First evaluation in humans of [11C]GSK215083 as a probe to image the 5-HT6 receptors

313 Objectives: Preclinical studies show that 5-HT6 receptor antagonism exert cognitive enhancing effects suggesting potential clinical usefulness in conditions such as Alzheimer disease (1). GSK215083 is a high affinity 5-HT6 receptor antagonist (pKi 5-HT6 =9.82) with promising imaging properties in the pig brain (2). This study aimed to examine [11C]GSK215083 brain distribution in human subjects. Because GSK215083 is also potent at the 5-HT2A receptor (pKi 5-HT2A =9.14) we assessed the contribution of 5-HT6 and 5-HT2A receptors binding in striatal and cortical areas, two regions known to be rich in the respectively aforementioned receptors (3). Methods: PET scans were acquired in 8 healthy male volunteers. Binding Potential (BPND) values were determined using SRTM with cerebellum as reference region. Four subjects (group A) were studied twice at baseline; 2 subjects (group B) were studied at baseline, after ketanserin (1mg/kg, iv, a 5HT2A blocker)and after SB742457 (175mg, oral, a 5HT6 blocker); 2 subjects (group C) were studied at baseline and on SB742457 (175mg, oral). Results: [11C]GSK215083 displayed appropriate brain uptake in humans. BPNDs were highest in striatal regions, followed by cortical regions (Fig.1). Striatal BPND was markedly reduced (40%) following pretreatment with SB742457 (groups B and C) but was unaffected by pretreatment with ketanserin (an observation consistent with the lower level of 5HT2A receptors in striatum compared to cortical areas). In contrast, cortical BPNDS were markedly reduced by ketanserin. Conclusions: These first human data suggest that GSK215083 is an appropriate PET radiotracer to quantify 5-HT6 receptors in the human striatum.