Pharmacological evaluation of an [123I] labelled imidazopyridine-3-acetamide for the study of benzodiazepine receptors

In vitro binding of the iodinated imidazopyridine, N′,N′-dimethyl-6-methyl-(4′-[123I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide [123I]IZOL to benzodiazepine binding sites on brain cortex, adrenal and kidney membranes is reported. Saturation experiments showed that [123I]IZOL, bound to a single class of binding site (nH = 0.99) on adrenal and kidney mitochondrial membranes with a moderate affinity (Kd = 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 [123I]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 [123I]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 [123I]IZOL in peripheral organs and in the brain. [123I]IZOL may deserve further development for imaging selectively peripheral benzodiazepine binding sites.