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

合成了一系列含吡咯烷酮n -氟乙基、n -氟丙基、n -对氟苯基或吡咯烷啶部分4位被氟取代（FP-eticlopride）的噻氯pride [(-) - (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，并评价了它们作为潜在的基于多巴胺能受体的正电子断层扫描放射性药物。还开发了通过氟-18取代磺酸酯来生产这些F-18标记类似物的放射性合成程序。利用大鼠纹状体组织中H-3 spiperone的竞争置换体外结合实验表明，依替氯pride的n -氟烷基衍生物的IC_<50>值为17-23 nM，而fp -依替氯pride的IC_<50>值为1.9 nM，与依替氯pride本身的IC_<50> 2.9 nM大致相等。在大鼠体内组织生物分布结果证实，与依替氯pride相比，依替氯pride的n -氟烷基化衍生物的多巴胺D-2结合亲和力降低，这反映在这些化合物的纹状体与小脑的比例较低。F-18标记的FP-eticlopride在大鼠体内的区域分布显示出与D-2受体相关的定位。注射后30 min，纹状体体内摄取量为0.56% /g， 90 min时，剂量为0.47% /g。纹状体与小脑的比值随时间的增加而增加，90 min时达到5.1。纹状体的摄取被已知的D-2拮抗剂氟哌啶醇预处理阻断（体内结合减少80%）。体内除氟在90分钟的时间间隔内发生了很大程度的变化。

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.