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Akira Odani - One of the best experts on this subject based on the ideXlab platform.
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Syntheses and evaluation of a homologous series of aza-vesamicol as improved radioiodine-labeled probes for Sigma-1 Receptor imaging.
Bioorganic & medicinal chemistry, 2019Co-Authors: Kazuma Ogawa, Takashi Kozaka, Kazuhiro Shiba, Ryohei Masuda, Kenji Mishiro, Mengfei Wang, Seigo Kinuya, Akira OdaniAbstract:Abstract Sigma-1 Receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the Sigma-1 Receptor. In this study, we aimed to develop probes with higher affinity for the Sigma-1 Receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the Sigma-1 Receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The Sigma-1 Receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol ( 5 ) (K i = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5 . The radioiodine labeled probe [ 125 I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([ 125 I] 10 ) showed high accumulation in the Sigma-1 Receptor expressing DU-145 cells both in vitro and in vivo . Co-injection of [ 125 I] 10 with an excess level of a Sigma Receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo , indicating Sigma Receptor-mediated tumor uptake. These results provide useful information for developing Sigma-1 Receptor imaging probes.
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Preparation and evaluation of an astatine-211-labeled Sigma Receptor ligand for alpha radionuclide therapy
Nuclear Medicine and Biology, 2015Co-Authors: Kazuma Ogawa, Yoshiaki Mizuno, Takashi Kozaka, Atsushi Shinohara, Kouhei Washiyama, Kiyoko Shiba, Nobuaki Takahashi, Akira OdaniAbstract:Introduction: Sigma Receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide Receptor therapy. We have previously synthesized and evaluated 131I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[131I]pIV], which has a high affinity for Sigma Receptors. Therefore, (+)-[131I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[211At]pAtV, an 211At-labeled Sigma Receptor ligand, that has potential use in alpha-radionuclide Receptor therapy. Methods: The radiolabeled Sigma Receptor ligand (+)-[211At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[211At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[211At]pAtV and (+)-[125I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the Sigma Receptors, and DU-145 tumor-bearing mice. Results: The lipophilicity of (+)-[211At]pAtV was similar to that of (+)-[125I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1h post-injection were also similar between (+)-[211At]pAtV and (+)-[125I]pIV. Namely, (+)-[211At]pAtV demonstrated high uptake and retention in tumor via binding to Sigma Receptors. Conclusion: These results indicate that (+)-[211At]pAtV could function as an new agent for alpha-radionuclide Receptor therapy.
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Development and evaluation of a novel radioiodinated vesamicol analog as a Sigma Receptor imaging agent
EJNMMI research, 2012Co-Authors: Kazuma Ogawa, Takashi Kozaka, Kazuhiro Shiba, Hiroya Kanbara, Yoji Kitamura, Tatsuto Kiwada, Akira OdaniAbstract:Background Sigma Receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-p IV), with a high affinity for Sigma Receptors and prepared radioiodinated (+)-p IV. As a result, (+)-[125I]p IV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-p IV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH).
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Development and evaluation of a novel radioiodinated vesamicol analog as a Sigma Receptor imaging agent
EJNMMI Research, 2012Co-Authors: Kazuma Ogawa, Takashi Kozaka, Kazuhiro Shiba, Hiroya Kanbara, Yoji Kitamura, Tatsuto Kiwada, Akira OdaniAbstract:Background Sigma Receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)- p IV), with a high affinity for Sigma Receptors and prepared radioiodinated (+)- p IV. As a result, (+)-[^125I] p IV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)- p IV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH). Methods (+)-[^125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[^125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[^125I]IV-OH and (+)-[^131I] p IV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[^125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice. Results The hydrophilicity of (+)-[^125I]IV-OH was much higher than that of (+)-[^125I] p IV. In biodistribution experiments, (+)-[^125I]IV-OH and (+)-[^131I] p IV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[^131I] p IV tended to be retained in most tissues, (+)-[^125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[^125I]IV-OH was significantly lower at all time points compared to those of (+)-[^131I] p IV. In the blocking studies, co-injection of an excess amount of Sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[^125I]IV-OH. Conclusions The results indicate that radioiodinated (+)-IV-OH holds a potential as a Sigma Receptor imaging agent.
Vadivel Ganapathy - One of the best experts on this subject based on the ideXlab platform.
