F Gourand1, P Emond2, J P Bergström3, A Takano3, B Gulyás3, D Guilloteau2, L Barré4, C Halldin3. 1. CEA, DSV/I2BM, LDM-TEP Group, GIP Cyceron, Bd Henri Becquerel, BP 5229, 14074 Caen Cedex, France; Université de Caen Basse-Normandie, Caen, France; CNRS, UMR ISTCT 6301, LDM-TEP Group, GIP Cyceron, Caen, France; Karolinska Institutet, Department of Clinical Neuroscience, Section of Psychiatry, SE-171 76 Stockholm, Sweden. Electronic address: gourand@cyceron.fr. 2. INSERM U930- Université François Rabelais de Tours, CHRU de Tours, Hopital Bretonneau, 2 boulevard Tonnellé, 37044 Tours, France. 3. Karolinska Institutet, Department of Clinical Neuroscience, Section of Psychiatry, SE-171 76 Stockholm, Sweden. 4. CEA, DSV/I2BM, LDM-TEP Group, GIP Cyceron, Bd Henri Becquerel, BP 5229, 14074 Caen Cedex, France; Université de Caen Basse-Normandie, Caen, France; CNRS, UMR ISTCT 6301, LDM-TEP Group, GIP Cyceron, Caen, France.
Abstract
INTRODUCTION: (11)C]MADAM is a radioligand suitable for PET studies of the serotonin transporter (SERT). Metabolite analysis in human and non-human plasma samples using HPLC separation has shown that [(11)C]MADAM was rapidly metabolized. A possible metabolic pathway is the S-oxidation which could lead to SOMADAM and SO2MADAM. In vitro evaluation of these two potential metabolites has shown that SOMADAM exhibited a good affinity for SERT and a good selectivity for SERT over NET and DAT. METHODS: Comparative PET imaging studies in non-human primate brain with [(11)C]MADAM and [(11)C]SOMADAM were carried out, and plasma samples were analyzed using reverse phase HPLC. We have explored the metabolism of [(11)C]MADAM in rat brain with a view to understand its possible interference for brain imaging with PET. RESULTS: PET imaging studies in non-human primate brain using [(11)C]SOMADAM indicated that this tracer does not bind with high amounts to brain regions known to be rich in SERT. The fraction of [(11)C]SOMADAM in non-human primate plasma was approximately 5% at 4min and 1% at 15min after [(11)C]MADAM injection. HPLC analysis of brain sample after [(11)C]MADAM injection to rats demonstrated that [(11)C]SOMADAM was not detected in the brain. CONCLUSIONS: (11)C]SOMADAM is not superior over [(11)C]MADAM as a SERT PET radioligand. Nevertheless, [(11)C]SOMADAM has been identified as a minor labeled metabolite of [(11)C]MADAM measured in monkey plasma. [(11)C]SOMADAM was not detected in rat brain.
INTRODUCTION: (11)C]MADAM is a radioligand suitable for PET studies of the serotonin transporter (SERT). Metabolite analysis in human and non-human plasma samples using HPLC separation has shown that [(11)C]MADAM was rapidly metabolized. A possible metabolic pathway is the S-oxidation which could lead to SOMADAM and SO2MADAM. In vitro evaluation of these two potential metabolites has shown that SOMADAM exhibited a good affinity for SERT and a good selectivity for SERT over NET and DAT. METHODS: Comparative PET imaging studies in non-human primate brain with [(11)C]MADAM and [(11)C]SOMADAM were carried out, and plasma samples were analyzed using reverse phase HPLC. We have explored the metabolism of [(11)C]MADAM in rat brain with a view to understand its possible interference for brain imaging with PET. RESULTS: PET imaging studies in non-human primate brain using [(11)C]SOMADAM indicated that this tracer does not bind with high amounts to brain regions known to be rich in SERT. The fraction of [(11)C]SOMADAM in non-human primate plasma was approximately 5% at 4min and 1% at 15min after [(11)C]MADAM injection. HPLC analysis of brain sample after [(11)C]MADAM injection to rats demonstrated that [(11)C]SOMADAM was not detected in the brain. CONCLUSIONS: (11)C]SOMADAM is not superior over [(11)C]MADAM as a SERT PET radioligand. Nevertheless, [(11)C]SOMADAM has been identified as a minor labeled metabolite of [(11)C]MADAM measured in monkey plasma. [(11)C]SOMADAM was not detected in rat brain.