Development of [ Carbonyl- 11 C]AZ13198083, a Novel Histamine Type-3 Receptor Radioligand with Favorable Kinetics.

The histamine subtype-3 receptor (H3 R) is implicated in a range of central nervous system disorders, and several radioligands have been developed for H3 R positron emission tomography imaging. However, a limitation of currently used PET radioligands for H3 R is the slow binding kinetics in high density brain regions. To address this, we herein report the development of three novel candidate H3 R radioligands, namely, [ carbonyl-11 C]AZ13153556 ([ carbonyl-11 C]4), [ carbonyl-11 C]AZD5213([ carbonyl-11 C]5), and [ carbonyl-11 C]AZ13198083 ([ carbonyl-11 C]6), and their subsequent preclinical evaluation in nonhuman primates (NHP). Radioligands [ carbonyl-11 C]4-6 were produced and isolated in high radioactivity (>1000 MBq), radiochemical purity (>99%), and moderate molar activity (19-28 GBq/μmol at time of injection) using a palladium-mediated 11 C-aminocarbonylation protocol. All three radioligands showed high brain permeability as well as a regional brain radioactivity distribution in accordance with H3 R expression (striatum > cortex > cerebellum). [ Carbonyl-11 C]6 displayed the most favorable in vivo kinetics and brain uptake, with an early peak in the striatal time-activity curve followed by a progressive washout from the brain. The specificity and on-target kinetics of [ carbonyl-11 C]6 were next investigated in pretreatment and displacement studies. After pretreatment or displacement with 5 (0.1 mg/kg), a uniformly low distribution of radioactivity across the NHP brain was observed. Collectively, this work demonstrates that [ carbonyl-11 C]6 is a promising candidate for H3 R imaging in human subjects.