Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid

7-CHLOROKYNURENIC acid (7-Cl-KYNA) and 5,7-dichlorokynurenic acid (5,7-Cl-2-KYNA) are of therapeutic interest as potent glycine/N-methyl-D-aspartate (NMDA) receptor antagonists, but are excluded from brain by the blood-brain barrier. We examined whether these compounds could be delivered to brain through their respective precursors, L-4-chlorokynurenine (4-Cl-KYN) and L-4,6-dichlorokynurenine (4,6-Cl-2-KYN), which are amino acids. 4-Cl-KYN was shown to be rapidly shuttled into the brain by the large neutral amino acid transporter of the blood-brain barrier (K-m = 105 +/- 14 mu M, V-max = 16.9 +/- 2.3 nmol min(-1) g(-1)) and to be converted intracerebrally to 7-Cl-KYNA. 4,6-Cl-2-KYN also expressed affinity for the transporter, but four-fold less than that of 4-Cl-KYN. In summary, the results show that because of their facilitated uptake 4-Cl-KYN and 4,6-Cl2KYN might be useful prodrugs for brain delivery of glycine-NMDA receptor antagonists.