In order to investigate systematically the effect of the position of the pyridine N-atom on the σ 1 receptor affinity four regioisomeric furopyridines 2a–d were synthesized and pharmacologically evaluated. The key steps of the synthesis comprise bromine/lithium exchange at regioisomeric bromopyridinecarbaldehyde acetals 7a–d, subsequent addition to 1-benzylpiperidin-4-one and cyclization. The regioisomeric acetals 7a–d were obtained either by o-metalation of bromopyridines 5b and 5c or by oxidation of bromopicolines 3a and 3d. In radioligand binding studies the regioisomeric furopyridines 2a–d showed 7- to 12-fold lower σ 1 affinity than the benzofuran analog 1. The reduced σ 1 affinity of the furopyridines 2a–d is explained with the reduced electron density of the pyridine ring. Since the four regioisomeric furopyridines show almost the same σ 1 affinity (K i = 4.9–10 nM), a directed interaction of the pyridine N-atom with the receptor protein can be excluded.