Synthesis and preliminary evaluation of [¹¹C]NE-100 labeled in two different positions as a PET σ 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 σ 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 σ receptors. Four σ 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 σ 1 receptors in the peripheral organs and the CNS because of high nonspecific binding.