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Sigma Receptor 1 modulates ER stress and Bcl2 in murine retina
Cell and Tissue Research, 2014Co-Authors: Arul K. Shanmugam, Shanu Markand, Eric Zorrilla, Vadivel Ganapathy, Sylvia B. SmithAbstract:Sigma Receptor 1 (σR1), a non-opiate transmembrane protein located on endoplasmic reticulum (ER) and mitochondrial membranes, is considered to be a molecular chaperone. Marked protection against cell death has been observed when ligands for σR1 have been used in in vitro and in vivo models of retinal cell death. Mice lacking σR1 ( σR1 ^-/-) manifest late-onset loss of retinal ganglion cells and retinal electrophysiological changes (after many months). The role of σR1 in the retina and the mechanisms by which its ligands afford neuroprotection are unclear. We therefore used σR1 ^-/- mice to investigate the expression of ER stress genes ( BiP / GRP78 , Atf6 , Atf4 , Ire1α ) and proteins involved in apoptosis (BCL2, BAX) and to examine the retinal transcriptome at young ages. Whereas no significant changes occurred in the expression of major ER stress genes (over a period of a year) in neural retina, marked changes were observed in these genes, especially Atf6 , in isolated retinal Müller glial cells. BCL2 levels decreased in σR1 ^-/- retina concomitantly with decreases in NFkB and pERK1/2. We postulate that σR1 regulates ER stress in retinal Müller cells and that the role of σR1 in retinal neuroprotection probably involves BCL2 and some of the proteins that modify its expression (such as ERK, NFκB). Data from the analysis of the retinal transcriptome of σR1 null mice provide new insights into the role of σR1 in retinal neuroprotection.
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in vivo protection against retinal neurodegeneration by Sigma Receptor 1 ligand pentazocine
Investigative Ophthalmology & Visual Science, 2008Co-Authors: Sylvia B. Smith, Penny Roon, Jennifer Duplantier, Barbara A Mysona, Pamela M Martin, Vadivel GanapathyAbstract:Sigma 1 Receptors (σR1) are Ca2+-sensitive, ligand-operated Receptor chaperones at the mitochondrion-associated endoplasmic reticulum (ER) membrane.1 Originally, they were thought to be a subtype of opiate Receptor, but it is clear now that σR1 is pharmacologically distinct from other known Receptors. Two types of Sigma Receptors (σR1 and σR2) have been identified2; σR1, the better characterized of the two, has been cloned from several species.3-7 σR1 cDNA predicts a protein of 223 amino acids (Mr 25-28 kDa).3 σR1 has been implicated in neuroprotection.8-14 In the brain, where σR1 is expressed abundantly, ligands for the Receptor have been useful in attenuating neuronal loss in in vitro9,11 and in vivo models of acute neurodegeneration.10,13,14 Over the past several years, σR1 expression has been analyzed in ocular tissue,15-21 including the retina.18-21 RT-PCR analysis amplified σR1 in neural retina and the RPE-choroid complex. In situ hybridization studies revealed abundant expression of σR1 in the ganglion cell layer, (GCL) inner nuclear layer (INL), inner segments of photoReceptor cells, and RPE cells.18 Immunohistochemical analysis confirmed these observations. Recent studies in which primary cultures of mouse Muller cells were used localized σR1 to the ER and nuclear membranes.21 These cells and other retinal cell types demonstrate robust σR1 binding activity with an apparent Kd of ∼25 nM.21 The promising evidence of neuroprotection by σR1 ligands in studies of brain tissue coupled with the finding that σR1 is expressed in retina led us to explore the usefulness of ligands for σR1 in retinal degeneration. Our initial studies were performed in vitro using a ganglion cell line, RGC-5,22 and subsequently using primary ganglion cells isolated from neonatal mouse retina.8 These studies demonstrated that treatment of cells with (+)-pentazocine, a highly-specific σR1 ligand, led to marked attenuation of cell death induced by the excitotoxins glutamate and homocysteine. These findings suggested that in vivo neurodegenerative diseases of the retina, such as glaucoma and diabetic retinopathy, which result in progressive loss of retinal neurons, may be amenable to treatment with σR1 ligands. Earlier studies, showing that σR1 continues to be expressed in neural retina under hyperglycemic conditions and during diabetic retinopathy,20 prompted analysis of neuroprotection in this disease. Diabetic retinopathy, a leading cause of blindness, is characterized by loss of retinal neurons and