title: An iodinated derivative of moclobemide as potential radioligand for brain MAO-A exploration.
abstract: In vivo evaluation of MAO-A would be of great value for the diagnosis and follow-up of therapy of depression. In order to perform this exploration by SPECT, we developed an iodinated derivative of the reversible MAO-A inhibitor, moclobemide. Ro 11-9900 was synthesized and analysed by IR, NMR and HPLC. Radioiodination was carried out by nucleophilic exchange of [125I] on the brominated precursor, and yielded [125I]-Ro 11-9900 with high specific activity. In vitro experiments on rat brain homogenates showed that Ro 11-9900 had poor inhibitory activity on MAO-A, as already described for moclobemide. By contrast, in vivo biodistribution in the rat brain showed that [125I]-Ro 11-990 accumulated in a region corresponding to the localization of locus coeruleus known for its high density of MAO-A. Moreover, preinjection of the irreversible MAO-A inhibitor clorgyline (10 mg.kg-1) prevented accumulation of radioactivity by 40 to 60% and we found that the radioactivity in the brain corresponded exclusively to [125I]-Ro 11-9900 and not to a metabolite. [125I]-Ro 11-9900 was highly accumulated in the pineal gland, both on MAO-A and on MAO-B sites. We concluded that the unmetabolized iodinated derivative of moclobemide, Ro 11-9900, preferentially labeled MAO-A in vivo in the rat brain. This compound would therefore be a potential tracer for evaluation of MAO-A by SPECT.
authors.affiliation: INSERM U316, Laboratoire de Biophysique Médicale et Pharmaceutique, Tours, France.
authors.forename: H
authors.initials: H
authors.lastname: Rafii
authors.forename: S
authors.initials: S
authors.lastname: Chalon
authors.forename: J E
authors.initials: JE
authors.lastname: Ombetta
authors.forename: Y
authors.initials: Y
authors.lastname: Frangin
authors.forename: L
authors.initials: L
authors.lastname: Pourcelot
authors.forename: J C
authors.initials: JC
authors.lastname: Besnard
authors.forename: S
authors.initials: S
authors.lastname: Bodard
authors.forename: D
authors.initials: D
authors.lastname: Guilloteau
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D007457:Iodine Radioisotopes; D007527:Isoenzymes / Q000032:analysis* / Q000037:antagonists & inhibitors; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D020912:Moclobemide; D008995:Monoamine Oxidase / Q000032:analysis*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013055:Spectrophotometry, Infrared; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D001549:Benzamides; D007457:Iodine Radioisotopes; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; C099175:4-iodo-N-(2-(4-morpholinyl)ethyl)benzamide; D008995:Monoamine Oxidase; D020912:Moclobemide