title: Pharmacokinetic Properties of a Novel D-Peptide Developed to be Therapeutically Active Against Toxic β-Amyloid Oligomers.
abstract: OBJECTIVE
  It has been shown that amyloid β (Aβ) oligomers play an important role in the pathology of Alzheimer's disease (AD). D3, a peptide consisting solely of D-enantiomeric amino acid residues, was developed to specifically eliminate Aβ oligomers and is therapeutically active in transgenic AD mice. D-peptides have several advantages over L-peptides, but little is known about their pharmacokinetic potential in vivo. Here, we analysed the pharmacokinetic properties of RD2, a rationally designed and potent D3 derivative.
  
  
  METHODS
  The pharmacokinetic analysis was performed using (3)H-RD2 after administration via several routes in mice. The time dependent amount of radiolabelled RD2 was measured in plasma and several organ homogenates by liquid scintillation counting. Furthermore, binding to plasma proteins was estimated.
  
  
  RESULTS
  RD2 penetrates into the brain, where it is thought to implement its therapeutic function. All administration routes result in a maximal brain concentration per dose (Cmax/D) of 0.06 (μg/g)/(mg/kg) with brain/plasma ratios ranging between 0.7 and 1.0. RD2 shows a small elimination constant and a long terminal half-life in plasma of more than 2 days. It also exhibits high bioavailability after i.p., s.c. or p.o. administration.
  
  
  CONCLUSIONS
  These excellent pharmacokinetic properties confirm that RD2 is a very promising drug candidate for AD.
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.
authors.forename: Leonie H E
authors.initials: LH
authors.lastname: Leithold
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Post
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.
authors.forename: Tamar
authors.initials: T
authors.lastname: Ziehm
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Schartmann
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Kutzsche
authors.affiliation: Institute of Neuroscience and Medicine, Medical Imaging Physics (INM-4), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.
authors.forename: N Jon
authors.initials: NJ
authors.lastname: Shah
authors.affiliation: Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Breitkreutz
authors.affiliation: Institute of Neuroscience and Medicine, Medical Imaging Physics (INM-4), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.|Clinic for Nuclear Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Langen
authors.affiliation: Institute of Neuroscience and Medicine, Medical Imaging Physics (INM-4), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany. a.willuweit@fz-juelich.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Willuweit
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany. d.willbold@fz-juelich.de.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany. d.willbold@fz-juelich.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D010455:Peptides
keywords: Alzheimer’s disease; D-enantiomer; peptide; pharmacokinetics; preclinical