disruption of vasculature.23,24 Patients with diabetes lose color and contrast sensitivity within 2 years of onset.25,26 Focal ERG (electroretinogram) analysis, which detects electrical responses of ganglion cells, reveals dysfunction of these cells early in diabetes.27,28 Analyses of retinal tissue samples from diabetic patients provide further support of an involvement of retinal neurons in diabetic retinopathy, including detection of several markers of apoptosis.29 The neuronal death observed in humans has also been reported in rodent models.30 Using the TUNEL assay, Barber et al.30 analyzed the retinas of diabetic patients as well as the streptozotocin-induced rat model and observed significantly more apoptotic neurons in retinas of diabetic subjects than in those of control subjects. Similar results were observed by Bek31 and Kerrigan et al.32 Recently, two mouse models of diabetic retinopathy were described in which retinal neuronal loss was reported.33,34 Spontaneously arising diabetes has been reported in the Ins2Akita/+ mouse, which has a point mutation of the Insulin2 gene leading to hyperglycemia and hypoinsulinemia in heterozygous mice by ∼4 weeks.35 In addition to increased retinal vascular permeability and an increase in acellular capillaries, Ins2Akita/+ mice demonstrate ∼20% to 25% reduction in the thickness of the inner plexiform layer (IPL), ∼16% reduction in the thickness of the INL, and ∼25% reduction in the number of cell bodies in the retinal GCL.33 Cells in the GCL are immunoreactive for active caspase-3 after 4 weeks of hyperglycemia, consistent with cell death by apoptosis. In an induced model of diabetes, mice made diabetic by multiple injections of the pancreatic toxin streptozotocin, but not maintained on insulin, demonstrated 20% to 25% fewer cells in the GCL by 14 weeks after the onset of diabetes.34 Data obtained using the TUNEL assay and analysis of active caspase-3 suggested that these neurons die by apoptosis. Viability is compromised in these animals, and most animals die by 16 to 20 weeks after onset of diabetes. Given that retinal neurons die over a relatively short period in these two mouse models, they were ideal for assessing neuroprotection by the σR1 ligand (+)-pentazocine. A pilot study to test (+)-pentazocine dosage was conducted in the streptozotocin-induced model and the comprehensive analysis of neuroprotection was performed in the Ins2Akita/+ model.
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Expression pattern of Sigma Receptor 1 mRNA and protein in mammalian retina.
Molecular Brain Research, 2001Co-Authors: M. Shamsul Ola, Vadivel Ganapathy, Pamela J. Moore, Amira El-sherbeny, Penny Roon, Neeraj Agarwal, Vijay P. Sarthy, Pierre Casellas, Sylvia B. SmithAbstract:Abstract Sigma Receptors are nonopiate and nonphencyclidine binding sites that are thought to be neuroprotective due to modulation of N-methyl- d -aspartate (NMDA) Receptors. Sigma Receptor 1 expression has been demonstrated in numerous tissues including brain. Recently, studies using binding assays have demonstrated Sigma Receptor 1 in neural retina, however these studies did not demonstrate in which retinal cell type(s) Sigma Receptor 1 was present nor did they establish unequivocally the molecular identity of the Receptor. The present study was designed to address these issues. Reverse transcription–polymerase chain reaction (RT–PCR) analysis amplified Sigma Receptor 1 in neural retina, RPE–choroid complex, and lens isolated from mice. A similar RT–PCR product was amplified also in three cultured cell lines, rat Muller cells, rat ganglion cells and human ARPE-19 cells. In situ hybridization analysis revealed abundant Sigma Receptor 1 expression in ganglion cells, cells of the inner nuclear layer, inner segments of photoReceptor cells and retinal pigment epithelial (RPE) cells. Immunohistochemical studies detected the Sigma Receptor 1 protein in retinal ganglion, photoReceptor, RPE cells and surrounding the soma of cells in the inner nuclear layer. These data provide the first cellular localization of Sigma Receptor 1 in neural retina and establish the molecular identity of Sigma Receptor 1 in retinal cells. The demonstration that Sigma Receptor 1 is present in ganglion cells is particularly noteworthy given the well-documented susceptibility of these cells to glutamate toxicity. Our findings suggest that retinal ganglion cells may be amenable to the neuroprotective effects of Sigma ligands under conditions of neurotoxicity such as occurs in diabetes.
