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
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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
Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus.
TL;DR: The presence of leptin receptor‐and STAT3‐immunoreactivities in hypocretin/orexin‐containing neurones of the lateral hypothalamus suggests that leptin may directly regulate these hypothalamic neurones, most likely via an inhibitory action on hypocretIn/oreXin expression and/or secretion resulting in reduced food intake.
Journal ArticleDOI
Orexins and orexin receptors: implication in feeding behavior.
TL;DR: The innervation of orexin neurons by peptidergic fibers corresponding to leptin-responsive cell types that reside in the arcuate nucleus may have a role in linking peripheral metabolic cues to autonomic regulatory sites and the cerebral cortical mantle, providing a neuroanatomic basis for regulation of feeding behavior.
Journal ArticleDOI
Structure and Function of Human Prepro-orexin Gene *
Takeshi Sakurai,Takashi Moriguchi,Keiko Furuya,Noriko Kajiwara,Toshiaki Nakamura,Masashi Yanagisawa,Katsutoshi Goto +6 more
TL;DR: It is suggested that this genomic fragment contains all the necessary elements for appropriate expression of the gene and will be useful for the targeted expression ofThe exogenous gene in orexin-containing neurons in transgenic mice.
Journal ArticleDOI
Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein.
TL;DR: The extent of ATP-hydrolysis in vitro may also be a useful parameter for in vivo prediction, particularly for eliminating P-gp substrates in high-throughput screening procedures.
Journal ArticleDOI
Difference in obesity phenotype between orexin-knockout mice and orexin neuron-deficient mice with same genetic background and environmental conditions
TL;DR: It is reported that the development of obesity in orexin neuron-ablated narcoleptic mice is critically dependent on their genetic background and environmental factors, and the phenotype is different from that of prepro-orexin knockout mice, suggesting that factors that co-localize in Orexin neurons might have important roles in the regulation of energy homeostasis.
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