科研之友
微信
新浪微博
Facebook
分享链接
摘要
Introduction: LBT-999, (E)-N-(4-fluorobut-2-enyl)-2 beta-carbomethoxy-3 beta-(4'-tolyl)nortropane, has been developed for PET imaging of the dopamine transporter. [F-18]LBT-999 PET studies in baboons showed a lower brain uptake than [C-11]LBT-999 and a high bone uptake, suggesting the presence of interfering metabolites. Therefore, in vitro and in vivo metabolism of these radiotracers was investigated.
Methods: Rat and human liver microsomal incubations, baboon plasma and rat brain extracts were analyzed by radio-HPLC and LC-MS-MS.
Results: In vitro experiments demonstrated the formation by P450s of five polar metabolites. The main routes of LBT-999 metabolism proposed were N-dealkylation, tolyl-hydroxylation and dealkylation plus tolyl-hydroxylation. In vivo in baboons, [F-18]LBT-999 was rapidly converted into a [F-18]hydroxylated metabolite likely oxidized in plasma into a [F-18]carboxylic acid and into unlabeled N-dealkyl-LBT-999. The latter was detected in baboon plasma and in rat brain by LC-MS-MS. The time course of unchanged [F-18]LBT-999 decreased rapidly in plasma and was higher than that of [C-11]LBT-999 due to the formation of unlabeled N-dealkyl-LBT-999. In rats, striatum-to-cerebellum ratios of [F-18]LBT-999, [F-18]hydroxylated and [F-18]acidic metabolite were 20, 4.2 and 1.65, respectively, suggesting a possible accumulation of the hydroxylated compound in the striatum.
Conclusion: P450s catalyzed the formation of dealkylated and hydroxylated metabolites of LBT-999. In baboons, an extensive metabolism of [F-18]LBT-999, with formation of unlabeled N-dealkyl-LBT-999, [F-18]fluorobutenaldehyde (or its oxidation product) and [F-18]hydroxy-LBT-999 able to penetrate the brain, prevented an easy and accurate estimation of the input function of the radiotracer. CYP3A4 being the main P450 involved in the metabolism of LBT-999, a similar pathway may occur in humans and confound PET quantification.
- 出版日期2012-4
- 单位中国地震局
