Endogenous competition against binding of [18F]DMFP and [18F]fallypride to dopamine D2/3 receptors in brain of living mouse |
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Authors: | Axel Rominger Erika Wagner Erik Mille Guido Böning Mouna Esmaeilzadeh Björn Wängler Franz‐Josef Gildehaus Sebastian Nowak Ariane Bruche Klaus Tatsch Peter Bartenstein Paul Cumming |
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Affiliation: | 1. Department of Nuclear Medicine, Ludwig‐Maximilian University, Munich, Germany;2. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden;3. Department of Nuclear Medicine, Municipal Hospital Karlsruhe Inc., Karlsruhe, Germany |
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Abstract: | Aim . Molecular imaging studies with benzamide radioligands can reveal competition from endogenous binding at D2/3‐receptors in living brain. However, single photon emission computed tomography (SPECT) methods suffer from limited spatial resolution, and [11C]‐labeled ligands are only available at positron emission tomography (PET) research sites with cyclotron‐radiochemistry facilities, whereas [18F] can be transported, due to its longer physical half‐life. Therefore, we endeavored to characterize the vulnerabilities of the benzamide antagonist [18F]desmethoxyfallypride (DMFP) and its high‐affinity congener [18F]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 (BPND) were calculated using cerebellum as reference region. Results . With 90‐min circulation, DMFP BPND 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 BPND 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 BPND were unbiased, whereas FP BPND in striatum was substantially underestimated. Both tracers proved suitable for revealing pharmacologically evoked changes in competition at D2/3‐receptors in striatum of living mice. Synapse 64:313–322, 2010. © 2009 Wiley‐Liss, Inc. |
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Keywords: | DA D2/3 receptor desmethoxyfallypride ex vivo fallypride microPET mouse brain |
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