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cloning and structural analysis of the cdna and the gene encoding the murine type 1 Sigma Receptor
Biochemical and Biophysical Research Communications, 1997Co-Authors: Pankaj Seth, Frederick H. Leibach, Vadivel GanapathyAbstract:We have isolated a mouse cDNA which codes for a functional type 1 Sigma Receptor. The functional identity of the cDNA was established by expressing the cDNA in mammalian cells and measuring the cDNA-induced binding of haloperidol. Using this cDNA as the probe, we have isolated a murine genomic clone which contains the type 1 Sigma Receptor gene in its entirety. We have sequenced the gene completely, deduced the exon-intron organization and analyzed the promoter region sequence for transcription factor binding sites. The gene (∼7 kbp) is TATA-less but contains CCAATC and GC boxes immediately upstream of the transcription start site. The gene consists of 4 exons and 3 introns. The 5′-flanking region contains putative binding sites for AP-1, AP-2, GATA-1 and steroid Receptors.
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Cloning and functional expression of the human type 1 Sigma Receptor (hSigmaR1).
Biochemical and biophysical research communications, 1996Co-Authors: Ramesh Kekuda, Puttur D. Prasad, You Jun Fei, Frederick H. Leibach, Vadivel GanapathyAbstract:We have isolated a cDNA clone from a human placental choriocarcinoma cell (JAR) cDNA library which codes for a functional type 1 Sigma Receptor. An RT-PCR product obtained from guinea pig kidney mRNA using primers specific for the guinea pig Sigma Receptor cDNA was used to screen the cDNA library. The hSigmaR1 cDNA predicts a protein of 223 amino acids with a single putative transmembrane domain. The amino acid sequence exhibits 93% identity with the guinea pig Sigma Receptor. When functionally expressed in HeLa cells, the hSigmaR1 cDNA enhances the binding of [3H]-haloperidol, a Sigma Receptor ligand, to the HeLa cell membranes. The inhibitor specificity of the cloned hSigmaR1 indicates that it is the type 1 Sigma Receptor. Several human tissues, including placenta, liver, and brain, and several human cell lines express the SigmaR1 mRNA (1.7 kb) to a variable extent.
Kazuma Ogawa - One of the best experts on this subject based on the ideXlab platform.
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Syntheses and evaluation of a homologous series of aza-vesamicol as improved radioiodine-labeled probes for Sigma-1 Receptor imaging.
Bioorganic & medicinal chemistry, 2019Co-Authors: Kazuma Ogawa, Takashi Kozaka, Kazuhiro Shiba, Ryohei Masuda, Kenji Mishiro, Mengfei Wang, Seigo Kinuya, Akira OdaniAbstract:Abstract Sigma-1 Receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the Sigma-1 Receptor. In this study, we aimed to develop probes with higher affinity for the Sigma-1 Receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the Sigma-1 Receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The Sigma-1 Receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol ( 5 ) (K i = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5 . The radioiodine labeled probe [ 125 I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([ 125 I] 10 ) showed high accumulation in the Sigma-1 Receptor expressing DU-145 cells both in vitro and in vivo . Co-injection of [ 125 I] 10 with an excess level of a Sigma Receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo , indicating Sigma Receptor-mediated tumor uptake. These results provide useful information for developing Sigma-1 Receptor imaging probes.
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Preparation and evaluation of an astatine-211-labeled Sigma Receptor ligand for alpha radionuclide therapy
Nuclear Medicine and Biology, 2015Co-Authors: Kazuma Ogawa, Yoshiaki Mizuno, Takashi Kozaka, Atsushi Shinohara, Kouhei Washiyama, Kiyoko Shiba, Nobuaki Takahashi, Akira OdaniAbstract:Introduction: Sigma Receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide Receptor therapy. We have previously synthesized and evaluated 131I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[131I]pIV], which has a high affinity for Sigma Receptors. Therefore, (+)-[131I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[211At]pAtV, an 211At-labeled Sigma Receptor ligand, that has potential use in alpha-radionuclide Receptor therapy. Methods: The radiolabeled Sigma Receptor ligand (+)-[211At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[211At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[211At]pAtV and (+)-[125I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the Sigma Receptors, and DU-145 tumor-bearing mice. Results: The lipophilicity of (+)-[211At]pAtV was similar to that of (+)-[125I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1h post-injection were also similar between (+)-[211At]pAtV and (+)-[125I]pIV. Namely, (+)-[211At]pAtV demonstrated high uptake and retention in tumor via binding to Sigma Receptors. Conclusion: These results indicate that (+)-[211At]pAtV could function as an new agent for alpha-radionuclide Receptor therapy.
