Abstract
BackgroundP-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer's disease, and in drug resistant epilepsy. Positron emission tomography using the Pgp substrate tracer (R)-[11C]verapamil enables in vivo quantification of Pgp function at the human blood-brain barrier. Knowledge of test-retest variability is important for assessing changes over time or after treatment with disease-modifying drugs. The purpose of this study was to assess reproducibility of several tracer kinetic models used for analysis of (R)-[11C]verapamil data.MethodsDynamic (R)-[11C]verapamil scans with arterial sampling were performed twice on the same day in 13 healthy controls. Data were reconstructed using both filtered back projection [FBP] and partial volume corrected ordered subset expectation maximization [PVC OSEM]. All data were analysed using single-tissue and two-tissue compartment models. Global and regional test-retest variability was determined for various outcome measures.ResultsAnalysis using the Akaike information criterion showed that a constrained two-tissue compartment model provided the best fits to the data. Global test-retest variability of the volume of distribution was comparable for single-tissue (6%) and constrained two-tissue (9%) compartment models. Using a single-tissue compartment model covering the first 10 min of data yielded acceptable global test-retest variability (9%) for the outcome measure K1. Test-retest variability of binding potential derived from the constrained two-tissue compartment model was less robust, but still acceptable (22%). Test-retest variability was comparable for PVC OSEM and FBP reconstructed data.ConclusionThe model of choice for analysing (R)-[11C]verapamil data is a constrained two-tissue compartment model.
Highlights
P-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer’s disease, and in drug resistant epilepsy
Several positron emission tomography [PET] tracers have been developed for quantifying Pgp function in vivo
Both (R) and (S) enantiomers of verapamil are substrates for Pgp, but (R)-[11C]verapamil is the preferred isomer for quantification of Pgp function as it is metabolised less than (S)-[11C]verapamil [16,17]. (R)-[11C]verapamil has been widely used both in healthy controls without
Summary
P-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer’s disease, and in drug resistant epilepsy. Positron emission tomography using the Pgp substrate tracer (R)-[11C] verapamil enables in vivo quantification of Pgp function at the human blood-brain barrier. The purpose of this study was to assess reproducibility of several tracer kinetic models used for analysis of (R)-[11C] verapamil data. P-glycoprotein [Pgp] is considered to be the most important efflux transporter at the human blood-brain barrier [BBB] because of its high expression and its ability to transport a wide range of substrates from the brain into the circulation and cerebrospinal fluid. Of these, (racemic) [11C] verapamil, (R)-[11C]verapamil and [11C]-N-desmethylloperamide have been used in humans [8,11,12,13,14,15] Both (R) and (S) enantiomers of verapamil are substrates for Pgp, but (R)-[11C]verapamil is the preferred isomer for quantification of Pgp function as it is metabolised less than (S)-[11C]verapamil [16,17]. Both (R) and (S) enantiomers of verapamil are substrates for Pgp, but (R)-[11C]verapamil is the preferred isomer for quantification of Pgp function as it is metabolised less than (S)-[11C]verapamil [16,17]. (R)-[11C]verapamil has been widely used both in healthy controls without [12,18,19,20] and with modulation of Pgp function [21,22]
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