| 16392798 |
Kumar JS, Majo VJ, Hsiung SC, Millak MS, Liu KP, Tamir H, Prabhakaran J, Simpson NR, Van Heertum RL, Mann JJ, Parsey RV: 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. J Med Chem. 2006 Jan 12;49(1):125-34.
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. |
36(0,1,1,6) |