title: In vitro assessment of the agonist properties of the novel 5-HT1A receptor ligand, CUMI-101 (MMP), in rat brain tissue.
abstract: BACKGROUND
  Development of agonist positron emission tomography (PET) radioligands for the 5-HT neurotransmitter system is an important target to enable the understanding of human 5-HT function in vivo. [(11)C]CUMI-101, proposed as the first 5-HT(1A) receptor agonist PET ligand, has been reported to behave as a potent 5-HT(1A) agonist in a cellular system stably expressing human recombinant 5-HT(1A) receptors. In this study, we investigate the agonist properties of CUMI-101 in rat brain tissue.
  
  
  METHODS
  [(35)S]-GTPγS binding studies were used to determine receptor function in HEK (human embryonic kidney) 293 cells transfected with human recombinant 5-HT(1A) receptors and in rat cortex and rat hippocampal tissue, following administration of CUMI-101 and standard 5-HT1A antagonists (5-HT, 5-CT and 8-OH-DPAT).
  
  
  RESULTS
  CUMI-101 behaved as an agonist at human recombinant 5-HT(1A) receptors (pEC(50) 9.2). However, CUMI-101 did not show agonist activity in either rat cortex or hippocampus at concentrations up to 10 μM. In these tissues, CUMI-behaved as an antagonist with pK(B)s of 9.2 and 9.3, respectively.
  
  
  CONCLUSIONS
  Our studies demonstrate that as opposed to its behavior in human recombinant system, in rat brain tissue CUMI-101 behaves as a potent 5-HT(1A) receptor antagonist.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, CM19 5AW Essex, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Hendry
authors.forename: Isabel
authors.initials: I
authors.lastname: Christie
authors.forename: Eugenii Alfredovich
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
authors.forename: Jeannette
authors.initials: J
authors.lastname: Watson
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology*
chemical_list: C529131:2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5-(2H,4H)-dione; D008024:Ligands; D010879:Piperazines; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D014227:Triazines; D044282:Receptor, Serotonin, 5-HT1A; D016244:Guanosine 5'-O-(3-Thiotriphosphate)