Secondary carbamate linker can facilitate the sustained release of dopamine from brain-targeted prodrug

To achieve the sustained release of dopamine in the brain for the symptomatic treatment of Parkinson's disease, dopamine was conjugated to L-tyrosine, an L-type amino acid transporter 1 (LAT1)-targeting vector, using a secondary carbamate linker. The resulting prodrug, dopa-CBT, inhibited the uptake of the LAT1 substrate [ ¹⁴ C]-L-leucine in LAT1-expressing MCF-7 cells with an IC ₅₀ value of 28 µM, which was 3.5-times lower than that of the gold standard for dopamine replacement therapy, L-dopa (IC ₅₀ ca. 100 µM). Despite its high affinity for LAT1, dopa-CBT was transported via LAT1 into MCF-7 cells 850-times more slowly (V _max < 3 pmol/min/mg) than L-dopa (V _max 2.6 nmol/min/mg), most likely due to its large size compared to L-dopa. However, dopa-CBT was significantly more stable in 10% rat liver homogenate than L-dopa, releasing dopamine and L-tyrosine, an endogenous dopamine precursor, slowly, which indicates that it may serve as a dual carrier of dopamine across the blood-brain barrier selectively expressing LAT1.