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      Radiosynthesis of [ 11C]SNAP-7941—the first PET-tracer for the melanin concentrating hormone receptor 1 (MCHR1)

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          Abstract

          The melanin concentrating hormone (MCH) system is a new target to treat human disorders. Our aim was the preparation of the first PET-tracer for the MCHR1. [ 11C]SNAP-7941 is a carbon-11 labeled analog of the published MCHR1 antagonist SNAP-7941. The optimum reaction conditions were 2 min reaction time, ≤25 °C reaction temperature, and 2 mg/mL precursor (SNAP-acid) in acetonitrile, using [ 11C]CH 3OTf as methylation agent. [ 11C]SNAP-7941 was prepared in a reliable and feasible manner with high radiochemical yields (2.9±1.6 GBq; 11.5±6.4% EOB, n=15).

          Abstract

          Graphical Abstract

          Radiosynthesis of [ 11C]SNAP-7941.

          Highlights

          ► Synthesis of the first PET-tracer for the MCHR1 [ 11C]SNAP-7941. ► High radiochemical incorporation yields 2.9±1.6 GBq; 11.5±6.4% EOB. ► Preparation and characterization of a suitable labeling precursor; SNAP-acid.

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          Most cited references20

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          The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization.

          In addition to a nonadecapeptide homologous to the teleost melanin-concentrating hormone (MCH), the amino acid sequence predicted from a rat prepro-MCH (ppMCH) cDNA suggested that at least one (neuropeptide EI, or NEI), and possibly a second (NGE), additional neuropeptide may be encoded by this precursor. Cross-reactivity with epitopes of NEI or NGE can account for reported localization of alpha-MSH, rat CRF, and human GRF in rat dorsolateral hypothalamic neurons. We have used antisera raised against rat MCH and NEI in immunohistochemical studies at the light and electron microscopic levels, along with hybridization histochemical localization of ppMCH mRNA, to define the organization of this system. As expected, ppMCH mRNA is prominently expressed in cells in the lateral hypothalamic area and zona incerta. The MCH and NEI peptides were extensively colocalized in neurons in both of these areas. In addition, smaller cell groups in the olfactory tubercle and pontine tegmentum were also positively hybridized for ppMCH mRNA and immunostained for MCH and NEI. Fibers stained for MCH and NEI were similarly, and very broadly, distributed throughout the central nervous system in patterns that generally conformed with known projection fields of the lateral hypothalamic area and zona incerta. A differential distribution was seen in at least one region, the interanterodorsal nucleus of the thalamus, which contained a prominent terminal field stained for MCH but not NEI. At the electron microscopic level, MCH-stained perikarya displayed a prominent staining associated with the Golgi apparatus; this was not encountered in NEI-stained cells. Both peptides were distributed similarly in terminals in the lateral hypothalamic area and median eminence, with staining associated principally with dense-cored vesicles. The results suggest that ppMCH-derived peptides may serve as neurotransmitters or modulators of prominence in a surprisingly expansive projection field of incerto-hypothalamic neurons. The terminal distributions of this system seem most compatible with functional roles in generalized arousal and sensorimotor integration, processes previously implicated as being subject to modulation by the lateral hypothalamic area.
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            Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism.

            Melanin-concentrating hormone (MCH) is a cyclic 19-aa hypothalamic neuropeptide derived from a larger prohormone precursor of MCH (Pmch), which also encodes neuropeptide EI (NEI) and neuropeptide GE (NGE). Pmch-deficient (Pmch-/-) mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice overexpressing Pmch are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis. The MCH 1 receptor (MCH1R) is one of two recently identified G protein-coupled receptors believed to be responsible for the actions of MCH. We evaluated the physiological role of MCH1R by generating MCH1R-deficient (Mch1r-/-) mice. Mch1r-/- mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly, Mch1r-/- mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, Mch1r-/- mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in Mch1r-/- mice. We conclude that MCH1R is a physiologically relevant MCH receptor in mice that plays a role in energy homeostasis through multiple actions on locomotor activity, metabolism, appetite, and neuroendocrine function.
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              Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist.

              Melanin concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide, which plays an important role in the complex regulation of energy balance and body weight. Here we show that SNAP-7941, a selective, high-affinity MCH1 receptor (MCH1-R) antagonist, inhibited food intake stimulated by central administration of MCH, reduced consumption of palatable food, and, after chronic administration to rats with diet-induced obesity, resulted in a marked, sustained decrease in body weight. In addition, after mapping the binding sites for [(3)H]SNAP-7941 in rat brain, we evaluated its effects in a series of behavioral models. SNAP-7941 produced effects similar to clinically used antidepressants and anxiolytics in three animal models of depression/anxiety: the rat forced-swim test, rat social interaction and guinea pig maternal-separation vocalization tests. Given these observations, an MCH1-R antagonist may be useful not only in the management of obesity but also as a treatment for depression and/or anxiety.
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                Author and article information

                Journal
                Appl Radiat Isot
                Appl Radiat Isot
                Applied Radiation and Isotopes
                Pergamon Press
                0969-8043
                1872-9800
                October 2012
                October 2012
                : 70
                : 10
                : 2287-2294
                Affiliations
                [a ]Radiochemistry and Biomarker Development Unit, Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria
                [b ]Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Austria
                [c ]Department of Drug and Natural Product Synthesis, University of Vienna, Austria
                [d ]Hospital Pharmacy of the General Hospital of Vienna, Austria
                [e ]Department of Psychiatry and Psychotherapy, Medical University of Vienna, 1090 Vienna, Austria
                [f ]Department of Inorganic Chemistry, University of Vienna, Austria
                Author notes
                [* ]Corresponding author at: Medical University of Vienna, Department of Nuclear Medicine, Radiochemistry and Biomarker Development Unit, Waehringer Guertel 18–20, A-1090 Vienna, Austria. Tel.: +43 1 40400 5255; fax: +43 1 40400 1559. wolfgang.wadsak@ 123456meduniwien.ac.at
                Article
                ARI5948
                10.1016/j.apradiso.2012.07.010
                3439630
                22858577
                68a68270-e063-46e9-84c7-1f1defee45fe
                © 2012 Elsevier Ltd.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 14 May 2012
                : 5 July 2012
                : 10 July 2012
                Categories
                Article

                Nuclear chemistry
                radioligand,pet,carbon-11,snap-7941,mchr1
                Nuclear chemistry
                radioligand, pet, carbon-11, snap-7941, mchr1

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