Presynaptic Selectivity of a Ligand for Serotonin 1A Receptors Revealed by In Vivo PET Assays of Rat Brain

Abstract

A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT1A) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT1A receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT1A receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT1A receptors. In addition, [35S]guanosine 5′-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT1A receptors. This finding has lent support to reports that diverse partial agonists for 5-HT1A receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

Evaluation of serotonin 5-HT1Areceptors in rodent models using [18F]mefway PET

“…Both the ex vivo microPET and ex vivo autoradiographs clearly showed the presence of [ 18 F]mefway binding in the dorsal raphe. Only one recent report on 5‐HT 1A receptors has evaluated the dorsal raphe in the rodent model (Saijo et al, ) but has been characterized in nonhuman primates (Wooten et al, ) and in humans (Parsey et al, ). As this region is where the serotonergic pathways emerge, the ability of [ 18 F]mefway to measure this region in vivo in the rodent model using [ 18 F]mefway is highly significant.…”

In Vivo Receptor Visualization and Evaluation of Receptor Occupancy with Positron Emission Tomography

“…A human PET experiment using flesinoxan and ziprasidone as test compounds confirmed competitive binding with respect to 2–12.1 in the brain, but there was a discrepancy compared with the results in rats, possibly due to differences in the distributions of 5-HT receptors in the brain between humans and rats. Other PET experiments using 2–12.1 confirmed competition at 5-HT receptors in the brain, − supporting the usefulness of this tracer.…”

“…[ 11 C]­WAY100635 ( 2–12.1 ) is widely used as a PET tracer targeting 5-HT 1A . − This tracer has high binding affinity for subtype 1A (IC 50 = 8.9 nM vs [ 3 H]­prazosin), and receptor occupancy of many test compounds has been evaluated in animals and humans . In addition, NAD298, a candidate for the treatment of depression targeting 5-HT 1A , was confirmed to exhibit competitive binding in monkey brain with ED 50 = 4–5 nM.…”

A Small-Animal Pharmacokinetic/Pharmacodynamic PET Study of Central Serotonin 1A Receptor Occupancy by a Potential Therapeutic Agent for Overactive Bladder

“…This finding also supports the reliability of PET assays for anesthetized rats to quantify 5-HT 1A RO. Indeed, the use of isoflurane-anesthetized rats for 5-HT1A RO determination was justified in a previous [ 11 C] WAY-100635-PET study, which demonstrated that in vivo ED 50 value for pindolol in the hippocampus (5.6 mg/kg) was rather close to hippocampal ED 50 value (8.5 mg/kg) estimated by an ex vivo autoradiographic measurement for unanesthetized rats [15]. …”