High-Efficacy 5-HT_1A Agonists for Antidepressant Treatment:  A Renewed Opportunity

Abstract

We report the discovery of novel 5-HT1A receptor agonists and describe the process that led to the antidepressant candidate 9 (F 15599). 9 has nanomolar affinity for 5-HT1A binding sites and is over 1000-fold selective with respect to the other 5-HT1 receptor subtypes, 5-HT2-7 receptor families, and also numerous GPCRs, transporters, ion channels, and enzymes. In a cellular model of signal transduction, 9 activates h5-HT1A receptors with an efficacy superior to that of the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT and comparators undergoing clinical trials. After acute oral administration in rats, 9 totally reverses immobility in the forced swimming test and produces behaviors characteristic of 5-HT1A receptor activation. However, these effects occurred at widely separated doses, suggesting that 9 discriminates between distinct populations of 5-HT1A receptors. While the clinical relevance of these observations is still unknown, this opens new perspectives for the treatment of depressive disorders.

Radiosynthesis and Preclinical Evaluation of 18F-F13714 as a Fluorinated 5-HT1A Receptor Agonist Radioligand for PET Neuroimaging

“…First, like its chemical analog F15599, F13714 exhibits an outstanding selectivity for 5-HT 1A receptors. With the exception of s-binding sites (inhibitory concentration of 50% [IC50], ;80 nM), the affinity of F13714 for 40 other receptors, enzymes, and transporters was at least 1,000-fold lower (27,30). Second, its chemical structure carries a fluorine atom amenable to radiofluoration (more convenient for clinical uses than 11 C radiolabeling).…”

“…Taken together, the differences observed here in the labeling patterns of comparison of 18 F-F13714 and 18 F-F15599 provide further evidence that these agonists distinguish 5-HT 1A receptor subpopulations in different brain areas. We are confident that the radiopharmacologic profile of 18 F-F13714 will be appropriate for clinical studies, taking into account its wellcharacterized pharmacology (27,30,39). A quantitative approach using kinetic models is now needed to complete this work.…”

“…In this context, we chose a highly selective 5-HT 1A agonist (F13714) that displays subnanomolar affinity for 5-HT 1A receptors (27). In this article, we discuss the radiosynthesis, in vitro autoradiographic, and in vivo PET studies of 18 F-F13714 as a prerequisite for future use as a PET ligand in humans.…”

The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats

“…This, too, may represent a compensatory process. Further, 5-HT 1A agonists, e.g., F15599, a preferential post-synaptic 5-HT 1A agonist (Maurel et al 2007;Newman-Tancredi et al 2009), improves cognition in rodents (see "Discussion").…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…Ligands acting via specific 5-HT 1A -recruited signaling pathways may offer the hope of future clinical exploitation. 68,116 5-HT 1B receptors have also been forwarded as mediators of antidepressant actions of SSRIs, together with 5-HT 2A and (controversially) 5-HT 2C and 5-HT 6 sites; 5-HT 4 receptors were also recently added to the inventory of potential serotonergic mechanisms for improving mood. 3,58,86,[117][118][119] No single receptor can account for the global therapeutic influence of antidepressants that increase monoamine levels.…”