title: Effects of a novel mGlu₂/₃ receptor agonist prodrug, LY2140023 monohydrate, on central monoamine turnover as determined in human and rat cerebrospinal fluid.
abstract: BACKGROUND
  Accumulating evidence suggests that the primary symptoms of schizophrenia may be associated with altered central glutamate transmission. LY2140023 monohydrate is the methionine prodrug of the selective mGlu(2/3) receptor agonist LY404039 and is currently being assessed for the treatment of schizophrenia.
  
  
  OBJECTIVE
  The objective of this study was to evaluate the central pharmacological activity of LY2140023 monohydrate in preclinical and clinical studies.
  
  
  METHODS
  Effects on neurotransmitter/metabolite concentrations were assessed in male rats following single oral doses of LY2140023 monohydrate (microdiasylates from the prefrontal cortex), single intraperitoneal injection of LY404039 [cerebrospinal fluid (CSF)], or LY2140023 monohydrate dosed once daily for 7 days (CSF). A clinical study in 16 healthy subjects assessed the effects of LY2140023 monohydrate 40 mg orally twice daily for 14 days in lumbar CSF.
  
  
  RESULTS
  Rat studies: Acute dosing with LY2140023 monohydrate resulted in significant dose-dependent increases in extracellular concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), but not 5-hydroxyindoleacetic acid (5-HIAA), in the prefrontal cortex. LY2140023 monohydrate dosing for 7 days elevated the concentrations of HVA in CSF, while acutely dosed LY404039 increased the concentrations of DOPAC, HVA, and methoxy-hydroxyphenylglycol (MHPG), but not 5-HIAA. Clinical study: Significant increases were seen for DOPAC, HVA, 5-HIAA, and MHPG in the CSF of subjects receiving LY2140023 monohydrate, but not placebo.
  
  
  CONCLUSIONS
  LY2140023 monohydrate and/or LY404039 dosing potently affected dopamine turnover and also significantly affected serotonin turnover in the human and rat central nervous systems. The measurement of biogenic amine metabolites such as DOPAC and HVA may serve as useful biomarkers of LY2140023 monohydrate and/or LY404039 central pharmacodynamic activity.
authors.affiliation: Lilly-NUS Centre for Clinical Pharmacology, Level 6 Clinical Research Centre (MD 11), National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore. lowe_stephen@lilly.com
authors.forename: Stephen
authors.initials: S
authors.lastname: Lowe
authors.forename: Robert
authors.initials: R
authors.lastname: Dean
authors.forename: Bradley
authors.initials: B
authors.lastname: Ackermann
authors.forename: Kimberley
authors.initials: K
authors.lastname: Jackson
authors.forename: Fanni
authors.initials: F
authors.lastname: Natanegara
authors.forename: Shelby
authors.initials: S
authors.lastname: Anderson
authors.forename: James
authors.initials: J
authors.lastname: Eckstein
authors.forename: Eunice
authors.initials: E
authors.lastname: Yuen
authors.forename: Mosun
authors.initials: M
authors.lastname: Ayan-Oshodi
authors.forename: Mary
authors.initials: M
authors.lastname: Ho
authors.forename: David
authors.initials: D
authors.lastname: McKinzie
authors.forename: Kenneth
authors.initials: K
authors.lastname: Perry
authors.forename: Kjell
authors.initials: K
authors.lastname: Svensson
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism; D000328:Adult; D000596:Amino Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D003499:Cyclic S-Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D017551:Microdialysis; D011355:Prodrugs; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012701:Serotonin / Q000378:metabolism; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D000596:Amino Acids; D054316:Biomarkers, Pharmacological; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; C534551:LY 2140023; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D004298:Dopamine; D006719:Homovanillic Acid