Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (-)-[18 F]Flubatine in humans

Introduction: (-)-[(18) F]Flubatine is a PET tracer with high affinity and selectivity for the nicotinic acetylcholine alpha(4)beta(2) 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 90 min. 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 90 min 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 3 min p.i. to 0.87 +/- 0.03 at 270 min 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. Discussion: (-)-[(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. (c) 2014 Elsevier Inc. All rights reserved.