title: Design, synthesis and brain uptake of LAT1-targeted amino acid prodrugs of dopamine.
abstract: OBJECTIVE
  Drug delivery to the brain is impeded by the blood-brain barrier (BBB). Here, we attempted to enhance the brain uptake of cationic dopamine by utilizing the large amino acid transporter 1 (LAT1) at the BBB by prodrug approach.
  
  
  METHODS
  Three amino acid prodrugs of dopamine were synthesized and their prodrug properties were examined in vitro. Their LAT1-binding and BBB-permeation were studied using the in situ rat brain perfusion technique. The brain uptake after intravenous administration and the dopamine-releasing ability in the rat striatum after intraperitoneal administration were also determined for the most promising prodrug.
  
  
  RESULTS
  All prodrugs underwent adequate cleavage in rat tissue homogenates. The prodrug with phenylalanine derivative as the promoiety had both higher affinity for LAT1 and better brain uptake properties than those with an alkyl amino acid - mimicking promoiety. The phenylalanine prodrug was taken up into the brain after intravenous injection but after intraperitoneal injection the prodrug did not elevate striatal dopamine concentrations above those achieved by corresponding L-dopa treatment.
  
  
  CONCLUSIONS
  These results indicate that attachment of phenylalanine to a cationic drug via an amide bond from the meta-position of its aromatic ring could be highly applicable in prodrug design for LAT1-mediated CNS-delivery of not only anionic but also cationic polar drugs.
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland. lauri.peura@uef.fi
authors.forename: Lauri
authors.initials: L
authors.lastname: Peura
authors.forename: Kalle
authors.initials: K
authors.lastname: Malmioja
authors.forename: Kristiina
authors.initials: K
authors.lastname: Huttunen
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Miia
authors.initials: M
authors.lastname: Hämäläinen
authors.forename: Markus M
authors.initials: MM
authors.lastname: Forsberg
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
authors.forename: Krista
authors.initials: K
authors.lastname: Laine
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015195:Drug Design; D004355:Drug Stability; D007275:Injections, Intravenous; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
chemical_list: D000596:Amino Acids; D027283:Large Neutral Amino Acid-Transporter 1; D011355:Prodrugs; D004298:Dopamine