A post-mortem study to compare the 5-HT1A receptor binding of a PET agonist and a PET antagonist in Alzheimer's disease

Abstract

Présentation oraleInternational audienceAim. The 5-HT1A serotonin receptors located in hippocampus are known to be linked to memory processes. PET clinical imaging studies with [18F]MPPF have documented the decrease of 5-HT1A receptor expression in Alzheimer's disease patients, interpreted as neuronal loss. Interestingly, other [18F]MPPF PET studies have reported a specific increase in hippocampal 5-HT1A receptor binding during a pre-dementia stage of Alzheimer's disease (mild cognitive impairment). If this increase in [18F]MPPF binding may be explained by compensatory mechanisms, the pharmacological properties of this PET radiotracer limit its biological interpretation. It is known indeed that [18F]MPPF, which is an antagonist like a majority of available PET receptor radioligands, binds non-specifically to the high-affinity state of 5-HT1A receptors (functional) and to the low-affinity state of these receptors (decoupled from G proteins and non-functional). On the contrary, an agonist binds selectively to the high-affinity state of the receptor which are functional. The Aim of this study is demonstrate that the binding of a 5-HT1A PET agonist provides complementary information to the binding of a 5-HT1A PET antagonist, to improve understanding of the functional impairment of 5-HT1A receptors during Alzheimer's disease. Materials and MJethods. We compared in postmortem human brain sections the specific binding of [18F]F15599, a 5-HT1A PET agonist we developed previously, with the specific binding of [18F]MPPF, a 5-HT1A PET antagonist. Thirty-µm coronal sections were cut across hippocampi of 18 patients at different Braak's stages (from 0 to VI). The days of radiotracers synthesis, the brain slides were incubated in a saline buffer containing 37 kBq/mL of [18F]MPPF or [18F]F15599. Hippocampal subregions were drawn according to a brain atlas and binding quantification was performed with extemporaneous fluorine-18 scales. The specific binding of both radiotracers was determined by addition of 100 nM of serotonin and the agonist binding of [18F]F15599 was revealed by addition of 10 μM of Gpp(NH)p. Results and Conclusion. The autoradiography distribution of both 5-HT1A PET radiotracers varied across hippocampus regions. The highest binding density was found in the pyramidal layer of CA1, followed by the molecular layer of the dentate gyrus. The incubation with 10 μM of Gpp(NH)p, a non-hydrolysable analogue of GTP, reduced significantly [18F]F15599 binding, confirming its specific binding to G-coupled 5-HT1A receptors. [18F]F15599 binding compared to [18F]MPPF binding revealed specific modifications of the density of functional 5-HT1A correlated to the Braak's stages. These results justify an extension of this concept of functional PET imaging in clinical studies