Abstract
Serotonin 1A (5-HT1A) receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB). Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB.
Highlights
Overactive bladder (OAB) is a pathological condition symptomatically diagnosed based upon “a symptom developing urinary urgency with or without urge incontinence and usually developing frequent urination with no proven infection or other obvious pathological factors [1].”, and is one of the most common diseases in the elderly
Binding assay in rat hippocampal microsomal fraction The affinity of E2110 for rat 5-HT1A receptors was examined in brain tissues. [3H] MPPF bound to membrane preparations from the rat hippocampus with a Kd value of 0.92 nM
5-HT1A receptor occupancy (RO) Studies As medial prefrontal cortex (MPFC) and dorsal raphe nucleus (DRN) represent brain areas enriched with post- and pre-synaptic 5-HT1A receptors, respectively, regions of interest (ROIs) were defined in these areas for subsequent analyses
Summary
Overactive bladder (OAB) is a pathological condition symptomatically diagnosed based upon “a symptom developing urinary urgency with or without urge incontinence and usually developing frequent urination with no proven infection or other obvious pathological factors [1].”, and is one of the most common diseases in the elderly. Most OAB cases are idiopathic, and anticholinergic agents are frequently used for its treatment. It is difficult to maintain sufficient dosage of an anticholinergic agent for expected efficacy without causing significant adverse events, such as dry mouth, gastrointestinal disorder, and urinary retention, thereby limiting its use [2,3,4]. Serotonin (5-HT) and its receptors may play an important role in the regulation of micturition reflex. Pharmacological studies suggested that serotonin 1A (5-HT1A) receptor stimulation by administration of its agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin
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