Synthesis and preliminary evaluation of [11C]NE-100 labeled in two different positions as a PET sigma receptor ligand.
N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine (NE-100) was labeled with 11C in two different positions by the alkylation of an N-despropyl precursor with [11C]propyl iodide and of an O-desmethyl precursor with [11C]methyl iodide and was evaluated for the potential as a tracer for mapping sigma 1 receptors in the CNS and peripheral organs by PET. Following i.v. injection of [N-propyl-11C]NE-100 or [O-methyl-11C]NE-100 into mice, the two tracers showed similar tissue distribution patterns except for the liver and brain. With the coinjected carrier NE-100 or haloperidol, the uptake of [N-propyl-11C]NE-100 by the liver, pancreas and spleen was significantly decreased at 15 min after injection, whereas the effect was not significant for [O-methyl-11C]NE-100. The coinjection of NE-100 enhanced the brain uptake of the two tracers. Haloperidol also enhanced the brain uptake of [N-propyl-11C]NE-100, but not that of [O-methyl-11C]NE-100. The regional brain distribution assessed with [O-methyl-3H]NE-100 was consistent with the distribution pattern of the sigma receptors. Four sigma drugs reduced the regional brain uptake of [O-methyl-3H]NE-100 to 70%-90% of the control. In an ex vivo autoradiographic study of the rat brain, the uptake of [O-methyl-11C]NE-100 was blocked by carrier NE-100 or haloperidol (53%-59% of the control in the cortex), which suggests a receptor-specific distribution. These results show that [O-methyl-11C]NE-100 has limited potential as a PET ligand for mapping sigma 1 receptors in the peripheral organs and the CNS because of high nonspecific binding.
Ishiwata
K
K
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Japan. ishiwata@pet.tmig.or.jp
Noguchi
J
J
Ishii
S
S
Hatano
K
K
Ito
K
K
Nabeshima
T
T
Senda
M
M
D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001345:Autoradiography; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D006220:Haloperidol / Q000494:pharmacology; D007202:Indicators and Reagents; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D008297:Male; D051379:Mice; D011437:Propylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000032:analysis* / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D014055:Tomography, Emission-Computed
D000840:Anisoles; D002250:Carbon Radioisotopes; D007202:Indicators and Reagents; D008024:Ligands; D011437:Propylamines; D017480:Receptors, sigma; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; D006220:Haloperidol