title: Pharmacological evaluation of an [(123)I] labelled imidazopyridine-3-acetamide for the study of benzodiazepine receptors.
abstract: In vitro binding of the iodinated imidazopyridine, N',N'-dimethyl-6-methyl-(4'-[(123)I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide [(123)I]IZOL to benzodiazepine binding sites on brain cortex, adrenal and kidney membranes is reported. Saturation experiments showed that [(123)I]IZOL, bound to a single class of binding site (n(H)=0.99) on adrenal and kidney mitochondrial membranes with a moderate affinity (K(d)=30 nM). The density of binding sites was 22+/-6 and 1.2+/-0.4 pmol/mg protein on adrenal and kidney membranes, respectively. No specific binding was observed in mitochondrial-synaptosomal membranes of brain cortex. In biodistribution studies in rats, the highest uptake of [(123)I]IZOL was found 30 min post injection in adrenals (7.5% ID/g), followed by heart, kidney, lung (1% ID/g) and brain (0.12% ID/g), consistent with the distribution of peripheral benzodiazepine binding sites. Pre-administration of unlabelled IZOL and the specific PBBS drugs, PK 11195 and Ro 5-4864 significantly reduced the uptake of [(123)I]IZOL by 30% (p<0.05) in olfactory bulbs and by 51-86% (p<0.01) in kidney, lungs, heart and adrenals, while it increased by 30% to 50% (p<0.01) in the rest of the brain and the blood. Diazepam, a mixed CBR-PBBS drug, inhibited the uptake in kidney, lungs, heart, adrenals and olfactory bulbs by 32% to 44% (p<0.01) but with no effect on brain uptake and in blood concentration. Flumazenil, a central benzodiazepine drug and haloperidol (dopamine antagonist/sigma receptor drug) displayed no effect in [(123)I]IZOL in peripheral organs and in the brain. [(123)I]IZOL may deserve further development for imaging selectively peripheral benzodiazepine binding sites.
authors.affiliation: Radiopharmaceuticals Research Institute, Australian Nuclear Science and Technology Organisation, PMB 1 Menai N.S.W. 2234, Sydney, Australia. mfp@ansto.gov.au
authors.forename: Filomena
authors.initials: F
authors.lastname: Mattner
authors.forename: Karine
authors.initials: K
authors.lastname: Mardon
authors.forename: Christian
authors.initials: C
authors.lastname: Loc'h
authors.forename: Andrew
authors.initials: A
authors.lastname: Katsifis
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D018757:GABA Modulators / Q000737:chemistry / Q000493:pharmacokinetics*; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D014018:Tissue Distribution; D000077334:Zolpidem
chemical_list: D018757:GABA Modulators; D007093:Imidazoles; C512153:N',N'-dimethyl-6-methyl-(4'-iodophenyl)imidazo(1,2-a)pyridine-3-acetamide; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem