Change in Expression of 5-HT₆ Receptor at Different Stages of Alzheimer’s Disease: A Postmortem Study with the PET Radiopharmaceutical [¹⁸F]2FNQ1P

Article type: Research Article

Authors: Courault, Pierre^{a; b} | Emery, Stéphane^a | Bouvard, Sandrine^a | Liger, François^c | Chauveau, Fabien^a | Meyronet, David^b | Fourier, Anthony^{a; b} | Billard, Thierry^{c; d} | Zimmer, Luc^{a; b; c; e; *} | Lancelot, Sophie^{a; b; c}

Affiliations: [a] Lyon Neuroscience Research Center (CRNL), Université de Lyon, CNRS, INSERM, Lyon, France | [b] Hospices Civils de Lyon (HCL), Lyon, France | [c] CERMEP-Imaging platform, Groupement Hospitalier Est, Bron, France | [d] Institute of Chemistry and Biochemistry (ICBMS), Université de Lyon, CNRS, Villeurbanne, France | [e] National Institute for Nuclear Science and Technology (INSTN), CEA, Saclay, France

Correspondence: [*] Correspondence to: Luc Zimmer, CERMEP, Groupement Hospitalier Est, 59 bd Pinel, 69677 Bron cedex, France. Tel.: +33(0) 04 72 68 86 09; E-mail: zimmer@univ-lyon1.fr.

Abstract: Background:The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer’s disease (AD) and associated disorders. Objective:The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages. Methods:Patients were classified according to the “ABC” NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD (“High”; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), “Low” (n = 18), “Int” (n = 20), and “High” (n = 15). Results:In vitro binding assays did not show significant differences for the KD and Bmax parameters between “High” and HC groups. In vitro quantitative autoradiography showed a significant difference between the “High” and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined (“Low”, “Intermediate”, and “High”) (p = 0.011). Conclusion:This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.

Keywords: 5-HT₆ receptor, Alzheimer’s disease, caudate nucleus, [¹⁸F]2FNQ1P, specific PET radiotracer

DOI: 10.3233/JAD-191278

Journal: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1329-1338, 2020