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-Cl2-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-Cl2-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 (Km = 105 ± 14 μM, Vmax = 16.9 ± 2.3 nmol min−1 g−1) and to be converted intracerebrally to 7-Cl-KYNA. 4,6-Cl2-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-Cl2-KYN might be useful prodrugs for brain delivery of glycine-NMDA receptor antagonists.