Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (-)-[(18)F]Flubatine in humans.
BACKGROUND
(-)-[(18)F]Flubatine is a PET tracer with high affinity and selectivity for the nicotinic acetylcholine α4β2 receptor subtype. A clinical trial assessing the availability of this subtype of nAChRs was performed. From a total participant number of 21 Alzheimer's disease (AD) patients and 20 healthy controls (HCs), the following parameters were determined: plasma protein binding, metabolism and activity distribution between plasma and whole blood.


METHODS
Plasma protein binding and fraction of unchanged parent compound were assessed by ultracentrifugation and HPLC, respectively. The distribution of radioactivity (parent compound+metabolites) between plasma and whole blood was determined ex vivo at different time-points after injection by gamma counting after separation of whole blood by centrifugation into the cellular and non-cellular components. In additional experiments in vitro, tracer distribution between these blood components was assessed for up to 90min.


RESULTS
A fraction of 15%±2% of (-)-[(18)F]Flubatine was found to be bound to plasma proteins. Metabolic degradation of (-)-[(18)F]Flubatine was very low, resulting in almost 90% unchanged parent compound at 90min p.i. with no significant difference between AD and HC. The radioactivity distribution between plasma and whole blood changed in vivo only slightly over time from 0.82±0.03 at 3min p.i. to 0.87±0.03 at 270min p.i. indicating the contribution of only a small amount of metabolites. In vitro studies revealed that (-)-[(18)F]Flubatine was instantaneously distributed between cellular and non-cellular blood parts.


CONCLUSIONS
(-)-[(18)F]Flubatine exhibits very favourable characteristics for a PET radiotracer such as slow metabolic degradation and moderate plasma protein binding. Equilibrium of radioactivity distribution between plasma and whole blood is reached instantaneously and remains almost constant over time allowing both convenient sample handling and facilitated fractional blood volume contribution assessment.
Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany. Electronic address: marianne.patt@uniklinik-leipzig.de.
Marianne
M
Patt
Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany.
Georg A
GA
Becker
Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany.
Udo
U
Grossmann
Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany.
Bernd
B
Habermann
Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany.
Andreas
A
Schildan
Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany.
Stephan
S
Wilke
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstrasse 15, D-04318 Leipzig, Germany.
Winnie
W
Deuther-Conrad
Department of Psychiatry, University of Leipzig, Semmelweisstrasse 10, D-04103 Leipzig, Germany.
Susanne
S
Graef
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstrasse 15, D-04318 Leipzig, Germany.
Steffen
S
Fischer
ABX advanced biochemical compounds GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany.
René
R
Smits
ABX advanced biochemical compounds GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany.
Alexander
A
Hoepping
Multimodal Image Processing, Central Institute ZEA-2-Electronic Systems, Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany.
Gudrun
G
Wagenknecht
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstrasse 15, D-04318 Leipzig, Germany.
Jörg
J
Steinbach
Department of Psychiatry, University of Leipzig, Semmelweisstrasse 10, D-04103 Leipzig, Germany.
Hermann-Josef
HJ
Gertz
Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany; Integrated Research and Treatment Centre (IFB) Adiposity Diseases, Leipzig University Medical Centre, Leipzig, Germany.
Swen
S
Hesse
Department of Psychiatry, University of Leipzig, Semmelweisstrasse 10, D-04103 Leipzig, Germany.
Peter
P
Schönknecht
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstrasse 15, D-04318 Leipzig, Germany.
Peter
P
Brust
Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany; Integrated Research and Treatment Centre (IFB) Adiposity Diseases, Leipzig University Medical Centre, Leipzig, Germany.
Osama
O
Sabri
D001549:Benzamides / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D011849:Radioactive Tracers
D001549:Benzamides; D001798:Blood Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011849:Radioactive Tracers; C115362:fluoronorchloroepibatidine
Clinical trial; Flubatine; Fluorine-18; Metabolism; PET; Plasma protein binding