Synthesis and initial PET imaging of new potential dopamine D 3 receptor radioligands ( E)-4,3,2-[ 11C]methoxy- N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides

Abstract

D 3 receptor radioligands ( E)-4,3,2-[ 11C]methoxy- N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4-[ 11C]MMC, [ 11C] 1a; 3-[ 11C]MMC, [ 11C] 1b; and 2-[ 11C]MMC, [ 11C] 1c) were synthesized for evaluation as novel potential positron emission tomography (PET) imaging agents for brain D 3 receptors. The new tracers 4,3,2-[ 11C]MMCs were prepared by O-[ 11C]methylation of corresponding precursors ( E)-4,3,2-hydroxy- N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-HMCs) using [ 11C]methyl triflate and isolated by the solid-phase extraction (SPE) purification procedure with 40–65% radiochemical yields, decay corrected to end of bombardment (EOB), and a synthesis time of 15–20 min. The PET dynamic studies of the tracers [ 11C] 1a– c in rats were performed using an animal PET scanner, IndyPET-II, developed in our laboratory. The results show that the brain uptake sequence was 4-[ 11C]MMC > 3-[ 11C]MMC > 2-[ 11C]MMC, which is consistent with their in vitro biological properties. The initial PET blocking studies of the tracers 4,3,2-[ 11C]MMCs with corresponding pretreatment drugs ( E)-4,3,2-methoxy- N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-MMCs, 1a– c) had no effect on 4,3,2-[ 11C]MMCs-PET rat brain imaging. These results suggest that the localization of 4,3,2-[ 11C]MMCs in rat brain is mediated by nonspecific processes, and the visualization of 4,3,2-[ 11C]MMCs-PET in rat brain is related to nonspecific binding.