title: Synthesis and in vivo validation of [O-methyl-11C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin- 1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione: a novel 5-HT1A receptor agonist positron emission tomography ligand.
abstract: Antagonist 5-HT(1A) PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [O-methyl-(11)C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (10), a potential high affinity (K(i) = 1.36 nM) 5-HT(1A) agonist PET tracer is described. Piperazine 10 is a 5-HT(1A) agonist with an EC(50) comparable to serotonin, based on cAMP formation and GTP(gamma)S binding assays. Radiosynthesis of [(11)C]10 has been achieved by reacting 2-{4-[4-(7-hydroxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (9) and [(11)C]CH(3)OTf in 25 +/- 5% (n = 15) yield at the end of synthesis (EOS). The chemical and radiochemical purities of [(11)C]10 were >99% with a specific activity 1500 +/- 300 Ci/mmol (n =15). PET studies in anesthetized baboon demonstrate [(11)C]10 specific binding in brain regions rich in 5-HT(1A) receptors. Binding of [(11)C]10 was blocked by WAY100635 and 8-OH-DPAT. The regional brain volumes of distribution (V(T)) of [(11)C]10 in baboon correlate with [(11)C]WAY100635 V(T) in baboons. These data provide evidence that [(11)C]10 is the first promising agonist PET tracer for the 5-HT(1A) receptors.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. dkumar@neuron.cpmc.columbia.edu
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
authors.forename: Vattoly J
authors.initials: VJ
authors.lastname: Majo
authors.forename: Shu-Chi
authors.initials: SC
authors.lastname: Hsiung
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Millak
authors.forename: Kuo-Peing
authors.initials: KP
authors.lastname: Liu
authors.forename: Hadassah
authors.initials: H
authors.lastname: Tamir
authors.forename: Jaya
authors.initials: J
authors.lastname: Prabhakaran
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: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D010215:Papio; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000494:pharmacology; D058825:Serotonin 5-HT1 Receptor Agonists; D013997:Time Factors; D014018:Tissue Distribution; D014227:Triazines / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: C507814:2-(4-(4-(7-methoxynaphthalen-1-yl)piperazin-1-yl)butyl)-4-methyl-2H-(1,2,4)triazine-3,5-dione; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D014227:Triazines; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin