bis-Pyridinium cyclophanes: novel ligands with high affinity for the blood-brain barrier choline transporter.

A series of bis-pyridinium cyclophane analogs designed as conformationally restricted bis-quaternary ammonium compounds were evaluated for their affinity for the blood-brain barrier (BBB) choline transporter. All the cyclophanes investigated exhibited high affinity compared to choline. Of these compounds, N, N'-(1,10-decanediyl)3,3'-(1,9-decadiyn-1,10-diyl)-bis-pyridinium diiodide (5c) and N,N'-(1,9-nonanediyl)3,3'-(1,9-decadiyn-1,10-diyl)-bis-pyridinium dibromide (5b) exhibited highest affinity with K(i) values of 0.8 microM and 1.4 microM, respectively, and constitute some of the most potent BBB choline transporter ligands reported.