Hideyuki Igawa 1 , Vladimir Stepanov 2 , Lenke Tari 2 , Shoki Okuda 3 , Syunsuke Yamamoto 3 , Shizuo Kasai 3 , Yasutaka Nagisa 4 , Jenny Haggkvist 2 , Marie Svedberg 2 , Miklos Toth 2 , Akihiro Takano 2 , Christer Halldin 2 Show Affiliations »
Abstract
BACKGROUND AND OBJECTIVE: Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents and many drug discovery programs have been dedicated to identify smallmolecule antagonists of melanin-concentrating hormone receptor 1 (MCHR1). The aim of this study was to develop a positron emission tomography (PET) tracer for MCHR1 for translation of preclinical pharmacology to clinic to enhance success rate of drug discovery programs. METHODS: We identified 4-(cyclopropylmethoxy)-N-[8-methyl-3-({[(1-methyl-1H-pyrrol-2-yl)methyl] amino}ethyl)quinolin-7-yl]benzamide (Compound II) from Takeda MCHR1 antagonist library by utilizing binding affinity, log D value, physicochemical parameters ideal for a central nerve system agent, and synthetic feasibility of corresponding carbon-11 labeled radioligands as selection parameters for tracer candidates. RESULTS: In the rat PET study, [11C] Compound II showed clear uptake in the caudate/putamen with the pretreatment of cyclosporine A and its uptake was higher than that in the cerebellum where expression of MCHR1 was reported to be low. CONCLUSION: In summary, [11C]Compound II is a promising lead compound for developing a suitable MCHR1 PET radioligand. [11C]Compound II, in combination with cyclosporine A, could be used as a research tool to visualize and quantify MCHR1 in rodents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
BACKGROUND AND OBJECTIVE: Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents and many drug discovery programs have been dedicated to identify smallmolecule antagonists of melanin-concentrating hormone receptor 1 (MCHR1 ). The aim of this study was to develop a positron emission tomography (PET) tracer for MCHR1 for translation of preclinical pharmacology to clinic to enhance success rate of drug discovery programs. METHODS: We identified 4-(cyclopropylmethoxy)-N-[8-methyl-3-({[(1-methyl-1H-pyrrol-2-yl)methyl] amino}ethyl)quinolin-7-yl]benzamide (Compound II) from Takeda MCHR1 antagonist library by utilizing binding affinity, log D value, physicochemical parameters ideal for a central nerve system agent, and synthetic feasibility of corresponding carbon-11 labeled radioligands as selection parameters for tracer candidates. RESULTS: In the rat PET study, [11C ] Compound II showed clear uptake in the caudate/putamen with the pretreatment of cyclosporine A and its uptake was higher than that in the cerebellum where expression of MCHR1 was reported to be low. CONCLUSION: In summary, [11C ]Compound II is a promising lead compound for developing a suitable MCHR1 PET radioligand. [11C ]Compound II, in combination with cyclosporine A , could be used as a research tool to visualize and quantify MCHR1 in rodents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Entities: Chemical
Gene
Species
Keywords:
Carbon-11; MCHR1; PET radioligand; brain imaging; cyclosporine A; positron emission tomography (PET)
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Year: 2017
PMID： 28034352 DOI： 10.2174/1874471009666161230113630
Source DB: PubMed Journal: Curr Radiopharm ISSN： 1874-4710