Pindolol occupancy of 5‐HT1A receptors measured in vivo using small animal positron emission tomography with carbon‐11 labeled WAY 100635

Positron emission tomography (PET), following an intravenous injection of [carbonyl‐11C]WAY 100635, was used to image central 5‐HT1A receptors in rat following pretreatment with graded doses of (‐)‐pindolol (0.001–3 mg/kg, i.v.). The use of PET had advantages over ex vivo radioligand binding methods in that it produced parametric image volumes and reduced errors due to inter‐rat variability. Time–radioactivity curves from regions of interest (ROI) acquired from individual rats enabled the estimation of specific binding of the radioligand using a compartmental model with reference tissue input. Binding potential (BP) of [11C]WAY 100635 was estimated for frontal cortex and hippocampus (postsynaptic), and midbrain raphe nuclei (presynaptic). In the latter ROI, pindolol dose‐dependently decreased BP. The saturation curve could be fitted to a single‐site model up to the lowest dose of pindolol used, giving an ED50 (dose to cause 50% occupancy) value of 0.26 ± 0.05 mg/kg, and inclusion of control (nonpindolol‐treated) rats did not affect the fit. In contrast, in cortex and hippocampus ROI, low doses of pindolol caused an increase in BP compared with controls. Pindolol doses greater than ∼0.1 mg/kg, resulted in a dose‐dependent decrease in BP, and ED50 values in cortex and hippocampus were estimated as 0.44 ± 0.13 and 0.48 ± 0.12 mg/kg, respectively. The increase in [11C]WAY 100635 binding at low pindolol doses is feasibly related to a decrease in basal receptor occupancy following reduced release of endogenous 5‐HT. Considering the apparently greater potency of pindolol at the midbrain raphe ROI, this effect could be mediated via agonist activity at the autoreceptor. Synapse 36:330–341, 2000. © 2000 Wiley‐Liss, Inc.