Abstract
Twelve optically pure enantiomers were obtained using either crystallization or chiral high performance liquid chromatography (HPLC) separation methodologies to resolve six racemic sigma-1 (σ(1)) receptor ligands. The in vitro binding affinities of each enantiomer for σ(1), σ(2) receptors and vesicular acetylcholine transporter (VAChT) were determined. Out of the 12 optically pure enantiomers, five displayed very high affinities for σ(1) (K(i)<2nM) and high selectivity for σ(1) versus σ(2) and VAChT (>100-fold). The minus enantiomer, (-)-14a ((-)-TZ3108) (K(i-)(σ)(1)=1.8±0.4nM, K(i-)(σ)(2)=6960±810nM, K(i-VAChT)=980±87nM), was chosen for radiolabeling and further in vivo evaluation in rodents and nonhuman primates (NHPs). A biodistribution study in Sprague Dawley rats showed brain uptake (%ID/gram) of (-)-[(18)F]TZ3108 reached 1.285±0.062 at 5min and 0.802±0.129 at 120min. NHP microPET imaging studies revealed higher brain uptake of (-)-[(18)F]TZ3108 and more favorable pharmacokinetics compared to its racemic counterpart. Pretreatment of the animal using two structurally different σ(1) ligands significantly decreased accumulation of (-)-[(18)F]TZ3108 in the brain. Together, our in vivo evaluation results suggest that (-)-[(18)F]TZ3108 is a promising positron emission tomography (PET) tracer for quantifying σ(1) receptor in the brain.