RT Journal Article
SR Electronic
T1 Evaluation of P-glycoprotein modulation of Fluorine-18-fallypride
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 161
OP 161
VO 51
IS supplement 2
A1 Markus Piel
A1 Ulrich Schmitt
A1 Nicole Bausbacher
A1 Sabine Höhnemann
A1 Hans-Georg Buchholz
A1 Christoph Hiemke
A1 Frank Rösch
YR 2010
UL http://jnm.snmjournals.org/content/51/supplement_2/161.abstract
AB 161 Objectives P-gp is a member of the highly conserved superfamily of ATP-binding cassette (ABC) transporter proteins and acts as an active efflux pump for a wide range of compounds, including a number of drugs and steroid hormones. P-gp at the BBB thus regulates intracerebral concentrations and may affect the PET imaging of ligands that are substrates of this transporter. Therefore we examined possible interactions between P-gp and Fluorine-18-fallypride, which is a routinely used ligand to determine the D2-receptor status in vivo. Methods Fluorine-18-fallypride was applied to Sprague Dawley rats half of them treated with the P-gp inhibitor cyclosporine A. In a second experimental series to P-gp KO (mdr1a/b -/-), and wild type mice with or without cyclosporine A treatment µPET was used to study the uptake kinetics, binding potential and standard uptake value of fluorine-18-fallypride. Results In Sprague Dawley rats the µPET imaging showed the same uptake kinetic of fluorine-18-fallypride for both groups, whilst having a BP of 13.7 and a SUV of 2.5 at 60 min in the striatum in untreated and a BP of 8.7 and a SUV of 4.2 in the striatum in treated animals. In the mouse models the brain uptake was determined resulting in 2.62 %ID/g in KO, 2.29 %ID/g in treated and 1.68 %ID/g in untreated wild type mice. Conclusions In the rat model the treated animals showed a reduction of the BP compared to the untreated animals, due to an increased unspecific uptake, but also a higher SUV because of a global increase of radioactivity in the brain. In the mouse a similar effect was seen, showing an increasing uptake from wild type to treated and KO mice, possibly since not all P-gp transporters can be blocked by cyclosporine A. These results indicate that fluorine-18-fallypride is a substrate of P-gp and therefore its uptake is modulated by this efflux pump