Evaluation of (5R,6R)-5-Bromo-6-Ethoxy-5-Ethyl-5,6-Dihydro-2'- Deoxyuridine as a Brain-Targeted Prodrug of 5-Ethyl-2'- Deoxyuridine

(+)-Trans-(5R,6R)-5-bromo-6-ethoxy-5-ethyl-5,6-dihydro-2'-deoxyuridine [(5R,6R)-BEEDU], a potential brain-targeted prodrug of 5-ethyl-2'-deoxyuridine (EDU), was synthesized by the regiospecific addition of BrOEt to the 5,6-olefinic bond of EDU. (5R,6R)-BEEDU is more lipophilic (log P = 0.04) than EDU (log P = -1.09). In vitro incubation of (5R,6R)-BEEDU with rat whole blood and brain homogenate resulted in a 53% and 16% conversion, respectively, to EDU. In contrast, (5R,6R)-BEEDU was not converted to EDU upon incubation with glutathione (GSH) at 37°C for 36 hours. After i.v. injection into rats, (5R,6R)-BEEDU was rapidly converted to EDU, which was then further metabolized like EDU. However, (5R,6R)-BEEDU provided a substantially higher concentration of EDU in blood, relative to that when EDU was injected. A biodistribution study of [4C]-(5R,6R)-BEEDU in Balb/c mice showed that (5R,6R)-BEEDU provided significantly higher (P < 0.05) radioactivity levels in brain samples at 8, 18 and 30 min post injection than observed after injection of [4C]-EDU. The higher radioactivity levels in liver samples after injection of [4C]-(5R,6R)-BEEDU, relative to those after [4C]-EDU, indicates that the 5,6-dihydro derivative undergoes a higher hepatic extraction than EDU. Clearance of radioactivity from blood and excretion into urine, after injection of [4-C]-EDU, was much faster than that after injection of [4-C]-(5R,6R)-BEEDU. Iran. Biomed. J. 2: 105-113, 1998