Workpackages
Objectives
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Task 1:
Develop optimal tracer pharmacokinetic models for quantitative analysis of (R)-[11C]verapamil and newly developed P-gp PET tracers
Task 2:
Determine test-retest variability of pharmacokinetic parameters derived from (R)-[11C]verapamil and newly developed P-gp PET tracers in healthy controls
Task 3:
Determine the effects of P-gp modulators on pharmacokinetic parameters derived from (R)-[11C]verapamil and newly developed P-gp PET tracers in healthy controls
Task 4:
Determine the effects of age and gender on pharmacokinetic parameters derived from (R)-[11C]verapamil and newly developed P-gp PET tracers in healthy controls
Task 5:
Develop methods to correct pharmacokinetic parameters derived from (R)-[11C]verapamil and newly developed P-gp PET tracers in healthy controls for partial volume effects
Background
The purpose of this WP is to (1) characterise novel P-gp tracers in healthy controls and (2) develop tracer kinetic models for quantifying P-gp related kinetic parameters.
Initially, studies will concentrate on (R)-[11C]verapamil. Studies using [11C]laniquidar and other newly developed P-gp tracers will be performed, as soon as they become available. In vitro studies have shown that [11C]laniquidar binds to P-gp, rather than being a substrate for P-gp. In theory, this should provide increased signal in case of overexpression, in contrast to (R)-[11C]verapamil (P-gp substrate), which shows decreased signal. The combination of these two tracers provides the possibility to assess both expression (binding tracer) and functionality (substrate tracer) of P-gp.
Task 1:
Development of tracer kinetic models.
A tracer kinetic model for (R)-[11C]verapamil is available, with volume of distribution as outcome parameter. Preliminary studies in normal subjects have shown excellent test-retest variability, but it is assumed that labelled metabolites enter the brain with similar kinetics as those of verapamil. To validate this assumption kinetics of both these labelled metabolites and (R)-[11C]verapamil will be studies in the same rats.
For newly developed P-gp tracers, tracer kinetic models will be developed.
Task 2:
Test-retest studies in healthy controls.
To assess whether kinetic parameters are different between patients and healthy subjects or before and after pharmacological interventions, it is important to know what variation can be expected in unchanged conditions. To characterise variability, preliminary (R)-[11C]verapamil test-retest data will be extended.
Test-retest data will also be acquired for [11C]laniquidar and other newly developed P-gp tracers.
Task 3:
Effects of P-gp modulators.
In order to interpret results in patients with epilepsy, studies in normal subjects are required in which the effects of P-gp inhibitors are measured. Although it has been shown that blocking efflux pumps with CsA increases cerebral uptake of racemic [11C]verapamil in a dose dependent manner, no data are available for the pure enantiomer. (R)-[11C]verapamil scans will be performed without and with co-administration of a selective P-gp inhibitor and the effects on relevant kinetic parameters will be quantified.
Task 4:
Effects of age and gender.
An age effect on (R)-[11C]verapamil uptake has been demonstrated in small groups of young and elderly healthy subjects. To substantiate these findings, further data will be acquired. As various patient populations are of different age ranges, this also guarantees that data from these populations can be compared with age matched healthy controls. By including an equal number of males and females, the effects of gender on (R)-[11C]verapamil uptake can also be addressed.
Similar studies will be performed for other newly developed P-gp tracers.
Task 5:
Effects of partial volume correction.
The hippocampus is an important, epileptogenic region in patients with TLE. In previous (R)-[11C]verapamil studies, this region could not be analysed due to significant spill-over of activity from the adjacent choroid plexus, a region with high uptake. For neuroreceptor ligand studies, several partial volume correction methods have been proposed, but these have never been investigated for (R)-[11C]verapamil. Various correction methods and MR segmentation routines will be investigated by applying them to the data acquired in Tasks 2 to 4.
