Serotonin 5-HT_1A Receptor Biased Agonists Induce Different Cerebral Metabolic Responses: A [¹⁸F]-Fluorodesoxyglucose Positron Emission Tomography Study in Conscious and Anesthetized Rats

Abstract

Serotonin 5-HT 1A receptors constitute an attractive therapeutic target for various psychiatric or neurodegenerative disorders. These receptors are expressed in multiple brain regions on different neuronal populations and can be coupled with distinct G-protein subtypes; such functional diversity complicates the use of 5-HT 1A ligands in several pathologies where it would be desirable to stimulate the receptors in a precise region. Therefore, using "biased agonists" able to target specifically certain subpopulations of 5-HT 1A receptors would enable achievement of better therapeutic benefit. Several 5-HT 1A receptor biased agonists are currently in development, including NLX-101 (aka F15599) and NLX-112 (aka F13640, befiradol), with preclinical data suggesting that they preferentially target different populations of 5-HT 1A receptors. However, most previous studies used invasive and regionally limited approaches. In this context, [ 18 F]-fluorodesoxyglucose (FDG)-positron emission tomography (PET) imaging constitutes an interesting technique as it enables noninvasive mapping of the regional brain activity changes following a pharmacological challenge in conscious animals. We report here the evaluation of cerebral glucose metabolism following intraperitoneal injection of different doses of NLX-112 or NLX-101 in conscious or isofluraneanesthetized rats. The biased agonists produced different metabolic "fingerprints" with distinct regional preferences, consistent with previous studies. At equal doses, the effect of NLX-101 was less marked than NLX-112 in the piriform cortex, in the striatum (in terms of inhibition), and in the pontine nuclei and the cerebellum (in terms of activation); furthermore, only NLX-112 increased the glucose metabolism in the parietal cortex, whereas only NLX-101 induced a clear activation in the colliculi and the frontal cortex, which may be related to its distinctive procognitive profile. Both agonist effects were almost completely unapparent in anesthetized animals, underlining the importance of studying serotonergic neurotransmission in the conscious state. In this regard, [ 18 F]FDG-PET imaging seems very complementary with other functional imaging techniques such as pharmacological MRI.

Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile

“…44 preferentially elicited antidepressant-like effects, whereas 56 more potently elicited LLR, thus suggesting that the balance of β-arrestin recruitment relative to ERK1/2 phosphorylation (functional selectivity) may be associated with accentuated activity in specific physiological and/or behavioral models. As discussed previously, such differences likely reflect activation of particular subpopulations of the 5-HT 1A receptors (regional selectivity) and may account for differential separation of therapeutic and side effects. ,, The novel 5-HT 1A agonists described herein, displaying diversified functional profiles, may constitute promising tool drugs to investigate the activity of 5-HT 1A receptor subpopulations and, potentially, could be developed as pharmacotherapeutics to treat CNS disorders involving dysfunctional serotonergic neurotransmission.…”

“…In terms of potency, the general trends (Tables 3 and 4) were similar to those established in affinity studies. Compared to 3, the derivatives substituted with the HBD in the meta position (43,45,47,48) were characterized by a rise in potency in all the signaling pathways. The same trend was observed for the bicyclic analogues (51,55,56,57), but the other derivatives showed mostly decreased potency in functional assays.…”

“…The highest ERK1/2 phosphorylation preference was found for compound 55 with a bias factor of 2.8 log. Three compounds (47, 48, and 51), preferred the cAMP pathway When comparing 3-chloro-4-fluorobenzoyl derivatives (29,38,40,47) with their 3,4-dichlorobenzoyl derivative counterparts (30,39,41,48), it is noticeable that the former always show a more pronounced biased profile than the latter compounds.…”

“…As discussed previously, such differences likely reflect activation of particular subpopulations of the 5-HT 1A receptors (regional selectivity) and may account for differential separation of therapeutic and side effects. 16,47,48 The novel 5-HT 1A agonists described herein, displaying diversified functional profiles, may constitute promising tool drugs to investigate the activity of 5-HT 1A receptor subpopulations and, potentially, could be developed as pharmacotherapeutics to treat CNS disorders involving dysfunctional serotonergic neurotransmission.…”

The selective 5-HT1A receptor biased agonists, F15599 and F13714, show antidepressant-like properties after a single administration in the mouse model of unpredictable chronic mild stress

“…A more likely explanation, therefore, is the regional selectivity of the compounds. In 18 F-FDG PET studies, F15599 induced a clear increase in labeling (reflecting increased activation) in the frontal cortex (Levigoureux et al 2019), while F13714 increased blood oxygen dependence in the cingulate and motor cortex, striatum, or thalamus (Becker et al 2016). Given that 5-HT 1A receptors in the frontal cortex are crucial for antidepressant-like effect, this might be the main reason why F15599 (which shows biased agonism for 5-HT 1A receptors in this brain region) has more prominent activity than F13714 for reduction of immobility in the forced swim test.…”