Synthesis and Radiolabelling of Ipratropium and Tiotropium for Use as PET Ligands in the Study of Inhaled Drug Deposition

Abstract

Ipratropium bromide [(1R,3r,5S,8r,2′RS)-3-(3′-hydroxy-2′-phenylpropionyloxy)-8-isopropyl-8-methyl-8-azabicyclo[3.2.1]octan-8-ium bromide] and tiotropium bromide [(1R,2R,4S,5S,7s)-7-[2′-hydroxy-2′,2′-di(thiophen-2′′-yl)acetoxy]-9,9-dimethyl-9-aza-3-oxatricyclo[3.3.1.02,4]nonan-9-ium bromide] are inhaled drugs used in the treatment of chronic obstructive pulmonary disease (COPD) and asthma. Tertiary amine precursors have been synthesized and radiolabelled with carbon-11 by N-alkylation with [11C]CH3I. The [11C]ipratropium and [11C]tiotropium positron emission tomography (PET) ligands are obtained with high radiochemical purity, in 0.3 and 0.5% non-decay corrected yields based on [11C]CO2 at end-of-synthesis and specific activities of 11 and 18 GBq μmol−1, respectively, calculated at end-of-synthesis. These PET radioligands can be used in the study of inhaled drug deposition.