[11C]MADAM Used as a Model for Understanding the Radiometabolism of Diphenyl Sulfide Radioligands for Positron Emission Tomography (PET)

Abstract

In quantitative PET measurements, the analysis of radiometabolites in plasma is essential for determining the exact arterial input function. Diphenyl sulfide compounds are promising PET and SPECT radioligands for in vivo quantification of the serotonin transporter (SERT) and it is therefore important to investigate their radiometabolism. We have chosen to explore the radiometabolic profile of [11C]MADAM, one of these radioligands widely used for in vivo PET-SERT studies. The metabolism of [11C]MADAM/MADAM was investigated using rat and human liver microsomes (RLM and HLM) in combination with radio-HPLC or UHPLC/Q-ToF-MS for their identification. The effect of carrier on the radiometabolic rate of the radioligand [11C]MADAM in vitro and in vivo was examined by radio-HPLC. RLM and HLM incubations were carried out at two different carrier concentrations of 1 and 10 μM. Urine samples after perfusion of [11C]MADAM/MADAM in rats were also analysed by radio-HPLC. Analysis by UHPLC/Q-ToF-MS identified the metabolites produced in vitro to be results of N-demethylation, S-oxidation and benzylic hydroxylation. The presence of carrier greatly affected the radiometabolism rate of [11C]MADAM in both RLM/HLM experiments and in vivo rat studies. The good concordance between the results predicted by RLM and HLM experiments and the in vivo data obtained in rat studies indicate that the kinetics of the radiometabolism of the radioligand [11C]MADAM is dose-dependent. This issue needs to be addressed when the diarylsulfide class of compounds are used in PET quantifications of SERT.

Dealing with PET radiometabolites

“…Diphenyl sulfide derivatives have proven to be potential PET/SPECT radiotracers for serotonin transporter (SERT) study in vivo and are thus extremely crucial to examine their radioactive metabolism [ 67 , 68 ]. Christer et al had explored the metabolic portfolio of [ 11 C]MADAM, a widely used diphenyl sulfide-based radiotracer for PET-SERT examination in vivo [ 69 ]. [ 11 C]MADAM/MADAM metabolism was demonstrated with liver microcosm from a rat (RLM) and a human (HLM) in association with radio-HPLC or UHPLC/Q-ToF-MS.…”

“…The urine samples were also examined with radio-HPLC (Fig. 7 ) [ 69 ]. The results suggest that the metabolites were produced in in vitro because of the following biotransformation: N-benzylic hydroxylation, S-oxidation, and demethylation (Fig.…”

“…The results suggest that the metabolites were produced in in vitro because of the following biotransformation: N-benzylic hydroxylation, S-oxidation, and demethylation (Fig. 7 ) [ 69 ]. Their study also revealed that the carrier presence significantly enhanced the [ 11 C]MADAM metabolism rate in RLM/HLM in in vitro experiments as well as in in vivo rat studies.…”

Sulfur K-Edge X-ray Absorption Spectroscopy of Aryl and Aryl–Alkyl Sulfides

“…Diphenyl sulfide derivatives are known to inhibit serotonin uptake by binding to the serotonin transporter (SERT) 1 and are promising radio-ligands for in vivo SERT quantification using either positron emission tomography or single photon emission computed tomography. 2 The aryl sulfide known as vortioxetine has found use as a serotonergic antidepressant. 3 Methyl phenyl sulfide, also known as thioanisole, is the simplest aryl−alkyl sulfide and is among the large number of sulfur compounds used in the food industry.…”

“…Diphenyl sulfide, also known as phenyl sulfide, phenylthiobenzene, diphenyl thioether, or phenylsulfanylbenzene, is the simplest of the aryl sulfides. Diphenyl sulfide derivatives are known to inhibit serotonin uptake by binding to the serotonin transporter (SERT) and are promising radio-ligands for in vivo SERT quantification using either positron emission tomography or single photon emission computed tomography . The aryl sulfide known as vortioxetine has found use as a serotonergic antidepressant .…”