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Development and evaluation of a novel radioiodinated vesamicol analog as a Sigma Receptor imaging agent
EJNMMI research, 2012Co-Authors: Kazuma Ogawa, Takashi Kozaka, Kazuhiro Shiba, Hiroya Kanbara, Yoji Kitamura, Tatsuto Kiwada, Akira OdaniAbstract:Background Sigma Receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-p IV), with a high affinity for Sigma Receptors and prepared radioiodinated (+)-p IV. As a result, (+)-[125I]p IV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-p IV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH).
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Development and evaluation of a novel radioiodinated vesamicol analog as a Sigma Receptor imaging agent
EJNMMI Research, 2012Co-Authors: Kazuma Ogawa, Takashi Kozaka, Kazuhiro Shiba, Hiroya Kanbara, Yoji Kitamura, Tatsuto Kiwada, Akira OdaniAbstract:Background Sigma Receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)- p IV), with a high affinity for Sigma Receptors and prepared radioiodinated (+)- p IV. As a result, (+)-[^125I] p IV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)- p IV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH). Methods (+)-[^125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[^125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[^125I]IV-OH and (+)-[^131I] p IV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[^125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice. Results The hydrophilicity of (+)-[^125I]IV-OH was much higher than that of (+)-[^125I] p IV. In biodistribution experiments, (+)-[^125I]IV-OH and (+)-[^131I] p IV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[^131I] p IV tended to be retained in most tissues, (+)-[^125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[^125I]IV-OH was significantly lower at all time points compared to those of (+)-[^131I] p IV. In the blocking studies, co-injection of an excess amount of Sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[^125I]IV-OH. Conclusions The results indicate that radioiodinated (+)-IV-OH holds a potential as a Sigma Receptor imaging agent.
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evaluation of radioiodinated vesamicol analogs for Sigma Receptor imaging in tumor and radionuclide Receptor therapy
Cancer Science, 2009Co-Authors: Kazuma Ogawa, Kouhei Washiyama, Kazuhiro Shiba, Seigo Kinuya, Nasima Akhter, Mitsuyoshi Yoshimoto, Keiichi Kawai, Hirofumi MoriAbstract:It has been reported that Sigma Receptors are highly expressed in a variety of human tumors. In this study, we selected (+)-2-[4-(4-iodophenyl)piperidino] cyclohexanol [(+)-pIV] as a Sigma Receptor ligand and evaluated the potential of radioiodinated (+)-pIV for tumor imaging and therapy. (+)-[125/131I]pIV was prepared by an iododestannylation reaction under no-carrier-added conditions with radiochemical purity over 99% after HPLC purification. Biodistribution experiments were performed by the intravenous injection of (+)-[125I]pIV into mice bearing human prostate tumors (DU-145). Blocking studies were performed by intravenous injection of (+)-[125I]pIV mixed with an excess amount of unlabeled Sigma ligand into DU-145 tumor-bearing mice. For therapeutic study, (+)-[131I]pIV was injected at a dose of 7.4 MBq followed by measurement of the tumor size. In biodistribution experiments, (+)-[125I]pIV showed high uptake and long residence in the tumor. High tumor to blood and muscle ratios were achieved because the radioactivity levels of blood and muscle were low. However, the accumulations of radioactivity in non-target tissues, such as liver and kidney, were high. The radioactivity in the non-target tissues slowly decreased over time. Co-injection of (+)-[125I]pIV with an excess amount of unlabeled Sigma ligand resulted in a significant decrease in the tumor/blood ratio, indicating Sigma Receptor-mediated tumor uptake. In therapeutic study, tumor growth in mice treated with (+)-[131I]pIV was significantly inhibited compared to that of an untreated group. These results indicate that radioiodinated (+)-pIV has a high potential for Sigma Receptor imaging in tumor and radionuclide Receptor therapy. (Cancer Sci 2009)
Dennis K. Miller - One of the best experts on this subject based on the ideXlab platform.
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The Sigma Receptor agonist SA4503 both attenuates and enhances the effects of methamphetamine.
