title: Targeting the cerebrovascular large neutral amino acid transporter (LAT1) isoform using a novel disulfide-based brain drug delivery system.
abstract: We describe a novel strategy to achieve high affinity recognition for the specific, cerebrovascular large neutral amino acid transporter (LAT1) isoform by covalent coupling of small molecules to the amino acid, L-cysteine (L-Cys). L-Cys (as the carrier) was covalently attached via a disulfide bond to either 6-mercaptopurine or 2-methyl-1-propanethiol (IBM) to form the brain-targeted drug delivery systems (BTDS). BTDS were designed for high affinity recognition by LAT1 at the cerebrovasculature. Using an in situ rat brain perfusion technique, competition between BTDS and the radiotracer [14C]L-Leu demonstrated significant inhibition of [14C]L-Leu brain uptake. BTDS possess affinity for cerebrovascular LAT1 in many distinct brain compartments, and the recognition of BTDS by LAT1 is influenced by hydrophobicity of the side-chain in BTDS. Thus, the BTDS strategy may be utilized for rapid shuttling of various neuropharmaceuticals into brain.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Killian
authors.forename: Suzanne
authors.initials: S
authors.lastname: Hermeling
authors.forename: Prashant J
authors.initials: PJ
authors.lastname: Chikhale
mesh_terms: D000465:Algorithms; D000818:Animals; D001667:Binding, Competitive; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004220:Disulfides / Q000737:chemistry*; D016503:Drug Delivery Systems; D007202:Indicators and Reagents; D007536:Isomerism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000097:blood*; D007930:Leucine / Q000378:metabolism; D008297:Male; D015122:Mercaptopurine / Q000737:chemistry; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D004220:Disulfides; D007202:Indicators and Reagents; D027283:Large Neutral Amino Acid-Transporter 1; D013438:Sulfhydryl Compounds; C061330:tert-butylthiol; D015122:Mercaptopurine; D007930:Leucine