The distribution of 5-HT1A receptors was examined in the post-mortem human brain using
whole hemisphere autoradiography and the selective 5-HT1A receptor antagonist [3H]WAY-100635
([O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2- pyridinyl)cyclohexanecarboxamide
trihydrochloride). The autoradiograms showed very dense binding to hippocampus, raphe
nuclei and neocortex. The labeling in neocortex was slightly lower than in the hippocampus
and was mainly at superficial layers, although a faintly labeled band could be seen
in deeper neocortical layers. Other regions, such as the amygdala, septum and claustrum,
showed low densities caudatus and putamen, in cerebellum or in structures of the brain
stem except in the raphe nuclei. The labeling of human 5-HT1A receptors with [3H]WAY-100635
was antagonised by the addition of 5-HT1A receptor ligands, 5-HT, buspirone, pindolol
or 8-OH-DPAT (10 microM), leaving a very low background of non-specific binding. Saturation
analysis of semiquantitative data from several human regions indicated that [3H]WAY-100635
has a Kd of approximately 2.5 nM. The selective labeling of 5-HT1A receptors with
[3H]WAY-100635 clearly show that this compound is useful for further studies of the
human 5-HT1a receptor subtype in vitro [11C]WAY-100635 is used for the characterization
of 5-HT1A receptors with positron emission tomography (PET). WAY-100635 was also radiolabeled
with the short-lived positron-emitting radionuclide carbon-11 (t1/2 = 20 min) and
used for in vitro autoradiography on human whole hemisphere cryosections. [11C]WAY-100635
gave images qualitatively similar to those of [3H]WAY-100635, although with a lower
resolution. Thus, the hippocampal formation was densely labeled, with lower density
in the neocortex. Buspirone, pindolol or 8-OH-DPAT (10 microM), blocked all binding
of [11C]WAY-100635. The in vitro autoradiography of the distribution of 5-HT1A receptors
obtained with radiolabeled WAY-100635 provide detailed qualitative and quantitative
information on the distribution of 5-HT1A-receptors in the human brain. Moreover,
the studies give reference information for the interpretation of previous initial
results at much lower resolution in humans with PET and [11C]Way-100635. These data
provide a strong basis for expecting [11C]WAY-100635 to behave as a highly selective
radioligand in vivo.