Kiichi Ishiwata

Sigma Receptor Ligands: Possible Application as Therapeutic Drugs and as Radiopharmaceuticals

Sigma receptors are classified into sigma(1) and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma(1) receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma(2) receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca(2+), and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.

Auditory triggered mental imagery of shape involves visual association areas in early blind humans

Previous neuroimaging studies identified a large network of cortical areas involved in visual imagery in the human brain, which includes occipitotemporal and visual associative areas. Here we test whether the same processes can be elicited by tactile and auditory experiences in subjects who became blind early in life. Using positron emission tomography, regional cerebral blood flow was assessed in six right-handed early blind and six age-matched control volunteers during three conditions: resting state, passive listening to noise sounds, and mental imagery task (imagery of object shape) triggered by the sound of familiar objects. Activation foci were found in occipitotemporal and visual association areas, particularly in the left fusiform gyrus (Brodmann areas 19-37), during mental imagery of shape by both groups. Since shape imagery by early blind subjects does involve similar visual structures as controls at an adult age, it indicates their developmental crossmodal reorganization to allow perceptual representation in the absence of vision.

PET tracers for imaging of the dopaminergic system

The dopaminergic system plays a major role in neurological and psychiatric disorders such as Parkinsons disease, Huntingtons disease, tardive dyskinea and schizophrenia. Knowledge on altered dopamine synthesis, receptor densities and status are important for understanding the mechanisms underlying the pathogenesis and therapy of diseases. PET provides a non-invasive tool to investigate these features in vivo, provided the availability of suitable radiopharmaceuticals. To investigate presynaptic function, PET-tracers have been developed to measure dopamine synthesis and transport. For the former the most commonly used tracers are 6-[(18)F]FDOPA and 6-[(18)F]FMT, whereas for the latter several (11)C/(18)F-labeled tropane analogues are being clinically used. Postsynaptically, dopamine exerts actions through several subtypes of the dopamine receptor. The dopamine receptor family consists of 5 subtypes D(1)-D(5). In order to investigate the role of each receptor subtype, selective and high-affinity PET-radioligands are required. For the dopamine D(1)-subtype the most commonly used ligand is [(11)C]SCH 23390 or [(11)C]NNC 112, whereas for the D(2)/D(3)-subtype [(11)C]raclopride is a common tracer. [(18)F]Fallypride is a suitable PET-tracer for the investigation of extrapyramidal D(2)-receptors. For the other subtypes no suitable radioligands have been developed yet. This paper gives an overview of the current status on dopamine PET-tracers and the development of new lead compounds as potential PET-tracers by medicinal chemistry.

Low density of sigma1 receptors in early Alzheimer’s disease

ObjectiveThe sigma1 receptor is considered to be involved in cognitive function. A postmortem study reported that the sigma1 receptors were reduced in the hippocampus in Alzheimer’s disease (AD). However, in vivo imaging of sigma1 receptors in the brain of AD patients has not been reported. The aim of this study is to investigate the mapping of sigma1 receptors in AD using [11C]SA4503 positron emission tomography (PET).MethodsWe studied five AD patients and seven elderly volunteers. A dynamic series of decay-corrected PET data acquisition was performed for 90 min starting at the time of the injection of 500 MBq of [11C]SA4503. A two-tissue three-compartment model was used to estimate K1, k2, k3, k4, and the delay between metabolite-corrected plasma and tissue time activity using a Gauss-Newton algorithm. The ratio of k3 to k4 was computed as the binding potential (BP), which is linearly related to the density of sigma1 receptors. Unpaired t tests were used to compare K1 and BP in patients with AD and normal subjects.ResultsAs compared with normals, BP in the AD was significantly lower in the frontal, temporal, and occipital lobe, cerebellum and thalamus, whereas K1 was significantly lower in the parietal lobe.Conclusions[11C]SA4503 PET can demonstrate that the density of cerebral and cerebellar sigma1 receptors is reduced in early AD.

Extraction of a plasma time-activity curve from dynamic brain PET images based on independent component analysis

A compartment model has been used for kinetic analysis of dynamic positron emission tomography (PET) data [e.g., 2-deoxy-2-/sup 18/F-fluoro-D-glucose (FDG)]. The input function of the model [the plasma time-activity curve (pTAC)] was obtained by serial arterial blood sampling. It is of clinical interest to develop a method for PET studies that estimates the pTAC without needing serial arterial blood sampling. For this purpose, we propose a new method to extract the pTAC from the dynamic brain PET images using a modified independent component analysis [extraction of the pTAC using independent component analysis (EPICA). Source codes of EPICA are freely available at http://www5f.biglobe.ne.jp//spl ap/ukimura/Software/top.html]. EPICA performs the appropriate preprocessing and independent component analysis (ICA) using an objective function that takes the various properties of the pTAC into account. After validation of EPICA by computer simulation, EPICA was applied to human brain FDG-PET studies. The results imply that the EPICA-estimated pTAC was similar to the actual measured pTAC, and that the estimated blood volume image was highly correlated with the blood volume image measured using /sup 15/O-CO inhalation. These results demonstrated that EPICA is useful for extracting the pTAC from dynamic PET images without the necessity of serial arterial blood sampling.

