Radiosynthesis and Characterization of 11C-GSK215083 as a PET Radioligand for the 5-HT6 Receptor

Journal of Nuclear Medicine

Christine A. Parker¹  Laurent Martarello¹  Marc Laruelle¹  Roger N. Gunn¹  Mark Slifstein¹  Steen Jakobsen¹  Cristian Salinas¹  Vincent J. Cunningham¹  Eugenii A. Rabiner¹  Christopher N. Johnson¹  Sylvain Houle¹  Robert Comley¹ 

关键词: PET;    serotonin;    5-HT6;    receptor;    radioligand;   

DOI  :  10.2967/jnumed.111.093419

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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.

【 授权许可】

Unknown