title: Preclinical Pharmacokinetic Studies of the Tritium Labelled D-Enantiomeric Peptide D3 Developed for the Treatment of Alzheimer´s Disease.
abstract: Targeting toxic amyloid beta (Aβ) oligomers is currently a very attractive drug development strategy for treatment of Alzheimer´s disease. Using mirror-image phage display against Aβ1-42, we have previously identified the fully D-enantiomeric peptide D3, which is able to eliminate Aβ oligomers and has proven therapeutic potential in transgenic Alzheimer´s disease animal models. However, there is little information on the pharmacokinetic behaviour of D-enantiomeric peptides in general. Therefore, we conducted experiments with the tritium labelled D-peptide D3 (3H-D3) in mice with different administration routes to study its distribution in liver, kidney, brain, plasma and gastrointestinal tract, as well as its bioavailability by i.p. and p.o. administration. In addition, we investigated the metabolic stability in liver microsomes, mouse plasma, brain, liver and kidney homogenates, and estimated the plasma protein binding. Based on its high stability and long biological half-life, our pharmacokinetic results support the therapeutic potential of D-peptides in general, with D3 being a new promising drug candidate for Alzheimer´s disease treatment.
authors.affiliation: Structural Biochemistry, Institute of Complex Systems (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Structural Biochemistry, Institute of Complex Systems (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Leonie H E
authors.initials: LH
authors.lastname: Leithold
authors.affiliation: Structural Biochemistry, Institute of Complex Systems (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Post
authors.affiliation: Structural Biochemistry, Institute of Complex Systems (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Tamar
authors.initials: T
authors.lastname: Ziehm
authors.affiliation: Medical Imaging Physics, Institute of Neuroscience and Medicine (INM-4), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Mauler
authors.affiliation: Structural Biochemistry, Institute of Complex Systems (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Gremer
authors.affiliation: Structural and functional organisation of the brain, Institute of Neuroscience and Medicine (INM-1), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Cremer
authors.affiliation: Structural Biochemistry, Institute of Complex Systems (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Schartmann
authors.affiliation: Medical Imaging Physics, Institute of Neuroscience and Medicine (INM-4), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: N Jon
authors.initials: NJ
authors.lastname: Shah
authors.affiliation: Structural Biochemistry, Institute of Complex Systems (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Kutzsche
authors.affiliation: Medical Imaging Physics, Institute of Neuroscience and Medicine (INM-4), Forschungszentrum Jülich GmbH, Jülich, Germany; Department of Nuclear Medicine, Universitätsklinikum der RWTH Aachen, Aachen, Germany.
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Langen
authors.affiliation: Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Breitkreutz
authors.affiliation: Structural Biochemistry, Institute of Complex Systems (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany; Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
authors.affiliation: Medical Imaging Physics, Institute of Neuroscience and Medicine (INM-4), Forschungszentrum Jülich GmbH, Jülich, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Willuweit
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D019540:Area Under Curve; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism; D002855:Chromatography, Thin Layer; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011485:Protein Binding; D012372:ROC Curve; D013237:Stereoisomerism; D014316:Tritium / Q000737:chemistry
chemical_list: D001798:Blood Proteins; C534952:D3 peptide; D009842:Oligopeptides; D014316:Tritium