CEA, I2BM, Service Hospitalier Frédéric Joliot, F-91406 Orsay, France.
Nucl Med Biol. 2013 Oct;40(7):887-95. doi: 10.1016/j.nucmedbio.2013.06.003. Epub 2013 Jul 25.
[(18)F]Fallypride, a fluorinated and substituted benzamide with high affinity for D2/D3 receptors, is a useful PET radioligand for the study of striatal/extrastriatal areas. Since [(18)F]fallypride is extensively metabolized in vivo and since PET examinations are long lasting in humans, the rapid measurement of the unchanged radiotracer in plasma is essential for the quantification of images. The present study aims: i) to evaluate if the radiometabolites of [(18)F]fallypride cross the blood-brain barrier in rodents, ii) to identify these radiometabolites in baboon plasma and iii) to develop a rapid solid phase extraction method (SPE) suitable for human applications to quantify both [(18)F]fallypride and its radiometabolites in plasma.
The metabolites P450-dependant in rat and human liver microsomes were characterized by LC-MS-MS and compared to those detected in vivo. Sequential solvent elution on Oasis®-MCX-SPE cartridges was used to quantify [(18)F]fallypride and its radiometabolites.
In rat microsomal incubations, five metabolites generated upon N/O-dealkylation or hydroxylation at the pyrrolidine and/or at the benzamide moiety were identified. No radiometabolite was detected in the rat brain. N-dealkylated and hydroxylated derivatives were detected in human microsomal incubations as well as in baboon plasma. The use of SPE (total recovery 100.2%± 2.8%, extraction yield 95.5%± 0.3%) allowed a complete separation of [(18)F]fallypride from its radiometabolites in plasma and evaluate [(18)F]fallypride at 150 min pi to be 22%± 5% of plasma radioactivity.
The major in vivo radiometabolites of [(18)F]fallypride were produced by N-dealkylation and hydroxylation. Allowing the rapid analysis of multiple plasma samples, SPE is a method of choice for the determination of [(18)F]fallypride until late images required for quantitative PET imaging in humans.
[（18）F]Fallypride 是一种氟代和取代的苯甲酰胺，对 D2/D3 受体具有高亲和力，是一种用于研究纹状体/纹状体外区域的有用 PET 放射性配体。由于[（18）F]Fallypride 在体内广泛代谢，并且人类的 PET 检查时间较长，因此快速测量血浆中未改变的示踪剂对于图像的定量至关重要。本研究旨在：i）评估[（18）F]Fallypride 的放射性代谢物是否穿过啮齿动物的血脑屏障，ii）鉴定狒狒血浆中的这些放射性代谢物，iii）开发一种快速固相萃取方法（SPE）适用于人类应用，以定量测定血浆中的[（18）F]Fallypride 及其放射性代谢物。
通过 LC-MS-MS 对大鼠和人肝微粒体中的代谢物 P450 依赖性进行了表征，并与体内检测到的代谢物进行了比较。Oasis®-MCX-SPE 小柱上的顺序溶剂洗脱用于定量[（18）F]Fallypride 及其放射性代谢物。
在大鼠微粒体孵育中，鉴定出在吡咯烷和/或苯甲酰胺部分发生 N/O-脱烷基化或羟化时生成的五种代谢物。在大鼠脑中未检测到放射性代谢物。在人微粒体孵育以及狒狒血浆中也检测到 N-脱烷基化和羟化衍生物。使用 SPE（总回收率 100.2%±2.8%，提取收率 95.5%±0.3%）可以完全分离血浆中的[（18）F]Fallypride 并评估在 150 分钟时 pi 为血浆放射性的 22%±5%。
[（18）F]Fallypride 的主要体内放射性代谢物是通过 N-脱烷基化和羟化产生的。SPE 允许快速分析多个血浆样本，是用于测定[（18）F]Fallypride 的首选方法，直到需要用于人类定量 PET 成像的晚期图像为止。
