[I-125] IODOPROXYFAN, A NEW ANTAGONIST TO LABEL AND VISUALIZE CEREBRAL HISTAMINE H-3 RECEPTORS

Iodoproxyfan, i.e., 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl e ther, is a novel potent and selective histamine H-3 receptor antagonis t. [I-125]Iodoproxyfan binding to membranes of the rat striatum was re versible and saturable. Specific binding defined with 1 mu M (R)-alpha -methylhistamine corresponded to 65% of the total at 30 pM. Scatchard analysis indicated a K-d of 65 pM and maximal binding capacity of 78 f mol/mg of protein. The specificity of [I-125]iodoproxyfan binding to H -3 receptors was demonstrated by its pharmacological profile. A series of H-3 receptor agonists inhibited [I-125]iodoproxyfan binding with a similar maximal effect and with the expected order of potency and ste reoselectivity ratio. H-3 receptor antagonists inhibited the specific binding with the expected K-i values. In the presence of guanylnucleot ides, 40% of sites exhibited a similar to 40-fold lower affinity for h istamine, indicating that the H-3 receptor belongs to the superfamily of G protein-coupled receptors and revealing the existence of two popu lations of sites. Well contrasted autoradiographic pictures of total [ I-125]iodoproxyfan binding to sections of the rat brain were obtained in a short time and over a low nonspecific binding. The heterogenous d istribution of H-3 receptors with high labeling of anterior cerebral c ortex, ventral striatum and other limbic areas was confirmed. In addit ion, a clearly distinguishable laminated pattern of labeling was evide nced in the cerebral cortex and hippocampal formation. Hence, this new probe should be useful for sensitive assay and localization of the H- 3 receptor.