Synthesis of (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives as high affinity probes for sigma1 and sigma2 binding sites

Selective ligands for either sigma1 (σ1) or σ2 binding sites are potentially useful for gaining a better understanding of the physiological functions of these proteins. Moreover, potent and selective homochiral σ1 and σ2 binding site ligands represent leads to potential radioligands for tumour imaging with positron emission tomography (PET). On the basis of their structural similarity to previous leads, new (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives were synthesised and their binding affinities for σ1 and σ2 binding sites were determined. Each enantiomer showed high affinity for both σ1 and σ2 binding sites, but only (-)-cis-methyl-2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropane- carboxylate, (-)-4, showed appreciable selectivity for binding to σ1 versus σ2 sites. The enantiomers of cis-(2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropyl)methanol, 6, expressed the highest affinity for σ1 and σ2 binding sites. Ligands (-)-4, (+)-6 and (-)-6 might be rapidly labelled in their N-methyl groups by methylation of the N-desmethyl analogues with [11C]iodomethane to provide prospective radioligands for PET. The N-desmethyl analogues, which are also high affinity ligands, were prepared and shown to undergo satisfactory methylation with iodomethane.