DRUG-DELIVERY TO THE BRAIN - DOPA PRODRUGS BASED ON A RING-CLOSURE REACTION TO QUATERNARY THIAZOLIUM COMPOUNDS

In order to explore the possibility of an alternative redox chemical d elivery system to a dihydropyridine-pyridinium interconversion system, we prepared DOPA prodrugs coupled with thiazolium precursors, like th iamine disulfides, by forming an ester bond with the amino acid carbox ylic moiety while protecting the catechol function with pivalyl groups . The disposition of the prodrugs was evaluated by measuring the conce ntrations of DOPA regenerated after intravenous administration of the prodrugs and the results were compared with those for DOPA itself. The plasma levels of DOPA demonstrated no significant differences between DOPA and the prodrugs. In contrast, however, brain levels of DOPA wer e remarkably elevated following administration of the prodrugs. Among the prodrugs examined, ZiPr-DOPA(P)(2) was found to most efficiently f acilitate delivery of DOPA to brain and this compound showed 30- and 3 .7-fold greater increases in the AUC and MRT of DOPA in brain, respect ively, than did DOPA itself. These findings suggest that a redox ring- closure system to a quaternary thiazolium can be used as an alternativ e chemical delivery system to the brain.