125I]iodobolpyramine, a highly sensitive probe for histamine H 1-receptors in guinea-pig brain

Abstract

[ 125I]Iodobolpyramine is a novel 125I-ligand for histamine H 1-receptors, synthesised using the 125I-Bolton Hunter reagent (2 000 Ci/mmol) for acylation of an aminopentyl analogue of mepyramine. Its specific binding varied linearly with the concentration of guinea-pig cerebellar membranes and represented about 80% of the total. Selective interaction with H 1-receptors was demonstrated by estimation of K i values of known agonists and antagonists and confirmed by the low affinity of histamine H 2- and H 3-receptor antagonists and of non-histaminergic agents. At 25°C, [ 125I]iodobolpyramine exhibited a slow associated rate (180–240 min to reach equilibrium) and a slow dissociation rate ( t 1 2 = 201 min) . Kinetic and saturation data yielded K D values of 0.05 and 0.15 nM, respectively, indicating that it is among the most potent H 1-receptor antagonist known. The sensitivity for detecting H 1-receptors in guinea-pig cerebellum using [ 125I]iodobolpyramine was increased 50-fold relative to use of [ 3H]mepyramine. Well-contrasted autoradiograms of guinea-pig brain, obtained after a short exposure time, confirmed previous H 1-receptor localisation established with [ 3H]mepyramine and revealed new localisations, e.g. in cerebral cortex and nucleus accumbens.