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Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine

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An Erratum to this article was published on 30 January 2013

ABSTRACT

Purpose

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.

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Abbreviations

AADC:

aromatic L-amino acid decarboxylase

AUC:

area under the curve

BBB:

blood-brain barrier

BBN:

9-borabicyclo[3.3.1]nonane

CNS:

central nervous system

COMT:

catechol-O-methyl transferase

EDC:

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

GluT1:

glucose transporter 1

HOBt:

1-hydroxybenzotriazole

LAT1:

large neutral amino acid transporter 1

LLOQ:

lower limit of quantification

PA:

brain permeability-surface area

SVTC2:

ascorbic acid transporter

TPSA:

topological polar surface area

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ACKNOWLEDGMENTS AND DISCLOSURES

Lauri Peura, Kalle Malmioja, Jarkko Rautio and Krista Laine share equal contribution to this work.

The authors would like to express their profound gratitude to laboratory technicians Helly Rissanen and Jaana Leskinen for their skillful assistance. Marko Lehtonen, M.Sc., is also acknowledged for his skillful help in the HPLC-EC-analytics, Tiina Kääriäinen, Ph.D., for her skillful help in the animal studies and Ewen MacDonald, Ph.D., for refining the English of this paper. We also thank Henna Härkönen, M.Sc., for the polar surface area calculations. The work was financially supported by the Graduate School of Pharmaceutical Research, the Academy of Finland (# 132637), the Orion-Farmos foundation, the Finnish Pharmaceutical Society, the Finnish Parkinson Foundation and the Emil Aaltonen Foundation.

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Authors and Affiliations

  1. School of Pharmacy, University of Eastern Finland, Kuopio, Finland

    Lauri Peura, Kalle Malmioja, Kristiina Huttunen, Jukka Leppänen, Miia Hämäläinen, Markus M. Forsberg, Jarkko Rautio & Krista Laine

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  1. Lauri Peura
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Correspondence to Lauri Peura.

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Peura, L., Malmioja, K., Huttunen, K. et al. Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine. Pharm Res 30, 2523–2537 (2013). https://doi.org/10.1007/s11095-012-0966-3

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