Binding Characteristics of a Histamine H₃-Receptor Antagonist, [³H]S-Methylthioperamide: Comparison with [³H](R)α-Methylhistamine Binding to Rat Tissues

Abstract

The release and synthesis of neuronal histamine are regulated by histaminergic autoreceptors named as histamine H₃ receptors. The development of radiolabeled histamine H₃ antagonists is needed to characterize the binding of antagonists to these receptors. Here we describe the binding characteristics of a new histamine H₃-receptor antagonist, [³H]S-methylthioperamide (SMT), to rat tissues, and compare its binding with that of [³H](R)α-methylhistamine ((R)αMH), a selective histamine H₃-receptor agonist. The binding of [³H]SMT to the membranes of rat forebrain was found to be stereoselective, saturable, reversible and temperature-dependent. Saturation binding experiments indicated a single class of high affinity sites for [³H]SMT in forebrain membranes (K_D=2.1 nM, B_max=24.3 pmol/g of tissue at 4°C). The B_max was approximately 3 times that of [³H](R)αMH binding to rat forebrain membranes (K_D=2.5 nM, B_max=7.3 pmol/g of tissue at 25°C). Autoradiographic images of [³H]SMT binding in the brain were essentially the same as those of [³H](R)αMH. [³H]SMT also bound appreciably to peripheral tissues (the liver, adrenal, stomach, ileum, kidney, lung and bladder), whereas the [³H](R)αMH bindings to these peripheral tissues were negligible. These results indicate that [³H]SMT binds to H₃ receptors primarily in the central nervous system, and that it also has high affinity toward non-H₃ receptors, probably hemoproteins, in peripheral tissues.