In vitro labeling of serotonin-S2 receptors: synthesis and binding characteristics of [3H]-7-aminoketanserin.

[3H]-7-Aminoketanserin (7-amino-3-[2-[4-(2-tritio-4-fluorobenzoyl)-1- piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione), an amino derivative of the selective serotonin-S2 antagonist ketanserin, was synthesized and tested for in vitro labeling of serotonin-S2 receptors. The compound showed a very high affinity for both membrane-bound and detergent-solubilized serotonin-S2 receptors with KD values of 0.35 and 2.03 nM, respectively. At nanomolar concentrations, binding to serotonin-S1 sites was totally absent. Serotonin-S2 receptor binding was characterized by a slow dissociation and a very low nonspecific binding. In rat frontal cortex preparations, binding could be displaced by nanomolar concentrations of different serotonin antagonists and micromolar concentrations of serotonin agonists. Compounds with other pharmacological profiles were poorly or not active. Introduction of an amino function in this new radioligand led to a decreased lipophilicity. Therefore, besides being a valuable radioligand for routine binding studies, [3H]-7-aminoketanserin will probably be a good ligand for labeling serotonin-S2 receptors on intact cells.