A radiometabolite study of the serotonin transporter PET radioligand [11C]MADAM

Gourand, Fabienne; Emond, Patrick; Bergström, Jonas; Takano, Akihiro; Gulyás, Balázs; Guilloteau, Denis; Barré, Louisa; Halldin, Christer

doi:10.1016/j.nucmedbio.2014.03.022

Cited by 3 publications

(6 citation statements)

References 31 publications

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“…However, a radioligand with a carbon-11 label in a tertiary N , N -dimethylamino group has a risk of being cleaved by monoamine oxidase within the brain to release [ 11 C]dimethylamine, which then becomes protonated and unable to leave brain [233], or of being metabolized to the radioactive secondary methylamine, which may well enter brain and in some cases show some specific binding to the target or other proteins. A notable exception is the SERT radioligand, [ 11 C]MAD-AM, which performs acceptably well with the carbon-11 label in its dimethylamino position [234]. …”

Section: Lack Of Accumulation Of Radiome-tabolites In Brain or Skullmentioning

confidence: 99%

Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging

Pike

2016

CMC

158

200

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The development of reversibly binding radioligands for imaging brain proteins in vivo, such as enzymes, neurotransmitter transporters, receptors and ion channels, with positron emission tomography (PET) is keenly sought for biomedical studies of neuropsychiatric disorders and for drug discovery and development, but is recognized as being highly challenging at the medicinal chemistry level. This article aims to compile and discuss the main considerations to be taken into account by chemists embarking on programs of radioligand development for PET imaging of brain protein targets.

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Section: Lack Of Accumulation Of Radiome-tabolites In Brain or Skullmentioning

confidence: 99%

Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging

Pike

2016

CMC

158

200

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“…Consequently, it could be hypothesized that MADAM would first oxidize to SOMADAM and then further to SO 2 MADAM ( Fig 2 ). These potential metabolites, SOMADAM and SO 2 MADAM, were synthesized in a previous study [ 10 ]. Two other potential metabolites, NHMADAM and NHSOMADAM ( Fig 2 ), are available as reference compounds and have been used as precursors for the carbon-11 labelling of PET radioligands [ 11 C]MADAM and [ 11 C]SOMADAM [ 10 ].…”

Section: Resultsmentioning

confidence: 99%

“…These potential metabolites, SOMADAM and SO 2 MADAM, were synthesized in a previous study [ 10 ]. Two other potential metabolites, NHMADAM and NHSOMADAM ( Fig 2 ), are available as reference compounds and have been used as precursors for the carbon-11 labelling of PET radioligands [ 11 C]MADAM and [ 11 C]SOMADAM [ 10 ]. To identify the metabolites of MADAM produced in vitro , the available synthesized references were analyzed by UHPLC/Q-ToF-MS in MS and MS E modes simultaneously and their chemical structures and MS E spectra are presented in Fig 3 .…”

Section: Resultsmentioning

confidence: 99%

“…SO 2 MADAM ( Fig 4 ) was not detected in any of the microsomal preparations. In previous PET studies, a minor in vivo peripheral oxidation of [ 11 C]MADAM to [ 11 C]SOMADAM was noted in macaque plasma [ 10 ]. This fraction corresponded to 5% of the total radioactivity 4 min after injection and 1% after 15 min.…”

Section: Resultsmentioning

confidence: 99%

“…Water and acetonitrile (both LC-MS grade) were obtained from Fisher Scientific, while the other solvents used were from Aldrich. The compounds MADAM, NHMADAM, SOMADAM, NHSOMADAM and SO 2 MADAM were obtained as reported previously [ 10 ]. [ 11 C]MADAM was synthesized from [ 11 C]methyl triflate ([ 11 C]CH 3 OTf) [ 6 ].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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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.

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An original radio-biomimetic approach to synthesize radiometabolites for PET imaging

Auvity

Breuil

Goislard

et al. 2020

Nuclear Medicine and Biology

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A radiometabolite study of the serotonin transporter PET radioligand [11C]MADAM

Cited by 3 publications

References 31 publications

Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging

Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging

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

An original radio-biomimetic approach to synthesize radiometabolites for PET imaging

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