Uptake and binding of the serotonin 5-HT1A antagonist [18F]-MPPF in brain of rats: effects of the novel P-glycoprotein inhibitor tariquidar.
We used microPET to map the dose-response to the novel P-glycoprotein (P-gp) inhibitor tariquidar (TQD) of the initial influx of the P-gp substrate [(18)F]-MPPF in rat brain, and to test for effects of P-gp inhibition on the subsequent binding of [(18)F]-MPPF to serotonin 5-HT(1A) receptors. Summation maps of [(18)F]-MPPF uptake during the first 100 seconds after intravenous injection were calculated in groups of rats with vehicle (glucose 5%) pretreatment, or following pretreatment with TQD at doses of 5, 15, or 30 mg/kg. The early summation image (K(1)-weighted), were validated as a surrogate marker for the physiological blood-brain clearance (K(1); ml g(-)(1) min(-1)) by linear graphic analysis of the unidirectional blood-brain clearance relative to an image-based arterial input measured in the left ventricle of the heart. In the same animals, parametric maps of the [(18)F]-MPPF binding potential (BP(ND)) were calculated from the entire 60-minute emission recordings using conventional reference tissue methods. All [(18)F]-MPPF recordings were followed by an [(18)F]-FDG emission recording, the summation of which was used for spatial normalization to a rat brain atlas. Test-retest variability of K(1)-weighted uptake and BP(ND) was 25%. TQD treatment evoked a global dose-dependent increase in K(1)-weighted summation, which increased 2.5-fold with TQD (30 mg/kg), suggesting an IC(50) of 5 mg/kg TQD. All TQD doses increased the apparent [(18)F]-MPPF BP(ND) calculated by the Logan method by 30%-40%, a bias likely arising due to increased free [(18)F]-MPPF concentrations in brain. TQD (15 mg/kg) evoked a 45% global increase in [(18)F]-FDG uptake, suggesting perturbation of brain energy metabolism due to P-gp blockade.
Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Germany. christian.lafougere@med.uni-muenchen.de
Christian
C
la Fougère
Guido
G
Böning
Hero
H
Bartmann
Björn
B
Wängler
Sebastian
S
Nowak
Theresa
T
Just
Erika
E
Wagner
Petra
P
Winter
Axel
A
Rominger
Stefan
S
Förster
Franz-Josef
FJ
Gildehaus
Pedro
P
Rosa-Neto
Luciano
L
Minuzzi
Peter
P
Bartenstein
Heidrun
H
Potschka
Paul
P
Cumming
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D010879:Piperazines / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods; D011725:Pyridines / Q000378:metabolism* / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D015203:Reproducibility of Results; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D016277:Ventricular Function, Left
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002491:Central Nervous System Agents; D010879:Piperazines; D011725:Pyridines; D011804:Quinolines; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C402343:tariquidar; C416325:4-(2'-methoxyphenyl)-1-(2'-(N-2'-pyridinyl)-p-(18F)fluorobenzamido )ethylpiperazine