Characterization of the binding of the first selective radiolabeled histamine H3‐receptor antagonist, [125I]‐iodophenpropit, to rat brain

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Abstract
1 The binding of the first selective radiolabeled histamine H3-receptor antagonist [125I]-iodophenpropit to rat cerebral cortex membranes was characterized. 2 [125I]-iodophenpropit, radiolabeled to a high specific activity of 1900 Ci mmol-1, saturably bound to a single class of sites with a KD of 0.57 ± 0.16 nm (n = 4) and Bmax of 268 ± 119 fmol mg-1 protein. 3 Specific binding at a concentration below 1 nm represented 50 to 60% of total binding. 4 Binding of [125I]-iodophenpropit to rat cerebral cortex membranes was readily displaced by histamine H3-agonists and antagonists. In contrast, the inhibitory potencies of selective histamine H1- and H2-receptor ligands were very low. 5 [125]-iodophenpropit was biphasically displaced by the histamine H3-receptor antagonists, burimamide and dimaprit, which may indicate the existence of histamine H3-receptor subtypes. Other histamine H3-receptor antagonists showed a monophasic displacement. 6 Competition binding curves of H3-agonists were biphasic and showed a rightward shift upon the addition of the nonhydrolysable GTP analogue, guanosine 5′-o-(3-thio) triphosphate (GTPγS; 100 μm) which implicates the interaction of histamine H3-receptors with G-proteins. The affinities of the H3-receptor antagonists iodophenpropit, thioperamide and burimamide were not altered by GTPγS. 7 Histamine competition binding curves were shifted to the right by different nucleotides (100 μm) with a rank order of potency GTPγS > Gpp(NH)p, GTP. 8 In vitro autoradiographic studies revealed a heterogeneous distribution of [125I]-iodophenpropit binding sites in rat brain, with highest densities observed in specific cerebral cortical areas and layers, the caudate-putamen complex, the olfactory tubercles, the hippocampal formation, the amygdala complex, the hypothalamic area and the mammillary bodies. 9 It is concluded that the histamine H3-receptor antagonist, [125I]-iodophenpropit, meets the criteria for a suitable radioligand for histamine H3-receptor binding studies in rat brain.

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