SELECTIVE IN-VIVO LABELING OF BRAIN 5-HT1A-RECEPTORS BY [H-3] WAY-100635 IN THE MOUSE

The novel selective 5-HT1A receptor antagonist radioligand [H-3]WAY 10 0635 nyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexane oxamide) was i njected i.v. to mice in an attempt to label in vivo central 5-HT1A rec eptors. Although 5 min after the i.v, injection of [H-3]WAY 100635 (4- 7.6 mu Ci per mouse) the amount of tritium found in the whole brain on ly accounted for 1.5-1.8% of the injected radioactivity, regional diff erences in H-3 accumulation already corresponded to those of 5-HT1A re ceptor density. Optimal data were obtained 1 h after [H-3]WAY 100635 i njection as the distribution of H-3 in brain was exactly that of 5-HT1 A receptor binding sites in mouse brain sections labelled in vitro wit h [H-3]WAY 100635. In particular, high level of labelling was found in the lateral septum, gyrus dentatus and CA1 area of Ammon's horn in th e hippocampus, dorsal raphe nucleus and entorhinal cortex. No labellin g was found in the substantia nigra, and H-3 accumulated in the cerebe llum represented only 12-14% of that found in the hippocampus. Pretrea tment with various drugs indicated that only 5-HT1A receptor ligands w ere able to decrease the accumulation of H-3 in all the brain areas ex amined except in the cerebellum. Assuming that only non-specific bindi ng took place in the latter structure, it was possible to calculate th e ID50 values of 5-HT1A receptor agonists (8-OH-DPAT (8-hydroxy-2-(di- n-propylamino)tetralin) S 14506 nzoylamino)ethyl]-4-(7-methoxynaphthyl )piperazine) and S 20499 thoxy-chroman-3-yl)-N-propylamino]butyl-8-aza spiro -(4,5)-decane-7,9-dione)) and antagonists (spiperone (-)-tertato lol, (+)-WAY 100135 thoxy-phenyl)piperazin-1-yl-2-phenyl-propanamide)) as inhibitors of H-3 accumulation in the hippocampus of [H-3]WAY 1006 35-injected mice. Comparison of these values with the in vitro affinit y of the same ligands for hippocampal 5-HT1A receptors revealed marked variations in the capacity of 5-HT1A receptor agonists and antagonist s to reach the brain when injected via the subcutaneous route in mice.