title: Compensation for cranial spill-in into the cerebellum improves quantitation of striatal dopamine D₂/₃ receptors in rats with prolonged [¹⁸F]-DMFP infusions.
abstract: The condition of steady-state receptor binding in positron emission tomography (PET) studies is best obtained through the use of a bolus plus steady-infusion paradigm. This is a particularly important consideration in the context of in vivo competition studies, where a pharmacological challenge can be administered during the interval of steady-state ligand binding, as in the case of [¹¹C]-raclopride studies with amphetamine challenge. However, the short half-life of ¹¹C imposes limits on the practical duration of constant infusions. Therefore, we chose to test [¹⁸F]-DMFP as a tracer for dopamine D₂/₃ receptors in rat striatum in the paradigm. Using a conventional bolus injection, the [¹⁸F]-DMFP BP(ND) was 3.8 in striatum of anesthetized rats. When followed by a constant infusion, we obtained quasi-stable BP(ND) estimates of 4.5 within an interval of 45 min. During infusions lasting up to 4 h, BP(ND) declined progressively. This seemed due to the progressive spill-in of radioactivity from the cranium to the cerebellum reference region, despite optimized iterative reconstruction of the images. Therefore, we propose a new concept of compensation for this spill-in effect using pharmacokinetic considerations, without requiring high-resolution anatomical images. Challenge with amphetamine (1 and 4 mg/kg) evoked an ∼25% reduction in BP(ND) . There was no clear evidence of dose-dependence in the striatal-binding changes, despite the considerably greater physiological effect, as documented by ECG. Thus, the general applicability of the bolus plus infusion method with [¹⁸F]-DMFP for small animal studies is impeded by the substantial labeling of the cranium. The cranial uptake was linear, indicating first-order kinetics for the enzymatic defluorination of the tracer. Based on this phenomenon, we developed an analytic method compensating for the effects of progressive cranial labeling on the estimation of specific binding in striatum.
authors.affiliation: Department of Nuclear Medicine, University Hospital of the Ludwig-Maximilians University of Munich, Munich, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Mille
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
authors.forename: Axel
authors.initials: A
authors.lastname: Rominger
authors.forename: Christian
authors.initials: C
authors.lastname: La Fougère
authors.forename: Klaus
authors.initials: K
authors.lastname: Tatsch
authors.forename: Björn
authors.initials: B
authors.lastname: Wängler
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.forename: Guido
authors.initials: G
authors.lastname: Böning
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002531:Cerebellum / Q000000981:diagnostic imaging; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005260:Female; D005462:Fluorine Radioisotopes / Q000008:administration & dosage; D007263:Infusions, Parenteral; D017072:Neostriatum / Q000737:chemistry*; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000032:analysis*; D050637:Receptors, Dopamine D3 / Q000032:analysis*; D012457:Salicylamides / Q000008:administration & dosage; D012886:Skull / Q000000981:diagnostic imaging
chemical_list: D018765:Dopamine Uptake Inhibitors; D005462:Fluorine Radioisotopes; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D012457:Salicylamides; C100958:desmethoxyfallypride; D000661:Amphetamine