Application of [11C]SA4503 to selection of novel σ1 selective agonists
Introduction
The σ1 receptors, which were initially regarded as one of the opioid receptor subtypes and later confused as the phencyclidine binding sites of the N-methyl-d-aspartate receptor, have now been confirmed to be independent receptors [1]. Recently, σ1 receptors have been shown to act as ligand-regulated molecular chaperones in the endoplasmic reticulum [2]. They are involved in the modulation of various neurotransmitter systems, particularly the cholinergic [3], [4] and glutamatergic pathways [5]. Diverse classes of central nervous system (CNS) drugs show high to moderate affinities for σ1 receptors, i.e., acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol), selective serotonin reuptake inhibitors (fluvoxamine), etc. [6], [7], [8]. These compounds can influence cognitive functions both via their primary targets and by activating σ1 receptors in the CNS [1]. Moreover, the discovery of selective ligands for σ1 receptors has suggested that these receptors may be useful potential targets for treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition) and brain ischemia [9]. Taken together, σ1 receptor selective ligands are now recognized as a new class of potential therapeutic agents for several disorders of the CNS.
Drug discovery and development are time-consuming and costly procedures. The challenges for the pharmaceutical industry range from evaluation of potential new drug candidates, determination of drug pharmacokinetics/pharmacodynamics, measurement of receptor occupancy as a determinant of drug efficacy, and pharmacological characterization of the mechanisms of action of novel agents. Positron emission tomography (PET) is a powerful quantitative imaging technique for analyzing biochemical pathways, molecular interactions, drug pharmacokinetics and pharmacodynamics, and estimation of receptor occupancy by drugs in the human brain. We found carbon-11-labeled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([11C]SA4503) to be a promising PET ligand for the mapping of σ1 receptors, and applied it to human subjects. Using PET with [11C]SA4503, we demonstrated that [11C]SA4503 is useful for evaluation of σ1 receptor occupancy rates by several therapeutic drugs in the living human brain [10], [11], [12]. This technique is also applicable to preclinical in vivo screening of drug candidates, and directly evaluates blood–brain barrier (BBB) permeability, receptor occupancy, and bioavailability at the same time.
In this study, we screened a new series of piperidine and piperazine derivatives containing arylalkylamine groups and cyclohexylamine derivatives containing phenyl groups. Three piperazine derivatives and three cyclohexylamine derivatives were selected from ninety compounds by in vitro binding assay for σ1 and σ2 receptors and agonistic activity evaluated by neurite outgrowth. We measured the in vivo σ1 receptor binding of these compounds using σ1-selective [11C]SA4503. The high specific binding and stable brain kinetics of [11C]SA4503 enabled us to assess receptor blocking by a tissue dissection method at a single time point [13]. This is a much more practical and high-throughput method for in vivo screening of drug candidates than using 3H-labeled radioligands or dynamic small animal PET scanning. The relationships among in vivo receptor blocking, σ1 receptor affinity, and rat oral bioavailability are also discussed.
Section snippets
General
SA4503 was synthesized by the method reported previously [14]. [11C]SA4503 was prepared at the Tokyo Metropolitan Institute of Gerontology as described previously [15]. The chemical structures of six newly synthesized σ1 agonists are shown in Fig. 1. These compounds were N-ethyl-N-[2-(phenylthio)ethyl]cyclohexylamine (MC-46), N-ethyl-N-{2-[(4-fluorophenyl)thio]ethyl}cyclohexylamine (MC-54), N-ethyl-N-[3-(4-fluorophenyl)propyl]cyclohexylamine (MC-128),
Results
In vitro receptor binding affinity, rat oral bioavailability, ClogP, and in vivo blocking rates at the middle dose (333 nmol/kg) of co-injection studies for test compounds are summarized in Table 1. Dose-dependent effects of each compound on [11C]SA4503 uptake in the brain, blood, and muscle are shown in Fig. 2. All of the newly synthesized compounds showed high (Ki < 10 nM) and specific (σ2/σ1 > 28) binding to the σ1 receptor. These in vitro binding properties of MC-128 were comparable to
Discussion
We assessed the in vivo blocking effects of novel σ1 agonists on the brain σ1 receptors with [11C]SA4503 by a tissue dissection method at a single time point. The major findings of this study are: 1) the most promising candidate of a novel σ1 agonist was MC-101, 2) piperazine derivatives showed some correlation between in vitro affinities and in vivo receptor blocking rates when considering oral bioavailability, and 3) in vivo receptor blocking of piperazine derivatives after oral
Acknowledgments
This work was supported by Grants-in Aid for Scientific Research (B) No. 22390241 and Challenging Exploratory Research No. 23659605 from the Japan Society for the Promotion of Science (to Jun Toyohara). The authors thank Mr. Kunpei Hayshi for technical assistance.
References (16)
- et al.
Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2 + signaling and cell survival
Cell
(2007) - et al.
Neurostaroids enhance spontaneous glutamate release in hippocampal neurons — possible role of metabotropic σ1-like receptors
J Biol Chem
(2002) - et al.
TAK-146, an acetylcholinesterase inhibitor, increases choline acetyltransferase activity in cultured rat septal cholinergic neurons
Neurosci Lett
(1999) - et al.
SA4503, a novel cognitive enhancer, with σ1 receptor agonistic properties
Behav Brain Res
(1997) - et al.
Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain
Eur J Parmacol
(1996) - et al.
High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron emission tomography study using [11C]SA4503
Biol Psychiatry
(2007) - et al.
Synthesis, structure and quantitative structure-activity relationships of σ receptor ligands, 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines
Bioorg Med Chem
(1997) - et al.
The role of sigma-1 receptors in the pathophysiology of neuropsychiatric diseases
J Receptor Ligand Channel Res
(2010)
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