[H-3] MDL-100,907 - A NOVEL SELECTIVE 5-HT2A RECEPTOR-LIGAND

In studies using standard radioligands, unlabeled MDL 100,907 -1-[2-(4 -fluorophenyl)ethyl]-4-piperidinemethanol) has been shown to have a hi gh degree of selectivity for the 5-HT2A receptor. The present study wa s undertaken to investigate the receptor binding characteristics of [H -3]MDL 100,907 in rat cortical homogenates. [H-3]MDL 100,907 was found to reach equilibrium at 37 degrees C after 15 min. Saturation experim ents indicated binding to a single site with a KD of 0.56 nM, Hill slo pe of 1.15, and a B-max of 512 fmol/mg protein. In parallel experiment s with the standard 5-HT2A receptor radioligand, [H-3]ketanserin, with prazosin added to block alpha(1) receptors, a similar Hill slope and B-max was noted but a two-fold higher K-D was found. In competition bi nding studies using 0.5 nM [H-3]MDL 100,907, some 19 standard ligands to various receptors including the 5-HT1A, D-2, alpha(1), and sigma re ceptors resulted in estimated K-I values that were consistent with [H- 3]MDL 100,907 selectively binding to the 5-HT2A receptor. A comparison of the K-I values for 17 standard 5-HT2A receptor agonists and antago nists displacing [H-3]MDL 100,907 versus [H-3]ketanserin resulted in a highly significant linear correlation (R(2) = 0.96, P<0.001). Taken t ogether these results suggest that [H-3]MDL 100,907 is binding to the 5-HT2A receptor with a sub-nanomolar affinity without the use of secon dary blocking agents.