Metabolism of CLINDE, a peripheral benzodiazepine receptor SPECT ligand

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dc.contributor.authorPeyronneau, MAen_AU
dc.contributor.authorMattner, Fen_AU
dc.contributor.authorHowell, NRen_AU
dc.contributor.authorJiang, Cen_AU
dc.contributor.authorPelegrini, Pen_AU
dc.contributor.authorGreguric, IDen_AU
dc.contributor.authorLoc'h, Cen_AU
dc.contributor.authorKatsifis, Aen_AU
dc.date.accessioned2011-02-10T05:21:49Zen_AU
dc.date.available2011-02-10T05:21:49Zen_AU
dc.date.issued2010-10-11en_AU
dc.date.statistics2010-10-11en_AU
dc.description.abstractAim: The iodinated imidazopyridine, N′, N′-diethyl-6-Chloro-(4′-[123I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide ([123I]CLINDE) has been characterized as a high affinity and selectivity ligand for SPECT imaging the peripheral benzodiazepine receptor (TSPO)1. As part of the development of this probe and for future investigations in humans, the metabolism of CLINDE was investigated in different species. The aim of this study was to identify the main metabolic pathways and the form(s) of cytochrome P450 (CYP) responsible for the biotransformation of this ligand. Materials and Methods: The in vitro metabolism of CLINDE and [123I]-CLINDE was carried out using rat and human liver microsomes as well as human recombinant CYP. Similar studies were performed in rat hepatocytes. Microsomalor hepatocyte incubations were analyzed by LC/MS and the structure of the metabolites characterized by MS-MS experiments. Results: In rat and human liver microsomes, CLINDE was converted to two main polar metabolites identified by LC/MS asN-dealkylated (m/z440)and hydroxylated metabolites (m/z484). In rat liver microsomes, the main metabolite resulted from hydroxylation of the ligand. In human liver microsomes, the metabolism of CLINDE was slower with major formation of anN-dealkyl metabolite. Microsomes from baculovirus-infected insect cells expressing human P450s isoforms (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18,2C19, 2D6, 2E1, 3A4, 3A5, SF9 control) were used to test their ability to catalyse the oxidation of CLINDE. CYP3A4 and CYP3A5 exhibited the highest catalytic activity for N-dealkylation, (3.3 and 3.8 nmol/nmolP450/min), followed byCYP2C19 (0.67 nmol/nmolP450/min) and CYP2D6 0.09 nmol/nmolP450/min). The other CYP isoforms did not form any detectable metabolites. For the hydroxylase activity relative to the formation of the molecular ion at m/z 484, CYP1A1 (4.05nmol/nmolP450/min), CYP1A2 (1.85 nmol/nmolP450/min) appeared to be the morecatalytically active, followed by CYP3A4 (0.95 nmol/nmolP450/min) and CYP2C19(0.42 nmol/nmolP450/min). The iodine atom was conserved in all the identified metabolites during the process of biotransformation. In rat hepatocytes, [123-I]-CLINDE was extensively and rapidly converted to at least five radiometabolites, the major metabolite being issued from methyl-hydroxylation. Conclusion: Cytochrome P450 catalysed in vitro studies of CLINDE, demonstrated the formation of N-dealkylated and hydroxylated metabolites. Species differences were observed in the rate of formation of rat and human metabolites. The above results suggest that CYP3A4 and CYP3A5 most markedly catalysed N-dealkylation of CLINDE while the hydroxylation was likely to depend more strongly on CYP1A isoforms (extrahepatic CYP1A1 and hepaticCYP1A2).en_AU
dc.description.urihttp://dx.doi.org/10.1007/s00259-010-1557-3en_AU
dc.identifier.articlenumberOP253en_AU
dc.identifier.citationPeyronneau, M., Mattner, F., Howell, N., Jiang, C., Pelegrini, P., Greguric, I., Loc'h, C., & Katsifis, A. (2010). Metabolism of CLINDE, a peripheral benzodiazepine receptor SPECT ligand. Paper presented to the 23rd Annual Congress of the European Association of Nuclear Medicine (EANM'10), 9th - 13th October 2010. Austria, Vienna: Austria Center. In European Journal of Nuclear Medicine and Molecular Imaging, 37(Suppl. 2, OP253), S242. doi:10.1007/s00259-010-1557-3en_AU
dc.identifier.conferenceenddate13 October 2010en_AU
dc.identifier.conferencename23rd Annual Congress of the European Association of Nuclear Medicine (EANM'10)en_AU
dc.identifier.conferenceplaceVienna, Austriaen_AU
dc.identifier.conferencestartdate9 October 2010en_AU
dc.identifier.govdoc3199en_AU
dc.identifier.issn1619-7070en_AU
dc.identifier.issueS2en_AU
dc.identifier.journaltitleEuropean Journal of Nuclear Medicine and Molecular Imagingen_AU
dc.identifier.pagination198-311en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/3006en_AU
dc.identifier.urihttps://doi.org/10.1007/s00259-010-1557-3en_AU
dc.identifier.volume37en_AU
dc.language.isoenen_AU
dc.publisherSpringeren_AU
dc.subjectSpectroscopyen_AU
dc.subjectOxidationen_AU
dc.subjectRatsen_AU
dc.subjectLigandsen_AU
dc.subjectIodine 123en_AU
dc.subjectReceptorsen_AU
dc.titleMetabolism of CLINDE, a peripheral benzodiazepine receptor SPECT liganden_AU
dc.typeConference Presentationen_AU
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