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Introduction: [F-18]Fallypride, a fluorinated and substituted benzamide with high affinity for D-2/D-3 receptors, is a useful PET radioligand for the study of striatal/extrastriatal areas. Since [F-18]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 [F-18]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 [F-18]fallypride and its radiometabolites in plasma.

Methods: 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(R)-MCX-SPE cartridges was used to quantify [F-18]fallypride and its radiometabolites.

Result: 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 [F-18]fallypride from its radiometabolites in plasma and evaluate [F-18]fallypride at 150 min pi to be 22% +/- 5% of plasma radioactivity.

Conclusions: The major in vivo radiometabolites of [F-18]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 [F-18]fallypride until late images required for quantitative PET imaging in humans. (C) 2013 Elsevier Inc. All rights reserved.