Development of [ ^<18>F]-Synthons and Application to Dopamine D-2 Receptor Ligands

点击翻译按钮获取中文摘要

A series of eticlopride [(-) - (S) -5-chloro-3-ethyl-N- [(1-ethyl-2-pyrrolidinyl) methyl] -6-methoxysalicylamide] derivatives bearing pyrrolidino N-fluoroethyl, N-fluoropropyl, N-p-fluorobenzyl or substituted with fluorine at the 4-position of the pyrrolidine moiety (FP-eticlopride) were synthesized and evaluated as potential dopaminergic receptor-based positron tomography radiopharmaceuticals. Radiosynthetic procedures for producing these F-18 labeled analogs by F-18 fluoride displacement of the sulfonate esters were also developed. In vitro binding assays using competitive displacement of H-3 spiperone from rat striatal tissue indicated that IC_<50> values of the N-fluoroalkyl derivatives of eticlopride were 17-23 nM, whereas the corresponding value for FP-eticlopride was 1.9 nM, approximately equal to that of eticlopride itself (IC_<50> 2.9 nM). The decreased Dopamine D-2 bindingaffinity of N-fluoroalkylated derivatives of eticlopride relative to eticlopride was corroborated by in vivo tissue biodistribution results in rats, as reflected by the low striatum to cerebellum ratios for these compounds. The regional distribution of F-18 labeled FP-eticlopride in rat showed a localization associated with D-2 receptors. In vivo uptake in the rat striatum was 0.56 %dose/g at 30 min and 0.47 %dose/g at 90 min after injection. The striatum-cerebellum ratio was strongly increasing with time and reached value of 5.1 at 90 min. Uptake in the striatum was blocked by pretreatment with known D-2 antagonist haloperidol (80% decrease of in vivo binding). In vivo defluorination took place to a significant degree over the 90 min-interval.