Endogenous competition against binding of [(18)F]DMFP and [(18)F]fallypride to dopamine D(2/3) receptors in brain of living mouse.
OBJECTIVE
Molecular imaging studies with benzamide radioligands can reveal competition from endogenous binding at D(2/3)-receptors in living brain. However, single photon emission computed tomography (SPECT) methods suffer from limited spatial resolution, and [(11)C]-labeled ligands are only available at positron emission tomography (PET) research sites with cyclotron-radiochemistry facilities, whereas [(18)F] can be transported, due to its longer physical half-life. Therefore, we endeavored to characterize the vulnerabilities of the benzamide antagonist [(18)F]desmethoxyfallypride (DMFP) and its high-affinity congener [(18)F]fallypride (FP) to competition from endogenous dopamine in living mouse brain.


METHODS
Groups of awake mice were pretreated with saline, amphetamine (10 mg/kg), or reserpine (5 mg/kg), followed by i.v. tracer injections. Mice were killed at 2.5-90 min (DMFP) or 2.5-180 min (FP) circulation times. Brains were dissected and regional radioactivity concentration measured by gamma counting. Other groups of mice were anesthetized for dynamic microPET recordings with DMFP or FP. Binding potentials (BP(ND)) were calculated using cerebellum as reference region.


RESULTS
With 90-min circulation, DMFP BP(ND) in striatum was 2.4 by dissection and 2.2 by microPET, which showed a 62% decrease in response to amphetamine-evoked dopamine release and a 33% increase after reserpine-evoked dopamine depletion. With 120-min circulation, FP BP(ND) in striatum was 24.1 by dissection and 9.2 by microPET, which showed a 31% decrease in the amphetamine group, but no effect of reserpine. Dissection showed similar sensitivities for FP binding, but only a 29% amphetamine-evoked reduction for DMFP.


CONCLUSIONS
Relative to gold standard ex vivo results, microPET estimates of DMFP BP(ND) were unbiased, whereas FP BP(ND) in striatum was substantially underestimated. Both tracers proved suitable for revealing pharmacologically evoked changes in competition at D(2/3)-receptors in striatum of living mice.
Rominger
Axel
A
Department of Nuclear Medicine, Ludwig-Maximilian University, Munich, Germany. axel.rominger@med.uni-muenchen.de
Wagner
Erika
E
Mille
Erik
E
Böning
Guido
G
Esmaeilzadeh
Mouna
M
Wängler
Björn
B
Gildehaus
Franz-Josef
FJ
Nowak
Sebastian
S
Bruche
Ariane
A
Tatsch
Klaus
K
Bartenstein
Peter
P
Cumming
Paul
P
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D001931:Brain Mapping; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005462:Fluorine Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography / Q000379:methods; D011759:Pyrrolidines / Q000378:metabolism / Q000493:pharmacokinetics*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D012457:Salicylamides / Q000378:metabolism / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D014851:Wakefulness
D015259:Dopamine Agents; D005462:Fluorine Radioisotopes; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C100958:desmethoxyfallypride; D000661:Amphetamine; D004298:Dopamine