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      Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent

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          Abstract

          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 ((+)- pIV), with a high affinity for sigma receptors and prepared radioiodinated (+)- pIV. As a result, (+)-[ 125I] pIV 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 (+)- pIV 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] pIV 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] pIV. In biodistribution experiments, (+)-[ 125I]IV-OH and (+)-[ 131I] pIV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[ 131I] pIV 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] pIV. 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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          Most cited references32

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          Purification, molecular cloning, and expression of the mammalian sigma1-binding site.

          Sigma-ligands comprise several chemically unrelated drugs such as haloperidol, pentazocine, and ditolylguanidine, which bind to a family of low molecular mass proteins in the endoplasmic reticulum. These so-called sigma-receptors are believed to mediate various pharmacological effects of sigma-ligands by as yet unknown mechanisms. Based on their opposite enantioselectivity for benzomorphans and different molecular masses, two subtypes are differentiated. We purified the sigma1-binding site as a single 30-kDa protein from guinea pig liver employing the benzomorphan(+)[3H]pentazocine and the arylazide (-)[3H]azidopamil as specific probes. The purified (+)[3H]pentazocine-binding protein retained its high affinity for haloperidol, pentazocine, and ditolylguanidine. Partial amino acid sequence obtained after trypsinolysis revealed no homology to known proteins. Radiation inactivation of the pentazocine-labeled sigma1-binding site yielded a molecular mass of 24 +/- 2 kDa. The corresponding cDNA was cloned using degenerate oligonucleotides and cDNA library screening. Its open reading frame encoded a 25.3-kDa protein with at least one putative transmembrane segment. The protein expressed in yeast cells transformed with the cDNA showed the pharmacological characteristics of the brain and liver sigma1-binding site. The deduced amino acid sequence was structurally unrelated to known mammalian proteins but it shared homology with fungal proteins involved in sterol synthesis. Northern blots showed high densities of the sigma1-binding site mRNA in sterol-producing tissues. This is also in agreement with the known ability of sigma1-binding sites to interact with steroids, such as progesterone.
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            The pharmacology of sigma-1 receptors.

            Originally considered an enigmatic protein, the sigma-1 receptor has recently been identified as a unique ligand-regulated molecular chaperone in the endoplasmic reticulum of cells. This discovery causes us to look back at the many proposed roles of this receptor, even before its molecular function was identified, in many diseases such as methamphetamine or cocaine addiction, amnesia, pain, depression, Alzheimer's disease, stroke, retinal neuroprotection, HIV infection, and cancer. In this review, we examine the reports that have clearly shown an agonist-antagonist relationship regarding sigma-1 receptors in models of those diseases and also review the relatively known mechanisms of action of sigma-1 receptors in an attempt to spur the speculation of readers on how the sigma-1 receptor at the endoplasmic reticulum might relate to so many diseases. We found that the most prominent action of sigma-1 receptors in biological systems including cell lines, primary cultures, and animals is the regulation and modulation of voltage-regulated and ligand-gated ion channels, including Ca(2+)-, K(+)-, Na(+), Cl(-), and SK channels, and NMDA and IP3 receptors. We found that the final output of the action of sigma-1 receptor agonists is to inhibit all above-mentioned voltage-gated ion channels, while they potentiate ligand-gated channels. The inhibition or potentiation induced by agonists is blocked by sigma-1 receptor antagonists. Other mechanisms of action of sigma-1 receptors, and to some extent those of sigma-2 receptors, were also considered. We conclude that the sigma-1 and sigma-2 receptors represent potential fruitful targets for therapeutic developments in combating many human diseases.
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              The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog.

              Three different syndromes produced by congeners of morphine have been identified in the nondependent chronic spinal dog. These syndromes have been attributed to interaction of agonists with three distinguishable receptors (mu, kappa and sigma). Morphine is the prototype agonist for the mu receptor, ketocyclazocine for the kappa receptor and SKF-10,047 for the sigma receptor. The morphine syndrome (mu) in the dog is characterized by miosis, bradycardia, hypothermia, a general depression of the nociceptive responses and indifference to environmental stimuli. Ketocyclazocine (kappa) constricts pupils, depresses the flexor reflex and produces sedation but does not markedly alter pulse rate or the skin twitch reflex. SKF-10,047 (sigma), in contrast to morphine and ketocyclazocine, causes mydriasis, tachypnea, tachycardia and mania. The effects of these three drugs can be antagonized by the pure antagonist naltrexone, indicating that they are agonists. Further, chronic administration of morphine, ketocyclazocine and SKF-10,047 induces tolerance to their agonistic effects. Morphine suppresses abstinence in morphine-dependent dogs while ketocyclazocine does not. Ketocyclazocine at best precipitated only a liminal abstinence syndrome in the morphine-dependent dog, indicating that it had little affinity for the morphine receptor. Ketocyclazocine thus appears to be a selective agonist at the kappa receptor. Further, it has been shown that buprenorphine is a partial agonist of the mu type which both suppressed and precipitated abstinence in the morphine-dependent dog while morphine and propoxyphene are stronger agonists. Apomorphine and SKF-10,047 produce similar pharmacologic effects suggesting that sigma activity may involve a dopaminergic mechanism.
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                Author and article information

                Journal
                EJNMMI Res
                EJNMMI Res
                EJNMMI Research
                Springer
                2191-219X
                2012
                28 September 2012
                : 2
                : 54
                Affiliations
                [1 ]Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
                [2 ]Advanced Science Research Center, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
                Article
                2191-219X-2-54
                10.1186/2191-219X-2-54
                3524758
                23021206
                9d2a9bff-9812-4f73-81e8-4010e2365a51
                Copyright ©2012 Ogawa et al.; licensee Springer.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 June 2012
                : 14 August 2012
                Categories
                Original Research

                Radiology & Imaging
                cancer,sigma receptor,imaging
                Radiology & Imaging
                cancer, sigma receptor, imaging

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