Expanding the clinical phenotype of SNCA duplication carriers.

SNCA duplication is a recognized cause of familial Parkinsons disease (PD). We aimed to explore the genetic and clinical variability in the disease manifestation. Molecular characterization was performed using real‐time PCR, SNP arrays, and haplotype analysis. We further studied those patients who were found to harbor SNCA duplication with olfactory function tests, polysomnography, and PET. We identified four new families and one sporadic patient with SNCA duplication. Eleven symptomatic patients from these four families presented with parkinsonism, of which three subsequently developed dementia. The lifetime estimate of overall penetrance was 43.8%. FDG–PET study of symptomatic patients showed hypometabolism in the occipital lobe, whereas asymptomatic carriers of SNCA duplication demonstrated normal glucose metabolism. Symptomatic patients showed abnormal olfactory function and polysomnography and asymptomatic carriers showed normal results. The clinical features of SNCA duplication include parkinsonism with or without dementia. Asymptomatic carriers displayed normal test results with the eldest individual aged 79 years; thus, even a carrier of SNCA duplication may escape the development of PD. This difference in age‐associated penetrance may be due to the genetic background or environmental exposures. Further studies of SNCA duplication carriers will help identify disease‐modifiers and may open novel avenues for future treatment.

In vivo evaluation of [11C]SA4503 as a PET ligand for mapping CNS sigma1 receptors

Abstract The potential of the 11 C-labeled selective sigma 1 receptor ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([ 11 C]SA4503) was evaluated in vivo as a positron emission tomography (PET) ligand for mapping sigma 1 receptors in rats. SA4503 is known to have a high affinity (IC 50 = 17.4 nM) and a higher selectivity (sigma 1 /sigma 2 = 103) for the sigma 1 receptor. A high and increasing brain uptake of [ 11 C]SA4503 was found. Pre-, co- and postinjection of cold SA4503 significantly decreased uptake of [ 11 C]SA4503 in the brain, spleen, heart, lung, and kidney in which sigma receptors are present as well as in the skeletal muscle. In the blocking study with one of four sigma receptor ligands including haloperidol, (+)-pentazocine, SA4503, and (−)-pentazocine (in the order of their affinity for sigma 1 receptor subtype), SA4503 and haloperidol significantly reduced the brain uptake of [ 11 C]SA4503 to approximately 30% of the control, but the other two benzomorphans did not. A high specific uptake of [ 11 C]SA4503 by the brain was also confirmed by ex vivo autoradiography (ARG) and PET. Ex vivo ARG showed a higher uptake in the vestibular nucleus, temporal cortex, cingulate cortex, inferior colliculus, thalamus, and frontal cortex, and a moderate uptake in the parietal cortex and caudate putamen. Peripherally, the blocking effects of the four ligands depended on their affinity for sigma 1 receptors. No 11 C-labeled metabolite was detected in the brain 30 min postinjection, whereas approximately 20% of the radioactivity was found as 11 C-labeled metabolites in plasma. These results have demonstrated that the 11 C-labeled sigma 1 receptor ligand [ 11 C]SA4503 has a potential for mapping sigma 1 receptors in the central nervous system and peripheral organs.

High Occupancy of Sigma-1 Receptors in the Human Brain after Single Oral Administration of Fluvoxamine: A Positron Emission Tomography Study Using [11C]SA4503

