Synthesis and evaluation of 1-{1-[5-(2′-[¹⁸F]Fluoroethyl)-2-thienyl]-cyclohexyl}piperidine as a potential in vivo radioligand for the NMDA receptor-Channel complex

1-{1-[5-(2′-[¹⁸F]Fluoroethyl)-2-thienyl]cyclohexyl}piperidine (¹⁸FE-TCP) was prepared as a fluorine-substituted analogue of the potent NMDA receptor channel blocker, 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), by the mesylate displacement with [¹⁸F]fluoride ion with isolated radiochemical yields of 6-12%, and the synthesis time including a two step HPLC purification was 120 min. The regional distribution in rat brain after i.v. injection of ¹⁸FE-TCP was heterogeneous and similar to the known distribution of phencyclidine recognition sites, with hippocampus-cerebellum, striatum-cerebellum and cerebral cortex-cerebellum concentration ratios of 2.08, 1.7 and 1.54, respectively, 15 min post-injection. Furthermore, this localized regional cerebral distribution was blocked by co-injection with the unlabelled FE-TCP or pretreatment with cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl)cyclohexane, with the greatest reductions seen in the hippocampus followed by the striatum and cerebral cortex. However, relatively low receptor binding affinity and high non-specific binding due to its high lipophilicity suggest that ¹⁸FE-TCP may not be a suitable radioligand for in vivo PET investigations of the NMDA receptor-channel complex.