with the MAXPROB method.…”

“…Taken together, these cross-species studies, although excluding non-human primates, revealed high levels in the striatum, moderate levels in the hippocampus and cerebral cortex and low levels in the cerebellum. In PET imaging studies, only two 5-HT 6 R ligands have been successfully used in vivo : [ 11 C]GSK215083, which binds to striatal 5-HT 6 Rs in pigs, baboons and humans but displays high affinity for 5-HT 2A Rs essentially in the frontal cortex (Parker et al, 2012, 2015) and [ 18 F]2FNQ1P, recently developed by our team, that binds with high affinity and specificity to 5-HT 6 Rs in cats and macaques and, interestingly, no affinity for 5-HT 2A Rs, nor 5-HT 1B Rs, 5-HT 2B Rs and 5-HT 2C Rs (Becker et al, 2014; Colomb et al, 2014). …”

A tricyclic antidepressant, amoxapine, reduces amyloid-β generation through multiple serotonin receptor 6-mediated targets

“…Revealed by a number of animal behaviour studies, the knockdown or antagonism of HTR6 attenuate the memory deficits in AD animal model and shows anti-depressive activity 32–34 . Based on our secondary screening data, HTR6 is responsible for the Aβ-reducing activity of amoxapine, suggesting that compounds targeting HTR6 may modulate both cognition and Aβ generation, which directly fine-tunes AD pathogenesis.…”