Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study

Abstract

Serotonin 1A (5-HT1A) receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target. The recent pharmacological concept of biased agonism asserts that highly selective agonists can preferentially direct receptor signaling to specific intracellular responses, opening the possibility of drugs targeting a receptor subtype in specific brain regions. The present study brings additional support to this concept thanks to functional magnetic resonance imaging (7 Tesla-fMRI) in anaesthetized rats. Three 5-HT1A receptor agonists (8-OH-DPAT, F13714 and F15599) and one 5-HT1A receptor antagonist (MPPF) were compared in terms of influence on the brain blood oxygen level-dependent (BOLD) signal. Our study revealed for the first time contrasting BOLD signal patterns of biased agonists in comparison to a classical agonist and a silent antagonist. By providing functional information on the influence of pharmacological activation of 5-HT1A receptors in specific brain regions, this neuroimaging approach, translatable to the clinic, promises to be useful in exploring the new concept of biased agonism in neuropsychopharmacology.

Marmoset Serotonin 5-HT1AReceptor Mapping with a Biased Agonist PET Probe18F-F13714: Comparison with an Antagonist Tracer18F-MPPF in Awake and Anesthetized States

“…Thus, F13714 potently inhibits 5-HT release in cortex and striatum (Assié et al, 2006; Iderberg et al, 2015), reverses L-DOPA-induced dyskinesia in Parkinsonian rats, and stimulates a BOLD signal in the raphe, striatum, and motor cortex (Becker et al, 2016), results that are consistent with the present study showing accentuated binding to these brain regions in marmoset brain. Although the molecular basis for this remains to be clarified, it is likely due to a preferential interaction of 18 F-F13714 with 5-HT 1A receptors that are coupled to specific G-protein subtypes and/or intracellular signaling mechanisms (Newman-Tancredi, 2011).…”

“…These considerations suggest that differences in labeling patterns between the 2 tracers may relate to the agonist properties of 18 F-F13714 that enable it to distinguish a 5-HT 1A receptor subpopulation of high-affinity sites (Assié et al, 2006; Maurel et al, 2007; Lemoine et al, 2012), a concept described previously for the 5-HT 1A receptor in baboons with 11 C-CUMI-101 (agonist) and 11 C-WAY100635 (antagonist) (Kumar et al, 2012). In the case of F13714, extensive evidence supports the notion that it acts as a biased agonist that preferentially targets 5-HT 1A receptors in specific brain regions, including the raphe, striatum, and thalamus (Assié et al, 2006; Iderberg et al, 2015; Becker et al, 2016). …”

“…In addition, a variety of rat electrophysiological, neurochemical, and behavioral studies have indicated F13714 exhibits a biased agonist profile of activity at specific 5-HT 1A receptor subpopulations, notably in the raphe region and the striatum (Newman-Tancredi et al, 2009; Iderberg et al, 2015; van Goethem et al, 2015; de Boer and Newman-Tancredi, 2016). A recent study in phMRI showed that F13714 and another biased agonist, F15599, induced specific pattern of changes in blood oxygen level dependent (BOLD) signal in a neuronal circuit in contrast to those induced by a classical agonist, 8-OH-DPAT, or a silent antagonist, MPPF, supporting the concept that biased agonists can preferentially target subpopulations of 5-HT 1A receptors in specific brain regions (Becker et al, 2016). Investigation of brain imaging with 18 F-F13714 is therefore desirable to better understand agonist interactions at subpopulations of 5-HT 1A receptors.…”

Functional selectivity – chance for better and safer drugs?

“…W testach funkcjonalnych in vitro związek F15599 wykazywał wyraźną preferencję (ok. 30 razy) wobec aktywacji fosforylacji kinazy ERK względem inhibicji cyklazy adenylanowej. Wykorzystując badania elektrofizjologiczne, mikrodializę i neuroobrazowanie, stwierdzono, że oddziałuje on preferencyjnie na postsynaptyczne receptory 5-HT 1A , szczególnie te zlokalizowane w korze mózgowej [67,68]. W konsekwencji odznacza się wysoką aktywnością w zwierzęcych modelach zaburzeń nastroju (test wymuszonego pływania, wokalizacja ultradźwiękowa) [69] oraz odwraca deficyty funkcji poznawczych u szczurów wywołane substancją psychozomimetyczną -fencyklidyną [70].…”

“…30x) for activation of phosphorylation of ERK with respect to inhibition of adenylate cyclase. Using electrophysiological studies, microdialysis and neuroimaging, it has been found that it acts preferentially on postsynaptic 5-HT 1A receptors, especially those located in the cerebral cortex [67,68]. As a result, it displays high activity in animal models of mood disorders (forced swimming test, ultrasonic vocalisation) [69], and reverses cognitive function deficits in rats induced by a psychotomimetic substance -phencyclidine [70].…”