Drug and alcohol dependence, 2011Co-Authors: Kelli R. Rodvelt, Clark E. Oelrichs, Lucas R. Blount, Kuo Hsien Fan, Susan Z. Lever, John R. Lever, Dennis K. MillerAbstract:Methamphetamine's behavioral effects have been attributed to its interaction with monoamine transporters; however, methamphetamine also has affinity for Sigma Receptors. The present study investigated the effect of the Sigma Receptor agonist SA 4503 and the Sigma Receptor antagonists BD-1047 and BD-1063 on methamphetamine-evoked [(3)H]dopamine release from preloaded rat striatal slices. The effect of SA 4503 on methamphetamine-induced hyperactivity and on the discriminative stimulus properties of methamphetamine also was determined. SA 4503 attenuated methamphetamine-evoked [(3)H]dopamine release in a concentration-dependent manner. BD-1047 and BD-1063 did not affect release. SA 4503 dose-dependently potentiated and attenuated methamphetamine-induced hyperactivity. SA 4503 pretreatment augmented the stimulus properties of methamphetamine. Our findings indicate that SA 4503 both enhances and inhibits methamphetamine's effects and that Sigma Receptors are involved in the neurochemical, locomotor stimulatory and discriminative stimulus properties of methamphetamine. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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The Sigma Receptor agonist SA4503 both attenuates and enhances the effects of methamphetamine.
Drug and Alcohol Dependence, 2011Co-Authors: Kelli R. Rodvelt, Clark E. Oelrichs, Lucas R. Blount, Kuo Hsien Fan, Susan Z. Lever, John R. Lever, Dennis K. MillerAbstract:Abstract Background Methamphetamine's behavioral effects have been attributed to its interaction with monoamine transporters; however, methamphetamine also has affinity for Sigma Receptors. Method The present study investigated the effect of the Sigma Receptor agonist SA 4503 and the Sigma Receptor antagonists BD-1047 and BD-1063 on methamphetamine-evoked [ 3 H]dopamine release from preloaded rat striatal slices. The effect of SA 4503 on methamphetamine-induced hyperactivity and on the discriminative stimulus properties of methamphetamine also was determined. Results SA 4503 attenuated methamphetamine-evoked [ 3 H]dopamine release in a concentration-dependent manner. BD-1047 and BD-1063 did not affect release. SA 4503 dose-dependently potentiated and attenuated methamphetamine-induced hyperactivity. SA 4503 pretreatment augmented the stimulus properties of methamphetamine. Conclusions Our findings indicate that SA 4503 both enhances and inhibits methamphetamine's effects and that Sigma Receptors are involved in the neurochemical, locomotor stimulatory and discriminative stimulus properties of methamphetamine.
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Could Sigma Receptor ligands be a treatment for methamphetamine addiction
Current drug abuse reviews, 2010Co-Authors: Kelli R. Rodvelt, Dennis K. MillerAbstract:Methamphetamine's effects are generally considered to be mediated via monoamine transporters; however, it has comparable affinity for Sigma Receptors. Sigma Receptors influence the downstream dopamine systems that are targeted by methamphetamine treatment. Research investigating the effect of Sigma Receptor agonists on methamphetamine-associated neurochemical and behavioral properties remains controversial; however, the general trend indicates an enhancement of stimulant effects. In contrast, Sigma Receptor antagonists attenuate methamphetamine-induced neurotoxic and behavioral properties. Together, these studies highlight an important role for Sigma Receptors in methamphetamine's addictive properties and the consequences of methamphetamine intoxication. Additional research is necessary to elucidate the precise mechanisms underlying their involvement and their role as a potential target for anti-methamphetamine pharmacotherapies.
Kazuhiro Shiba - One of the best experts on this subject based on the ideXlab platform.
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Syntheses and evaluation of a homologous series of aza-vesamicol as improved radioiodine-labeled probes for Sigma-1 Receptor imaging.
