[3H]ketanserin labels serotonin 5-HT2 and alpha 1-adrenergic receptors in human brain cortex

The binding of [3H]ketanserin and [125I]BE 2254 [( beta-(4-hydroxyphenyl)ethylaminomethyl]tetralone) was characterized in human brain cortex membranes. As observed in saturation experiments, [3H]ketanserin (a reportedly selective serotonin 5-HT2 ligand) and [125I]BE 2254 (a selective alpha 1-adrenergic antagonists) labeled, apparently, a homogeneous class of high-affinity recognition sites. Competition experiments performed with [125I]BE 2254 and a series of 20 structurally different compounds resulted in steep and monophasic competition curves. In contrast, competition curves of these compounds for [3H]ketanserin binding were often shallow or biphasic, suggesting a heterogeneity of the sites labeled by [3H]ketanserin. In particular, alpha-adrenoceptor-selective ligands (e.g., prazosin, BE 2254, WB 4101, phentolamine) showed clearly biphasic curves displacing about 20% of [3H]ketanserin binding with nanomolar affinity. On the other hand, cinanserin, a selective 5-HT2 antagonist, showed nanomolar affinity for 80% of the sites labeled by [3H]ketanserin, and micromolar affinity for the other 20%. There was a highly significant correlation between [125I]BE 2254 binding and the minor component of [3H]ketanserin in human brain cortex membranes (r = 0.910, p less than 0.0001, n = 20). The data show that [3H]ketanserin binds in the nanomolar concentration range (1.5-1.8 nM) to both 5-HT2 and alpha 1-adrenergic receptors. Similar results were obtained in rat and pig brain membranes. The data suggest that ketanserin possesses a rather limited degree of selectivity in human tissue.