title: Agonist and antagonist bind differently to 5-HT1A receptors during Alzheimer's disease: A post-mortem study with PET radiopharmaceuticals.
abstract: PET imaging studies using 5-HT1A receptor radiotracers show a decreased density of this receptor in hippocampi of patients with Alzheimer's disease (AD) at advanced stages. However, current 5-HT1A receptor radiopharmaceuticals used in neuroimaging are antagonists, thought to bind to 5-HT1A receptors in different functional states (i.e., both the one which displays high affinity for agonists and is thought to mediate receptor activation, as well as the state which has low affinity for agonists). Comparing the PET imaging obtained using an agonist radiotracer, which binds selectively to functional receptors, with the PET imaging obtained using an antagonist radiotracer would therefore provide original information on 5-HT1A receptor impairment during AD. Quantitative autoradiography using [(18)F]F13640 and [(18)F]MPPF, a 5-HT1A agonist and antagonist, respectively, was measured in hippocampi of patients with AD (n = 25, at different Braak stages) and control subjects (n = 9). The neuronal density was measured in the same tissues by NeuN immunohistochemistry. The specific binding of both radiotracers was determined by addition of WAY-100635, a selective 5-HT1A receptor antagonist. The autoradiography distribution of both 5-HT1A PET radiotracers varied across hippocampus regions. The highest binding density was in the pyramidal layer of CA1. Incubation with Gpp(NH)p, a non-hydrolysable analogue of GTP, reduced significantly [(18)F]F13640 binding in hippocampal regions, confirming its preferential interaction with G-coupled receptors, and slightly increased [(18)F]MPPF binding. In the CA1 subfield, [(18)F]F13640 binding was significantly decreased at Braak stages I/II (-19%), Braak stages III/IV (-23%), and Braak stages V/VI (-36%) versus control. In contrast, [(18)F]MPPF binding was statistically reduced only at the most advanced Braak stages V/VI compared to control (-33%). Since [(18)F]F13640 and [(18)F]MPPF can be used in vivo in humans, this neuropharmacological paradigm supports testing the concept of functional imaging using agonist radiopharmaceuticals in future clinical studies.
authors.affiliation: Lyon Neuroscience Research Center, Université Claude Bernard Lyon1, CNRS, INSERM, Lyon, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vidal
authors.affiliation: Lyon Neuroscience Research Center, Université Claude Bernard Lyon1, CNRS, INSERM, Lyon, France; Hospices Civils de Lyon, Lyon, France.
authors.forename: Johan
authors.initials: J
authors.lastname: Sebti
authors.affiliation: Lyon Neuroscience Research Center, Université Claude Bernard Lyon1, CNRS, INSERM, Lyon, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Verdurand
authors.affiliation: Lyon Neuroscience Research Center, Université Claude Bernard Lyon1, CNRS, INSERM, Lyon, France; CERMEP-Imaging Platform, Lyon, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Fieux
authors.affiliation: CERMEP-Imaging Platform, Lyon, France; Institute of Chemistry and Biochemistry, Université Claude Bernard Lyon 1, CNRS, Villeurbanne, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Billard
authors.affiliation: Hospices Civils de Lyon, Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Streichenberger
authors.affiliation: MRC London Neurodegenerative Diseases Brain Bank, King's College London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Neurolixis Inc., Dana Point, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
authors.affiliation: Lyon Neuroscience Research Center, Université Claude Bernard Lyon1, CNRS, INSERM, Lyon, France; Hospices Civils de Lyon, Lyon, France; CERMEP-Imaging Platform, Lyon, France. Electronic address: zimmer@univ-lyon1.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Zimmer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001344:Autopsy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000378:metabolism*
chemical_list: D010880:Piperidines; D011725:Pyridines; D019275:Radiopharmaceuticals; D044282:Receptor, Serotonin, 5-HT1A; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; C473959:befiradol
keywords: 5-HT(1A) receptor; Alzheimer’s disease; F13640; MPPF; PET; Serotonin