RT Journal Article SR Electronic T1 Radiosynthesis and Characterization of 11C-GSK215083 as a PET Radioligand for the 5-HT6 Receptor JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 295 OP 303 DO 10.2967/jnumed.111.093419 VO 53 IS 2 A1 Parker, Christine A. A1 Gunn, Roger N. A1 Rabiner, Eugenii A. A1 Slifstein, Mark A1 Comley, Robert A1 Salinas, Cristian A1 Johnson, Christopher N. A1 Jakobsen, Steen A1 Houle, Sylvain A1 Laruelle, Marc A1 Cunningham, Vincent J. A1 Martarello, Laurent YR 2012 UL http://jnm.snmjournals.org/content/53/2/295.abstract AB The development of a PET radioligand for imaging 5-hydroxytryptamine (5-HT) 6 receptors in the brain would, for the first time, enable in vivo imaging of this target along with assessment of its involvement in disease pathophysiology. In addition, such a tool would assist in the development of novel drugs targeting the 5-HT6 receptor. Methods: On the basis of in vitro data, GSK215083 was identified as a promising 5-HT6 radioligand candidate and was radiolabeled with 11C via methylation. The in vivo properties of 11C-GSK215083 were evaluated first in pigs (to investigate brain penetration and specific binding), second in nonhuman primates (to confirm brain penetration, specific binding, selectivity, and kinetics), and third in human subjects (to confirm brain penetration and biodistribution). Results: 11C-GSK215083 readily entered the brain in all 3 species, leading to a heterogeneous distribution (striatum > cortex > cerebellum) consistent with reported 5-HT6 receptor densities and distribution determined by tissue-section autoradiography in preclinical species and humans. In vivo saturation studies using escalating doses of GSK215083 in primates demonstrated saturable, dose-dependent binding to the 5-HT6 receptor in the striatum. Importantly, 11C-GSK215083 also exhibited affinity for the 5-HT2A receptor; however, given the differential localization of these 2 receptors in the central nervous system, the discrete 5-HT6 binding properties of this radioligand were able to be determined. Conclusion: These data demonstrate the utility of 11C-GSK215083 as a promising PET radioligand for probing the 5-HT6 receptor in vivo in both preclinical and clinical species.