Several 3H-spiro[[2]benzofuran-1,4'-piperidines] bearing a p-fluorobenzyl residue at the N-atom and various substituents in position 3 of the benzofuran system were synthesized. The crucial reaction steps are the addition of a lithiated benzaldehyde derivative to the p-fluorobenzylpiperidone 5 and the BF(3).OEt(2) catalyzed substitution of the methoxy group of 2a by various nucleophiles. Structure-affinity relationship studies revealed that compounds with two protons (2d), a methoxy group (2a), and a cyano group (2e) in position 3 possess subnanomolar sigma(1) affinity (K(i)=0.18 nM, 0.79 nM, 0.86 nM) and high selectivity against the sigma(2) subtype. The metabolites of 2a, 2d, and 2e, which were formed upon incubation with rat liver microsomes, were identified. Additionally, the rate of metabolic degradation of 2a, 2d, and 2e was determined and compared with the degradation rate of the non-fluorinated spirocyclic compound 1. For the synthesis of the potential PET tracers [(18)F]2a and [(18)F]2e two different radiosynthetic approaches were followed.