68Ga-Labelled Tropane Analogues for the Visualization of the Dopaminergic System

The development of radiometal-labelled pharmaceuticals for neuroimaging could offer great potential due to easier handling during labelling and availability through radionuclide generator systems. Nonetheless, to date, no such tracers are available for positron emission tomography, primarily owing to the challenge of crossing the blood-brain barrier (BBB) and loss of affinity through chelator attachment. We have prepared a variety of Ga-68-labelled phenyltropanes showing that, through a simple hydrocarbon-linker, it is possible to introduce a chelator onto the lead structure while maintaining its high affinity for hDAT (human dopamine transporter) and simultaneously achieving adequate lipophilicity. One of the candidates, [Ga-68]Ga-HBED-hexadiyne-tropane, showed an IC50 value of 66 nM, together with a log D-7.4 of 0.96. A mu PET study in a hemi-parkinsonian rat model showed a fast wash-out of the tracer, and no specific uptake in the brain, thus implying an inability to penetrate the BBB.

Automated summary

The research indicates that introducing a chelator onto the lead structure through a simple hydrocarbon-linker can maintain high affinity while achieving adequate lipophilicity. However, in vivo studies show rapid clearance of the tracer and lack of specific uptake in the rodent brain, suggesting an inability to penetrate the blood-brain barrier.