TY - JOUR T1 - Human Kinetic Modeling of the 5HT6 PET Radioligand <sup>11</sup>C-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 JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1901 LP - 1909 DO - 10.2967/jnumed.115.162743 VL - 56 IS - 12 AU - Christine A. Parker AU - Eugenii A. Rabiner AU - Roger N. Gunn AU - Graham Searle AU - Laurent Martarello AU - Robert A. Comley AU - Maria Davy AU - Alan A. Wilson AU - Sylvain Houle AU - Romina Mizrahi AU - Marc Laruelle AU - Vincent J. Cunningham Y1 - 2015/12/01 UR - http://jnm.snmjournals.org/content/56/12/1901.abstract N2 - 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 (11C-GSK215083) in healthy volunteers and its use to measure occupancies achieved at various doses of SB742457. Results: Kinetic analysis of 11C-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 11C-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 11C-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. ER -