Development and biological evaluation of 99mTc-BAT-tropane esters

Two 99mTc-BAT-tropane conjugates, i.e., technetium(V)-oxo-3-[N-(2-mercaptoethyl), N-(N′-(2-mercaptoethyl)-2-aminoethyl)]-aminopropyl 3β-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1]octane-2β-carboxylate and the corresponding norchloro derivative, were prepared and evaluated as potential imaging agents for the central nervous dopamine transporter (DAT) system. In these compounds, a tropane and a 99mTc-BAT moiety were linked through an ester bond. Both compounds were formed as a mixture of two diastereomers which could be purified and isolated using reversed-phase high-performance liquid chromatography (HPLC). Radio-LC-MS analysis supported the hypothesised structure of the synthesised technetium complexes. After intravenous injection in mice and rats, the compounds were stable in vivo, and no important metabolites were found in plasma or urine. In vitro testing suggested specific competitive binding to the DAT system, but in vivo experiments in rats showed no significant brain uptake for the diastereomers of both compounds; neither was there any specific uptake in the striatum. The results suggest that replacement of a methylene linker by an ester does not seriously affect the binding properties of the tropane conjugates to the dopamine transporter but results in a drastic reduction of passage over the blood-brain barrier (BBB).