title: Discovery and Preclinical Validation of [(11)C]AZ13153556, a Novel Probe for the Histamine Type 3 Receptor.
abstract: The histamine type 3 receptor (H3) is a G protein-coupled receptor implicated in several disorders of the central nervous system. Herein, we describe the radiolabeling and preclinical evaluation of a candidate radioligand for the H3 receptor, 4-(1S,2S)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl]-N-methyl-benzamide (5), and its comparison with one of the frontrunner radioligands for H3 imaging, namely, GSK189254 (1). Compounds 1 and 5 were radiolabeled with tritium and carbon-11 for in vitro and in vivo imaging experiments. The in vitro binding of [(3)H]1 and [(3)H]5 was examined by (i) saturation binding to rat and nonhuman primate brain tissue homogenate and (ii) in vitro autoradiography on tissue sections from rat, guinea pig, and human brain. The in vivo binding of [(11)C]1 and [(11)C]5 was examined by PET imaging in mice and nonhuman primates. Bmax values obtained from Scatchard analysis of [(3)H]1 and [(3)H]5 binding were in good agreement. Autoradiography with [(3)H]5 on rat, guinea pig, and human brain slices showed specific binding in regions known to be enhanced in H3 receptors, a high degree of colocalization with [(3)H]1, and virtually negligible nonspecific binding in tissue. PET measurements in mice and nonhuman primates demonstrated that [(11)C]5 binds specifically and reversibly to H3 receptors in vivo with low nonspecific binding in brain tissue. Whereas [(11)C]1 showed similar binding characteristics in vivo, the binding kinetics appeared faster for [(11)C]5 than for [(11)C]1.
  
  
  CONCLUSIONS
  [(11)C]5 has suitable properties for quantification of H3 receptors in nonhuman primate brain and has the potential to offer improved binding kinetics in man compared to [(11)C]1.
authors.affiliation: AstraZeneca Translational Science Centre at Karolinska Institutet, PET Centre of Excellence, Department of Clinical Neuroscience, S-17176 Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Schou
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet , S-17176 Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.affiliation: AstraZeneca, Research & Development, Innovative Medicines, S-151 85 Södertälje, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Jureus
authors.affiliation: AstraZeneca, Research & Development, Innovative Medicines, S-151 85 Södertälje, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ahlgren
authors.affiliation: AstraZeneca, Research & Development, Innovative Medicines, S-151 85 Södertälje, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Malmquist
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet , S-17176 Stockholm, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Häggkvist
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet , S-17176 Stockholm, Sweden.
authors.forename: Lenke
authors.initials: L
authors.lastname: Tari
authors.affiliation: AstraZeneca, Research & Development, Innovative Medicines, Cambridge, Massachusetts 02451, United States.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Wesolowski
authors.affiliation: AstraZeneca, Research & Development, Innovative Medicines, Waltham, Massachusetts 02139, United States.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Throner
authors.affiliation: AstraZeneca, Research & Development, Innovative Medicines, Waltham, Massachusetts 02139, United States.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Brown
authors.affiliation: AstraZeneca, Research & Development, Innovative Medicines, S-151 85 Södertälje, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Nilsson
authors.affiliation: AstraZeneca Translational Science Centre at Karolinska Institutet, PET Centre of Excellence, Department of Clinical Neuroscience, S-17176 Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Johnström
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet , S-17176 Stockholm, Sweden.
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet , S-17176 Stockholm, Sweden.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet , S-17176 Stockholm, Sweden.
authors.forename: Nahid
authors.initials: N
authors.lastname: Amini
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet , S-17176 Stockholm, Sweden.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.affiliation: AstraZeneca Translational Science Centre at Karolinska Institutet, PET Centre of Excellence, Department of Clinical Neuroscience, S-17176 Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D000882:Haplorhini; D018494:Histamine Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D015203:Reproducibility of Results; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C000612083:4-(1S,2S)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)-N-methyl-benzamide; D001549:Benzamides; D001552:Benzazepines; D002250:Carbon Radioisotopes; D018494:Histamine Agents; D010879:Piperazines; D018100:Receptors, Histamine H3; D014316:Tritium; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide
keywords: PET; carbon-11; histamine; imaging; radioligand; receptor