CHAPTER 42 – A Human Liver Model of Metabolism as a Tool in the Identification of Potential PET Radiotracers1

The potent 5-HT1A antagonist WAY 100635 is metabolized in vivo by human liver. The metabolite, WAY 100634, readily crosses the blood-brain barrier and may confound positron emission tomography (PET) studies of [11C]WAY 100635. WAY 100635 and three analogs were studied by an in vitro model of human liver metabolism using HPLC to analyze the reaction mixtures. The objective of the study was to determine whether the analogs were likely to suffer the same metabolic fate as WAY 100635 in vivo, an outcome that would limit their potential as PET radiotracers for imaging 5-HT1A receptors. In human liver cytosolic media, WAY 100635 was quantitatively metabolized to WAY 100634 (amide hydrolysis), but none of the three analogs were affected. In human liver microsomal media, WAY 100635 was again metabolized predominantly to WAY 100634 with some more polar products as well. All three analogs were also metabolized to some extent in the microsomal preparations, but none followed the major pathway of WAY 100635, i.e., no metabolite from simple amide hydrolysis was detected. The metabolic products from microsomal incubation were all more polar (by reverse-phase HPLC) than the anticipated product of amide hydrolysis. In vitro screening of potential PET ligands using human liver preparations can provide useful information in helping decide which ligands merit further study.