[Synthesis of prodrugs of tacrine hydrochloride and evaluation of the stability and biodistribution in mice].
OBJECTIVE
To synthesize acylated prodrug of tacrine hydrochloride (THA) to improve the infiltration ability across the blood brain barrier (BBB).


METHODS
A series of prodrugs were prepared by acylation of the 7-amino group of THA. The degradation of prodrugs was investigated under different conditions. Biodistribution studies of N-butyramide-THA (BTHA) in mice were carried out to evaluate the function of brain targeting.


RESULTS
The structures of prodrugs were confirmed by IR, 1HNMR and MS. All prodrugs were stable in different medium. Octanol-water partition coefficients indicated increased lipophlicity for various prodrugs compared to the THA. In vivo distribution studies showed that BTHA was mainly distributed in brain, blood and liver (the maximum concentrations were 17.5725, 13.1400 and 22.8279 mg.L-1, respectively), while the THA concentration were very low in lung and heart (the maximum concentrations were 4.9475 and 4.4925 mg.L-1, respectively). The BTHA concentration (2.4159 mg.L-1) was relatively high even 12 h after administration, showing that BTHA degraded more slowly in brain than in other tissues.


CONCLUSIONS
The infiltration ability of THA across BBB was increased in the form of N-acylate-THA prodrug, indicating that this kind of prodrug is a promising brain-targeting delivery system.
Jiang
Yu
Y
Center for Drug Evaluation of China, Beijing 100038, China.
Zhang
Yan
Y
Zhang
Zhi-rong
ZR
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004355:Drug Stability; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013619:Tacrine / Q000031:analogs & derivatives / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*
D002800:Cholinesterase Inhibitors; C482141:N-butyramide-tacrine; D011355:Prodrugs; D013619:Tacrine