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
Role of orexin/hypocretin in dependence and addiction.
TL;DR: It is posited that orexin functioning contributes to both drug reward and drug-related stress/aversive responsiveness; however, diverse anatomical substrates, and perhaps receptor specificity, contribute differentially to reward and stress components.
Journal ArticleDOI
Computer-controlled large scale production of high specific activity [11C]RO 15-1788 for PET studies of benzodiazepine receptors
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Journal ArticleDOI
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Journal ArticleDOI
Selective expression of Narp, a secreted neuronal pentraxin, in orexin neurons.
TL;DR: It is demonstrated that orexin neurons display robust expression of neuronal activity‐regulated pentraxin (Narp), a secreted neuronal pentraxIn, implicated in regulating clustering of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA) receptors, and found that hypothalamic melanin‐concentrating hormone (MCH) neurons, which form a peptidergic pathway thought to oppose the effects of the
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