Journal ArticleDOI
Synthesis and evaluation of novel radioligands for positron emission tomography imaging of the orexin-2 receptor.
Norihito Oi,Norihito Oi,Norihito Oi,Michiyuki Suzuki,Michiyuki Suzuki,Taro Terauchi,Masaki Tokunaga,Yosuke Nakatani,Yosuke Nakatani,Yosuke Nakatani,Noboru Yamamoto,Toshimitsu Fukumura,Ming-Rong Zhang,Tetsuya Suhara,Tetsuya Suhara,Makoto Higuchi,Makoto Higuchi +16 more
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TLDR
The design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridIn-2-yl)-2-(3- fluorophenyl)cyclopropanecarboxamide) applicable to positron emission tomography (PET) imaging are described.Abstract:
Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling, and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [11C]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX2Rs). In vivo PET study of [11C]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and ...read more
Citations
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Journal ArticleDOI
Recent trends in orexin research—2010 to 2015
Christoph Boss,Catherine Roch +1 more
TL;DR: The Orexin system, consisting of the two orexin-neuropeptides and two G-protein-coupled receptors, is as well involved in reward and addictive behaviors.
Journal ArticleDOI
Recent progress in [11C]carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]CO) chemistry
Carlotta Taddei,Antony D. Gee +1 more
TL;DR: Novel approaches to generate [11C]CO using CO‐releasing molecules (CO‐RMs), such as silacarboxylic acids and disilanes, applied to radiochemistry are described and compared with standard [11 C]CO production methods.
Journal ArticleDOI
Synthesis of [11C]MK-1064 as a new PET radioligand for imaging of orexin-2 receptor
TL;DR: The reference standard MK-1064 was synthesized from methyl 2-chloro-5-iodonicotinate and 5-(chloropyridin-3-yl)boronic acid in 4 steps with 33% overall chemical yield and the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-555GBq/μmol.
Journal ArticleDOI
Development of Novel PET Probes for Central 2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid Receptors.
Norihito Oi,Norihito Oi,Masaki Tokunaga,Michiyuki Suzuki,Michiyuki Suzuki,Yuji Nagai,Yosuke Nakatani,Yosuke Nakatani,Noboru Yamamoto,Jun Maeda,Takafumi Minamimoto,Ming-Rong Zhang,Tetsuya Suhara,Makoto Higuchi +13 more
TL;DR: The current approach has facilitated the discovery of a PET probe potentially suitable for translational research and development focused on AMPA receptors that was shown by autoradiography to specifically bind to the neocortex and hippocampus, consistent with AMPA receptor localization.
Patent
Substituted 2-azabicycles and their use as orexin receptor modulators
Coate Heather R,Curt A. Dvorak,Anne E. Fitzgerald,Lebold Terry Patrick,Cathy Preville,Brock T. Shireman +5 more
TL;DR: In this article, the present invention is directed to compounds of Formula (I): Methods of making the compounds of formula I are also described, and the invention also relates to pharmaceutical compositions comprising compounds of the formula (I).
References
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Journal ArticleDOI
Genetic Ablation of Orexin Neurons in Mice Results in Narcolepsy, Hypophagia, and Obesity
Junko Hara,Carsten T. Beuckmann,Tadahiro Nambu,Jon T. Willie,Richard M. Chemelli,Christopher M. Sinton,Fumihiro Sugiyama,Ken-ichi Yagami,Katsutoshi Goto,Masashi Yanagisawa,Takeshi Sakurai +10 more
TL;DR: Evidence is provided that orexin-containing neurons play important roles in regulating vigilance states and energy homeostasis and the pathophysiology and treatment of narcolepsy.
Journal ArticleDOI
A role for lateral hypothalamic orexin neurons in reward seeking
TL;DR: It is shown that activation of lateral hypothalamus orexin neurons is strongly linked to preferences for cues associated with drug and food reward and reinstates an extinguished drug-seeking behaviour.
Journal ArticleDOI
Distribution of orexin neurons in the adult rat brain.
Tadahiro Nambu,Takeshi Sakurai,Katsuyoshi Mizukami,Yasuhiko Hosoya,Masashi Yanagisawa,Katsutoshi Goto +5 more
TL;DR: A further study of the distribution of ORX-containing neurons in the adult rat brain to provide a general overview of the ORX neuronal system was conducted in this article. But, the results were limited to the lateral hypothalamic area (LHA) and dorsomedial hypothalamic nucleus (DMH), the regions classically implicated in feeding behavior.
Journal ArticleDOI
Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems
Yukari Date,Yoichi Ueta,Hiroshi Yamashita,Hideki Yamaguchi,Shigeru Matsukura,Kenji Kangawa,Takeshi Sakurai,Masashi Yanagisawa,Masamitsu Nakazato +8 more
TL;DR: The unique neuronal distribution of orexins and their functional activation of neural circuits suggest specific complex roles of the peptides in autonomic and neuroendocrine control.
Journal ArticleDOI
The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.
Emmanuel Mignot,Gert Jan Lammers,Beth Ripley,Michele L. Okun,Sonia Nevsimalova,Sebastiaan Overeem,Jitka Vankova,Jed Black,John R. Harsh,Claudio L. Bassetti,Harald Schrader,Seiji Nishino +11 more
TL;DR: Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context, in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).
Related Papers (5)
Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior
Takeshi Sakurai,Akira Amemiya,Makoto Ishii,Ichiyo Matsuzaki,Richard M. Chemelli,Hirokazu Tanaka,S. Clay Williams,James A. Richardson,Gerald P. Kozlowski,Shelagh Wilson,Jonathan R.S. Arch,Robin E. Buckingham,Andrea C. Haynes,Steven A. Carr,Roland S. Annan,Dean E. McNulty,Wu Schyong Liu,Jonathan A. Terrett,Nabil Elshourbagy,Derk J. Bergsma,Masashi Yanagisawa +20 more