BACKGROUND Sigma-1 receptors might be implicated in the pathophysiology of psychiatric diseases, as well as in the mechanisms of action of some selective serotonin reuptake inhibitors (SSRIs). Among the several SSRIs, fluvoxamine has the highest affinity for sigma-1 receptors (Ki = 36 nM), whereas paroxetine shows low affinity (Ki = 1893 nM). The present study was undertaken to examine whether fluvoxamine binds to sigma-1 receptors in living human brain. METHODS A dynamic positron emission tomography (PET) data acquisition using the selective sigma-1 receptor ligand [(11)C]SA4503 was performed with arterial blood sampling to evaluate quantitatively the binding of [(11)C]SA4503 to sigma-1 receptors in 15 healthy male volunteers. Each subject had two PET scans before and after randomly receiving a single dose of either fluvoxamine (50, 100, 150, or 200 mg) or paroxetine (20 mg). The binding potential of [(11)C]SA4503 in 9 regions of the brain was calculated by a 2-tissue 3-compartment model. In addition, we examined the effects of functional polymorphisms of the sigma-1 receptor (SIGMAR1) gene on the binding potential of [(11)C]SA4503. RESULTS Fluvoxamine bound to sigma-1 receptors in all brain regions in a dose-dependent manner, whereas paroxetine did not bind to sigma-1 receptors. However, there was no association between the SIGMAR1 gene polymorphism GC-241-240TT and binding potential. CONCLUSIONS The study demonstrated that fluvoxamine bound to sigma-1 receptors in living human brain at therapeutic doses. These findings suggest that sigma-1 receptors may play an important role in the mechanism of action of fluvoxamine.

Sigma Receptors in Oncology: Therapeutic and Diagnostic Applications of Sigma Ligands

Sigma receptors (subtypes sigma-1 and sigma-2) are a unique class of binding sites expressed throughout the mammalian body. The endogenous ligand for these sites has not been identified, but steroid hormones (particularly progesterone), sphingolipid-derived amines and N,N-dimethyltryptamine can bind with fairly high affinity. Sigma receptors are overexpressed in rapidly proliferating cells, like cancer cells. Particularly the sigma-2 subtype is upregulate when cells divide and down regulated when they become quiescent. Sigma ligands, especially sigma-2 agonists, can inhibit proliferation and induce apoptosis by a mechanism involving changes in cytosolic Ca(2+), ceramide and sphingolipid levels. Tumor cells are much more sensitive to such treatment than cells from their tissue of origin. Sigma ligands induce apoptosis not only in drug-sensitive but also in drug-resistant cancer cells (e.g., cells with p53 mutations, or caspase dysfunction). Moreover, sigma ligands may abrogate P-glycoprotein-mediated drug resistance and at subtoxic doses, they can potentiate the effect of conventional cytostatics. Thus, sigma-2 agonists may be developed as antineoplastic agents for the treatment of drug-resistant tumors. A large number of radiolabeled sigma ligands has been prepared for SPECT (single-photon emission computed tomography) and PET (positron emission tomography) imaging. Such radiopharmaceuticals can be used for tumor detection, tumor staging, and evaluation of anti-tumor therapy. There is still a need for the development of ligands with (1) high selectivity for the sigma-2 subtype, (2) defined action (agonist or antagonist) and (3) optimal pharmacokinetics (low affinity for P-glycoprotein, high and specific tumor uptake, and rapid washout from non-target tissues).

Adenosine A2A Receptors Measured with [11C]TMSX PET in the Striata of Parkinson's Disease Patients

Adenosine A2A receptors (A2ARs) are thought to interact negatively with the dopamine D2 receptor (D2R), so selective A2AR antagonists have attracted attention as novel treatments for Parkinsons disease (PD). However, no information about the receptor in living patients with PD is available. The purpose of this study was to investigate the relationship between A2ARs and the dopaminergic system in the striata of drug-naïve PD patients and PD patients with dyskinesia, and alteration of these receptors after antiparkinsonian therapy. We measured binding ability of striatal A2ARs using positron emission tomography (PET) with [7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([11C]TMSX) in nine drug-naïve patients with PD, seven PD patients with mild dyskinesia and six elderly control subjects using PET. The patients and eight normal control subjects were also examined for binding ability of dopamine transporters and D2Rs. Seven of the drug-naïve patients underwent a second series of PET scans following therapy. We found that the distribution volume ratio of A2ARs in the putamen were larger in the dyskinesic patients than in the control subjects (p<0.05, Tukey-Kramer post hoc test). In the drug-naïve patients, the binding ability of the A2ARs in the putamen, but not in the head of caudate nucleus, was significantly lower on the more affected side than on the less affected side (p<0.05, paired t-test). In addition, the A2ARs were significantly increased after antiparkinsonian therapy in the bilateral putamen of the drug-naïve patients (p<0.05, paired t-test) but not in the bilateral head of caudate nucleus. Our study demonstrated that the A2ARs in the putamen were increased in the PD patients with dyskinesia, and also suggest that the A2ARs in the putamen compensate for the asymmetrical decrease of dopamine in drug-naïve PD patients and that antiparkinsonian therapy increases the A2ARs in the putamen. The A2ARs may play an important role in regulation of parkinsonism in PD.