Regiospecific and conformationally restrained analogs of melphalan and DL-2-NAM-7 have been synthesized and their affinities for the large neutral amino acid transporter (LAT1) of the blood-brain barrier have been determined to assess their potential for accessing the CNS via facilitated transport. Several analogs had K(i) values in the range 2.1-8.5 microM with greater affinities than that of either L-phenylalanine (K(i)=11 microM) or melphalan (K(i)=55 microM), but lower than DL-2-NAM-7 (K(i)=0.08 microM). The results indicate that regiospecific positioning of the mustard moiety on the aromatic ring in these analogs is very important for optimal affinity for the large neutral amino acid transporter, and that conformational restriction of the DL-2-NAM-7 molecule in benzonorbornane and indane analogs leads to 25- to 60-fold loss, respectively, in affinity.