Measuring endogenous changes in serotonergic neurotransmission in humans: a [11C]CUMI-101 PET challenge study

Serotonin (5-HT) neurotransmission is implicated in cognitive and emotional processes and a number of neuropsychiatric disorders. The use of positron emission tomography (PET) to measure ligand displacement has allowed estimation of endogenous dopamine release in the human brain; however, applying this methodology to assess central 5-HT release has proved more challenging. The aim of this study was to assess the sensitivity of a highly selective 5-HT1A partial agonist radioligand [C-11]CUMI-101 to changes in endogenous 5-HT levels induced by an intravenous challenge with the selective 5-HT re-uptake inhibitor (SSRI), citalopram, in healthy human participants. We studied 15 healthy participants who underwent PET scanning in conjunction with ([1)1C]CUMI-101 after receiving an intravenous infusion of citalopram 10 mg or placebo in a double-blind, crossover, randomized design. Regional estimates of binding potential (BPND) were obtained by calculating total volumes of distribution (V-T) for presynaptic dorsal raphe nucleus (DRN) and postsynaptic cortical regions. Relative to placebo, citalopram infusion significantly increased [C-11]CUMI-101 BPND at postsynaptic 5-HT1A receptors in several cortical regions, but there was no change in binding at 5-HT1A autoreceptors in the DRN. Across the postsynaptic brain regions, citalopram treatment induced a mean 7% in [C-11]CUMI-101 BPND (placebo 1.3 (0.2); citalopram 1.4 (0.2); paired t-test P = 0.003). The observed increase in postsynaptic [C-11]CUMI-101 availability identified following acute citalopram administration could be attributable to a decrease in endogenous 5-HT availability in cortical terminal regions, consistent with preclinical animal studies, in which acute administration of SSRIs decreases DRN cell firing through activation of 5-HT1A autoreceptors to reduce 5-HT levels in postsynaptic regions. We conclude that [C-11]CUMI-101 may be sensitive to changes in endogenous 5-HT release in humans.