Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier

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Abstract
The relative affinity of six anticancer amino acid drugs for the neutral amino acid carrier of the blood-brain barrier was examined in rats using an in situ brain perfusion technique. Affinity was evaluated from the concentration-dependent inhibition ofl-[14C]-leucine uptake into rat brain during perfusion at tracer leucine concentrations and in the absence of competing amino acids. Of the six drugs tested, five, including melphalan, azaserine, acivicin, 6-diazo-5-oxo-l-norleucine, and buthionine sulfoximine, exhibited only low affinity for the carrier, displaying transport inhibition constants (K i, concentrations producing 50% inhibition) ranging from 0.09 to 4.7 mM. However, one agent −d,l-2-amino-7-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-naphthoic acid (d,l-NAM) — demonstrated remarkably high affinity for the carrier, showing aK i value of ∼0.2 μM. The relative affintty (1/K i) ofd,l-NAM was >100-fold that of the other drugs and >10-fold that of any compound previously tested. As the blood-brain barrier penetrability of most endogenous neutral amino acids is related to their carrier affinity, the results suggest thatd,l-NAM may be a promising agent which may show enhanced uptake and distribution to brain tumors.