title: Neurokinin-3 Receptor Binding in Guinea Pig, Monkey, and Human Brain: In Vitro and in Vivo Imaging Using the Novel Radioligand, [18F]Lu AF10628.
abstract: Previous autoradiography studies have suggested a marked interspecies variation in the neuroanatomical localization and expression levels of the neurokinin 3 receptor, with high density in the brain of rat, gerbil, and guinea pig, but at the time offered no conclusive evidence for its presence in the human brain. Hitherto available radioligands have displayed low affinity for the human neurokinin 3 receptor relative to the rodent homologue and may thus not be optimal for cross-species analyses of the expression of this protein.
  
  
  
  A novel neurokinin 3 receptor radioligand, [(18)F]Lu AF10628 ((S)-N-(cyclobutyl(3-fluorophenyl)methyl)-8-fluoro-2-((3-[(18)F]-fluoropropyl)amino)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide), was synthesized and used for autoradiography studies in cryosections from guinea pig, monkey, and human brain as well as for positron emission tomography studies in guinea pig and monkey.
  
  
  
  The results confirmed previous observations of interspecies variation in the neurokinin 3 receptor brain localization with more extensive distribution in guinea pig than in primate brain. In the human brain, specific binding to the neurokinin 3 receptor was highest in the amygdala and in the hypothalamus and very low in other regions examined. Positron emission tomography imaging showed a pattern consistent with that observed using autoradiography. The radioactivity was, however, found to accumulate in skull bone, which limits the use of this radioligand for in vivo quantification of neurokinin 3 receptor binding.
  
  
  
  Species differences in the brain distribution of neurokinin 3 receptors should be considered when using animal models for predicting human neurokinin 3 receptor pharmacology. For positron emission tomography imaging of brain neurokinin 3 receptors, additional work is required to develop a radioligand with more favorable in vivo properties.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.). katarina.varnas@ki.se.
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Marie
authors.initials: M
authors.lastname: Svedberg
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Søren
authors.initials: S
authors.lastname: Møller Nielsen
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Nikolay A
authors.initials: NA
authors.lastname: Khanzhin
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Karsten
authors.initials: K
authors.lastname: Juhl
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden (Drs Varnäs, Finnema, Stepanov, Takano, Tóth, Svedberg, Halldin, and Farde); Lundbeck Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark (Drs Møller Nielsen, Khanzhin, Juhl, and Bang-Andersen); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm, Sweden (Dr Farde).Present address: Glycom A/S, Diplomvej 373, 1, DK-2800 Kgs. Lyngby, Denmark (N.A.K.).
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000818:Animals; D001345:Autoradiography; D001842:Bone and Bones / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D008252:Macaca fascicularis; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D018042:Receptors, Neurokinin-3 / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D018042:Receptors, Neurokinin-3
keywords: NK3 receptor; autoradiography; positron emission tomography; tachykinin receptor