title: Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl- 11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates.
abstract: OBJECTIVE
  Serotonin1A (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [11C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [11C]MMP as an agonist PET tracer for 5-HT1A receptors in baboons.
  
  
  METHODS
  In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [11C] labeling of MMP was performed by reacting desmethyl-MMP with [11C]CH(3)OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (+/-)-8-OH-DPAT.
  
  
  RESULTS
  MMP is a selective 5-HT1A receptor agonist (Ki 0.15 nM). Radiosynthesis of [11C]MMP was achieved in 30 +/- 5% (n = 15) yield at EOS with a specific activity of 2,600 +/- 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [11C]MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (+/-)-8-OH-DPAT.
  
  
  CONCLUSIONS
  We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, USA. dkumar@neuron.cpmc.columbia.edu
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
authors.forename: Jaya
authors.initials: J
authors.lastname: Prabhakaran
authors.forename: Vattoly J
authors.initials: VJ
authors.lastname: Majo
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Milak
authors.forename: Shu-Chi
authors.initials: SC
authors.lastname: Hsiung
authors.forename: Hadassah
authors.initials: H
authors.lastname: Tamir
authors.forename: Norman R
authors.initials: NR
authors.lastname: Simpson
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Van Heertum
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.forename: Ramin V
authors.initials: RV
authors.lastname: Parsey
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D010215:Papio; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D058825:Serotonin 5-HT1 Receptor Agonists; D014018:Tissue Distribution; D014227:Triazines / Q000493:pharmacokinetics*
chemical_list: C510616:(O-methyl-11C) 2-(4-(4-(3-methoxyphenyl)piperazin-1-yl)-butyl)-4-methyl-2H-(1,2,4)-triazine-3,5-dione; D010879:Piperazines; D019275:Radiopharmaceuticals; D058825:Serotonin 5-HT1 Receptor Agonists; D014227:Triazines