Agonist and antagonist bind differently to 5-HT1A receptors during Alzheimer’s disease: A post-mortem study with PET radiopharmaceuticals

• Published in: Neuropharmacology Vol. 109; pp. 88 - 95
• Main Authors: Vidal, Benjamin, Sebti, Johan, Verdurand, Mathieu, Fieux, Sylvain, Billard, Thierry, Streichenberger, Nathalie, Troakes, Claire, Newman-Tancredi, Adrian, Zimmer, Luc
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2016
• Subjects: 5-HT1A receptor; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer’s disease; Autopsy; F13640; Female; Humans; Male; Middle Aged; MPPF; PET; Piperidines - metabolism; Positron-Emission Tomography; Protein Binding - physiology; Pyridines - metabolism; Radiopharmaceuticals - metabolism; Receptor, Serotonin, 5-HT1A - metabolism; Serotonin; Serotonin 5-HT1 Receptor Agonists - metabolism; Serotonin 5-HT1 Receptor Antagonists - metabolism; Alzheimer’s disease; Serotonin; MPPF; 5-HT1A receptor; PET; F13640; 5-HT(1A) receptor
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.05.009

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 [18F]F13640 and [18F]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 [18F]F13640 binding in hippocampal regions, confirming its preferential interaction with G-coupled receptors, and slightly increased [18F]MPPF binding. In the CA1 subfield, [18F]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, [18F]MPPF binding was statistically reduced only at the most advanced Braak stages V/VI compared to control (−33%). Since [18F]F13640 and [18F]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. •5-HT1A receptor autoradiography was performed in hippocampi of AD patients.•Two 5-HT1A PET ligands were compared: an agonist, [18F]F13640, vs an antagonist, [18F]MPPF.•[18F]F13640 labels specifically G-coupled receptors, i.e. the functional receptors.•[18F]MPPF labels all 5-HT1A receptors, regardless of their G-protein coupling state.•Comparison of these distinct bindings is proposed as new neuropharmacological paradigm for PET.