Bioorganic & medicinal chemistry, 2019Co-Authors: Kazuma Ogawa, Takashi Kozaka, Kazuhiro Shiba, Ryohei Masuda, Kenji Mishiro, Mengfei Wang, Seigo Kinuya, Akira OdaniAbstract:Abstract Sigma-1 Receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the Sigma-1 Receptor. In this study, we aimed to develop probes with higher affinity for the Sigma-1 Receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the Sigma-1 Receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The Sigma-1 Receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol ( 5 ) (K i = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5 . The radioiodine labeled probe [ 125 I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([ 125 I] 10 ) showed high accumulation in the Sigma-1 Receptor expressing DU-145 cells both in vitro and in vivo . Co-injection of [ 125 I] 10 with an excess level of a Sigma Receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo , indicating Sigma Receptor-mediated tumor uptake. These results provide useful information for developing Sigma-1 Receptor imaging probes.
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Development and evaluation of a novel radioiodinated vesamicol analog as a Sigma Receptor imaging agent
EJNMMI research, 2012Co-Authors: Kazuma Ogawa, Takashi Kozaka, Kazuhiro Shiba, Hiroya Kanbara, Yoji Kitamura, Tatsuto Kiwada, Akira OdaniAbstract:Background Sigma Receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-p IV), with a high affinity for Sigma Receptors and prepared radioiodinated (+)-p IV. As a result, (+)-[125I]p IV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-p IV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH).
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Development and evaluation of a novel radioiodinated vesamicol analog as a Sigma Receptor imaging agent
EJNMMI Research, 2012Co-Authors: Kazuma Ogawa, Takashi Kozaka, Kazuhiro Shiba, Hiroya Kanbara, Yoji Kitamura, Tatsuto Kiwada, Akira OdaniAbstract:Background Sigma Receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)- p IV), with a high affinity for Sigma Receptors and prepared radioiodinated (+)- p IV. As a result, (+)-[^125I] p IV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)- p IV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH). Methods (+)-[^125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[^125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[^125I]IV-OH and (+)-[^131I] p IV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[^125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice. Results The hydrophilicity of (+)-[^125I]IV-OH was much higher than that of (+)-[^125I] p IV. In biodistribution experiments, (+)-[^125I]IV-OH and (+)-[^131I] p IV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[^131I] p IV tended to be retained in most tissues, (+)-[^125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[^125I]IV-OH was significantly lower at all time points compared to those of (+)-[^131I] p IV. In the blocking studies, co-injection of an excess amount of Sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[^125I]IV-OH. Conclusions The results indicate that radioiodinated (+)-IV-OH holds a potential as a Sigma Receptor imaging agent.
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evaluation of radioiodinated vesamicol analogs for Sigma Receptor imaging in tumor and radionuclide Receptor therapy
Cancer Science, 2009Co-Authors: Kazuma Ogawa, Kouhei Washiyama, Kazuhiro Shiba, Seigo Kinuya, Nasima Akhter, Mitsuyoshi Yoshimoto, Keiichi Kawai, Hirofumi MoriAbstract:It has been reported that Sigma Receptors are highly expressed in a variety of human tumors. In this study, we selected (+)-2-[4-(4-iodophenyl)piperidino] cyclohexanol [(+)-pIV] as a Sigma Receptor ligand and evaluated the potential of radioiodinated (+)-pIV for tumor imaging and therapy. (+)-[125/131I]pIV was prepared by an iododestannylation reaction under no-carrier-added conditions with radiochemical purity over 99% after HPLC purification. Biodistribution experiments were performed by the intravenous injection of (+)-[125I]pIV into mice bearing human prostate tumors (DU-145). Blocking studies were performed by intravenous injection of (+)-[125I]pIV mixed with an excess amount of unlabeled Sigma ligand into DU-145 tumor-bearing mice. For therapeutic study, (+)-[131I]pIV was injected at a dose of 7.4 MBq followed by measurement of the tumor size. In biodistribution experiments, (+)-[125I]pIV showed high uptake and long residence in the tumor. High tumor to blood and muscle ratios were achieved because the radioactivity levels of blood and muscle were low. However, the accumulations of radioactivity in non-target tissues, such as liver and kidney, were high. The radioactivity in the non-target tissues slowly decreased over time. Co-injection of (+)-[125I]pIV with an excess amount of unlabeled Sigma ligand resulted in a significant decrease in the tumor/blood ratio, indicating Sigma Receptor-mediated tumor uptake. In therapeutic study, tumor growth in mice treated with (+)-[131I]pIV was significantly inhibited compared to that of an untreated group. These results indicate that radioiodinated (+)-pIV has a high potential for Sigma Receptor imaging in tumor and radionuclide Receptor therapy. (Cancer Sci 2009)
