A highly sensitive secondary ion mass spectrometry method was developed to image distributions of trace elements in frozen sections of postmortem human brain. Studies were initiated on the distribution of aluminum and other key elements in neurofibrillary tangle-bearing neurons in Alzheimer's disease. The brain transport of manganese, an essential trace metal that produces a Parkinsonian-like syndrome at high concentrations, was studied in rats and found to be mediated by an uptake system that is influenced by plasma protein binding, oxidation state and trace metal competition. The basic amino acid transporter at the blood- brain barrier was cloned and shown to be homologous to System y+, the classic sodium-independent cationic amino acid carrier. Drugs with high affinity for the large neutral amino acid transporter of the blood-brain barrier were identified and tested for rapid uptake into brain. One drug, D,L-NAM, with high affinity for the neutral amino acid carrier exhibited 20-40 fold greater brain uptake than its clinical analog, L-melphalan, and demonstrated that the saturable nutrient carriers of the blood-brain barrier could be used to improve drug delivery to brain for the treatment of central nervous system diseases.
