title: Development of a Novel Carbon-11 Labeled PET Radioligand for Melanin- Concentrating Hormone Receptor 1.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2- Chome, Fujisawa, Kanagawa 251-8555. Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Igawa
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm. Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm. Sweden.
authors.forename: Lenke
authors.initials: L
authors.lastname: Tari
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555. Japan.
authors.forename: Shoki
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555. Japan.
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555. Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Kasai
authors.affiliation: CVM Marketing Japan Pharma Business Unit, Takeda Pharmaceutical Co., Ltd. 12-10, Nihonbashi 2-Chome, Chuo-ku, Tokyo 103-8686. Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Nagisa
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm. Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Haggkvist
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm. Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Svedberg
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm. Sweden.
authors.forename: Miklos
authors.initials: M
authors.lastname: Toth
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm. Sweden.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm. Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D016572:Cyclosporine / Q000494:pharmacology; D015195:Drug Design; D055808:Drug Discovery; D007028:Hypothalamic Hormones / Q000037:antagonists & inhibitors*; D008024:Ligands; D008543:Melanins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010907:Pituitary Hormones / Q000037:antagonists & inhibitors*; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017481:Receptors, Somatostatin
chemical_list: C000592627:4-(cyclopropylmethoxy)-N-(8-methyl-3-(1-(pyrrolidin-1-yl)ethyl)quinolin-7-yl)benzamide; D019440:Anti-Obesity Agents; D001549:Benzamides; D002250:Carbon Radioisotopes; C000615233:Carbon-11; D007028:Hypothalamic Hormones; D008024:Ligands; C491208:MCHR1 protein, rat; D008543:Melanins; D010907:Pituitary Hormones; D011804:Quinolines; D017481:Receptors, Somatostatin; C019463:melanin-concentrating hormone; D016572:Cyclosporine
keywords: Carbon-11; MCHR1; PET radioligand; brain imaging; cyclosporine A; positron emission tomography (PET)