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

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)alpha-methylhistamine ((R)alpha MH), 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 (KD = 2.1 nM, Bmax = 24.3 pmol/g of tissue at 4 degrees C). The Bmax was approximately 3 times that of [3H](R)alpha MH binding to rat forebrain membranes (KD = 2.5 nM, Bmax = 7.3 pmol/g of tissue at 25 degrees C). Autoradiographic images of [3H]SMT binding in the brain were essentially the same as those of [3H](R)alpha MH. [3H]SMT also bound appreciably to peripheral tissues (the liver, adrenal, stomach, ileum, kidney, lung and bladder), whereas the [3H](R)alpha MH 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.