AIT-082, a cognitive enhancer, is transported into brain by a nonsaturable influx mechanism and out of brain by a saturable efflux mechanism.

A fundamental feature of any drug designed to treat a disease of the central nervous system is the ability to cross the blood-brain barrier. Passage across the blood-brain barrier of AIT-082, a cognitive enhancer, was investigated in mice. [(14)C]AIT-082 crossed the blood-brain barrier in young male Swiss-Webster mice with a mean influx constant (K(i)) of 0.6 +/- 0.2 microl g(-1) min(-1). Furthermore, [(14)C]AIT-082 was transported into brain of both young and old male C57BL/6 mice with a K(i) of 0.35 +/- 0.06 and 0.33 +/- 0.02 microl g(-1) min(-1), respectively. There was no significant effect of age or strain on the movement of [(14)C]AIT-082 across the blood-brain barrier in mice. When 110- or 650-fold excess unlabeled AIT-082 was included in the injection solution, the K(i) was not significantly changed in either Swiss-Webster or C57BL/6 mice. This indicated that [(14)C]AIT-082 crossed the blood-brain barrier by a nonsaturable mechanism. The passage of AIT-082 into brain extracellular fluid was confirmed with capillary depletion and microdialysis. The efflux of [(14)C]AIT-082 from brain also was examined. After i.c.v. injection, [(14)C]AIT-082 levels in brain decreased over time with a t(1/2) of 20.0 +/- 1.0 min. Excess unlabeled AIT-082 (600-fold) increased the t(1/2) to 35.5 +/- 3.6 min. Together, these data indicate that AIT-082 moves into brain via a nonsaturable mechanism and is actively transported out of brain.