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

摘要

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 ~(68)Ga-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,[~(68)Ga] Ga-HBED-hexadiyne-tropane,showed an IC_(50)value of 66 nM,together with a logD_(7.40)of 0.96.A μPET study in a hemiparkinsonian 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.