Positron emission tomography study of pindolol occupancy of 5-HT1A receptors in humans: Preliminary analyses

Preclinical studies in rodents suggest that augmentation of serotonin reupt ake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine(1A) (5-HT1A) rece ptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pin dolol to potentiate the increase in serotonin (5-HT) transmission induced b y SSRIs, an effect achieved by blockade of the 5-HT1A autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT1A receptors following tre atment with controlled release pindolol in nine healthy volunteers with pos itron-emission tomography (PET). Each subject was studied four times: at ba seline (scan 1), following 1 week of oral administration of pindolol CR (7. 5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT1A receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) o f the radiolabelled selective 5-HT1A antagonist [carbonyl-C-11]WAY-100635 o r [carbonyl-C-11] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)-N-(2-pyridyl)cyc lohexanecarboxamide abbreviated as [C-11]WAY-100635. Pindolol dose-dependen tly decreased [C-11]WAY-100635 BP. Combining all the regions, occupancy was 20 +/- 8% at scan 2, 14 +/- 8% at scan 3, and 44 +/- 8% at scan 4 The resu lts of this study suggest that at doses used in clinical studies of augment ation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT 1A receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the oth er hand, at each dose tested, pindolol occupancy of 5-HT1A receptors was hi gher in the DRN compared to cortical regions, demonstrating a significant i n vivo selectivity for DRN 5-HT1A autoreceptors relative to cortico-limbic postsynaptic receptors. This selectivity is necessary for the potentiation of 5-HT transmission, and this finding represents an important proof of con cept in the development of 5-HT1A agents for this application. Early evalua tion of new drugs with PET imaging will enable rapid screening of compounds based on DRN selectivity and more appropriate determination of doses for c linical trials. NUCL MED BIOL 27;5: 523-527, 2000. (C) 2000 Elsevier Scienc e Inc. All rights reserved.