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-HT 1A receptor radiotracers show a decreased density of this receptor in hippocampi of patients with Alzheimer's disease (AD) at advanced stages. However, current 5-HT 1A receptor radiopharmaceuticals used in neuroimaging are antagonists, thought to bind to 5-HT 1A 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-HT 1A receptor impairment during AD. Quantitative autoradiography using [

Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist

“…[43] Based on the present data, it may be anticipated that NLX-112 preferentially activates 5-HT 1A receptors in those brain regions where they are coupled to Gao, including hippocampus. An autoradiographic study on post-mortem human brain sections showed that NLX-112 has clear agonist-like properties in this brain region [44] and other studies have shown that [ 18 F]NLX-112 has a distinctive pattern of in vivo micro-PET rat brain binding, with pronounced labelling of subcortical structures. [45] Such observations suggest that NLX-112 possesses G-protein activation and signal transduction properties that differentiate it from other 5-HT 1A agonists such as (AE)8-OH-DPAT, (+)8-OH-DPAT F15599 or F13714.…”

L’imagerie TEP pour une meilleure compréhension de la neurotransmission normale et pathologique

“…Le développement récent de radiotraceurs 5-HT 1A agonistes a permis d'apporter les premiers éléments favorables à cette hypothèse. Ainsi, la comparaison de la fixation in vitro d'un agoniste 5-HT 1A , le [ 18 F]F13640, et de l'antagoniste correspondant, le [ 18 F] MPPF, a montré des différences de fixation sur des tissus cérébraux de sujets Alzheimer, indiquant un découplage des récepteurs à des stades précoces de la pathologie, avant que l'antagoniste ne révèle une diminution de la densité totale des récepteurs, à un stade de Braak plus avancé (Vidal et al, 2016). Après validation in vivo de ce radiotraceur agoniste dans différentes espèces animales (Vidal et al, 2018), une première étude chez l'Homme a été menée afin d'établir la preuve de concept de cette imagerie spécifique des récepteurs fonctionnels, c'est-àdire couplés à leurs protéines de transduction (Colom et al, 2019).…”

Pharmacological agonists for more-targeted CNS radio-pharmaceuticals

“…One of these, F13640, was radiolabeled by replacing a non-radioactive fluorine-19 by a radioactive fluorine-18, [ 18 F]-F13640, with exactly the same chemical structure. Importantly, in-vitro autoradiographic studies showed that [ 18 F]-F13640 binding was drastically reduced by pharmacologic uncoupling of the receptor from its G-protein, indicating the agonist behavior of this molecule [6]. Under the same experimental conditions, [ 18 F]-MPPF, an antagonist of the same receptor, showed unchanged or slightly increased binding [6].…”

“…Importantly, in-vitro autoradiographic studies showed that [ 18 F]-F13640 binding was drastically reduced by pharmacologic uncoupling of the receptor from its G-protein, indicating the agonist behavior of this molecule [6]. Under the same experimental conditions, [ 18 F]-MPPF, an antagonist of the same receptor, showed unchanged or slightly increased binding [6]. These autoradiographic experiments on human brain tissue provided encouraging results for this novel radiopharmacologic concept of targeting functional receptors by a radiolabeled agonist.…”

“…Here again, exploring 5-HT 1A receptors opens up the possibility of transposition to other neurotransmission systems. Our preliminary autoradiography studies on hippocampal tissue from Alzheimer patients [6, 8] showed that, in advanced disease on Braak staging, the fall-off in radioactive agonist binding was significantly earlier and stronger than for the reference antagonist, [ 18 F]-MPPF. In other words, imaging the agonist revealed uncoupling (i.e., loss of 5-HT 1A receptor function) at early stages.…”