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

Area of Science:

• Radiochemistry
• Neuroscience
• Pharmacology

Background:

• The dopamine transporter (DAT) is a key target for neuroimaging agents.
• Tropane derivatives are known to bind to DAT.
• Developing novel radiotracers for DAT imaging is crucial for understanding neurological disorders.

Purpose of the Study:

• To synthesize and evaluate two new (99m)Tc-BAT-tropane conjugates as potential imaging agents for the central nervous dopamine transporter (DAT) system.
• To investigate the effect of replacing a methylene linker with an ester bond on DAT binding and blood-brain barrier (BBB) penetration.

Main Methods:

• Synthesis of two (99m)Tc-BAT-tropane conjugates with an ester linkage.
• Purification and isolation of diastereomers using reversed-phase high-performance liquid chromatography (HPLC).
• Structural confirmation using radio-LC-MS.
• In vitro binding assays and in vivo studies in mice and rats, including biodistribution and metabolite analysis.

Main Results:

• The synthesized technetium complexes were stable in vivo with no significant metabolites found.
• In vitro studies indicated specific competitive binding to the DAT system.
• In vivo experiments in rats demonstrated no significant brain uptake or striatal uptake for either compound.
• The ester linkage drastically reduced passage over the blood-brain barrier (BBB).

Conclusions:

• While the tropane conjugates retain binding affinity for the dopamine transporter, the ester linkage significantly impairs their ability to cross the blood-brain barrier.
• These compounds are not suitable for in vivo imaging of the central nervous system DAT system due to poor BBB penetration.
• Further modifications are needed to develop effective DAT imaging agents based on tropane conjugates.