Difficulties in Dopamine Transporter Radioligand PET Analysis: the Example of LBT-999 Using [18F] and [11C] Labelling

Background: LBT-999 (E)-N-(4-fluorobut-2-enyl)-2 beta-carbomethoxy-3 beta-(4'-tolyl)nortropane is a dopamine transporter (DAT) ligand. [F-18] LBT-999 was first labelled with carbon-11; we will now describe its in vivo behaviour in comparison to that of [C-11]LBT-999.Methods/Results: Positron emission tomography (PET) experiments (baboons) confirmed the high affinity/specificity of [F-18]LBT-999 for DAT. The brain regional distribution was in accordance with that of DAT. Pre-treatment with LBT-999 (I mg/kg iv), but not with desipramine, a norepinephrine (NET) antagonist, reduced the striatum-to-cerebellum ratio by 96%, confirming the specificity for DAT vs. NET. The parent compound decreased rapidly and represented 24.3 +/- 5.0% of plasma radioactivity at 30 min pi. Whole-body scans showed an important bone uptake of free fluorine following metabolism of [F-18]LBT-999. In the cerebellum and striatum, distribution volumes increased by 30-40% between 80 and 230 min, suggesting the polluting role of a radiometabolite(s). [C-11}LBT-999 exhibited a 40% higher standardized uptake value in the striata. This difference is likely due to N-dealkylation followed by [F-18]fluoride release. 2 beta-Carbomethoxy-3 beta-(4'-tolyl) nortropane is then formed, while [C-11]2 beta-carbomethoxy-3 beta-(4'-tolyl) nortropane is formed following injection of [C-11]LBT-999. This metabolite has high affinity for the DAT. In one specific PET experiment, intravenous injection of this metabolite induced a strong displacement of [F-18]LBT-999 in the striata, confirming that this metabolite readily crosses the blood-brain barrier (BBB) and binds to DAT.Conclusions: [F-18]LBT-999 is N-dealkylated in vivo to yield (I) a nonradioactive metabolite that crosses the BBB and has a high affinity for the DAT and (2) a [F-18]fluoro-alkyl chain which is further defluorinated. The temporal changes in distribution volumes are consistent with the accumulation of a radiometabolite(s) in the brain. Therefore, the quantification of DAT density with [F-18]LBT-999 is rather difficult. (C) 2012 Elsevier Inc. All rights reserved.