title: Endogenous competition against binding of [(18)F]DMFP and [(18)F]fallypride to dopamine D(2/3) receptors in brain of living mouse.
abstract: 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.
authors: Department of Nuclear Medicine, Ludwig-Maximilian University, Munich, Germany. axel.rominger@med.uni-muenchen.de
authors: Axel
authors: A
authors: Rominger
authors: Erika
authors: E
authors: Wagner
authors: Erik
authors: E
authors: Mille
authors: Guido
authors: G
authors: Böning
authors: Mouna
authors: M
authors: Esmaeilzadeh
authors: Björn
authors: B
authors: Wängler
authors: Franz-Josef
authors: FJ
authors: Gildehaus
authors: Sebastian
authors: S
authors: Nowak
authors: Ariane
authors: A
authors: Bruche
authors: Klaus
authors: K
authors: Tatsch
authors: Peter
authors: P
authors: Bartenstein
authors: Paul
authors: P
authors: Cumming
mesh_terms: 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
chemical_list: D015259:Dopamine Agents; D005462:Fluorine Radioisotopes; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C100958:desmethoxyfallypride; D000661:Amphetamine; D004298:Dopamine