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

合成了一系列具有吡咯烷基N-氟乙基、N-氟丙基、N-对氟苄基或吡咯烷基4-位被氟取代的[（-）-（S）-5-氯-3-乙基-N- [（1-乙基-2-吡咯烷基）甲基] -6-甲氧基水杨酰胺]衍生物（FP-依替氯必利），并评价了其作为潜在的基于多巴胺受体的正电子断层扫描放射性药物的活性。还开发了通过F-18氟化物置换磺酸酯来生产这些F-18标记的类似物的放射合成程序。在体外结合试验中，使用大鼠纹状体组织中的H-3螺哌隆的竞争性置换，表明<50>依替氯必利的N-氟烷基衍生物的IC_值为17-23 nM，而FP-依替氯必利的相应值为1.9 nM，约等于依替氯必利本身的IC_值（IC_<50>2.9 nM）。依替氯必利的N-氟烷基化衍生物相对于依替氯必利的多巴胺D-2结合亲和力的降低被大鼠体内组织生物分布结果所证实，如这些化合物的低纹状体与小脑比率所反映的。F-18标记的FP-依替氯必利在大鼠体内的区域分布显示与D-2受体相关的定位。注射后30 min和90 min大鼠纹状体中的体内摄取分别为0.56%剂量/g和0.47%剂量/g。随着时间的推移，纹状体-小脑的比例强烈增加，并在90分钟时达到5.1的值。在纹状体中的摄取被阻断预处理与已知的D-2拮抗剂氟哌啶醇（在体内结合减少80%）。在90分钟的时间间隔内，体内去甲发生了显著的程度。

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.