In vitro autoradiography and in vivo evaluation in cynomolgus monkey of [18F]FE-PE2I, a new dopamine transporter PET radioligand

• Published in: Synapse (New York, N.Y.) Vol. 63; no. 10; pp. 871 - 880
• Main Authors: Varrone, Andrea, Steiger, Carsten, Schou, Magnus, Takano, Akihiro, Finnema, Sjoerd J., Guilloteau, Denis, Gulyás, Balázs, Halldin, Christer
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2009
• Subjects: Animals; Autoradiography - methods; Binding, Competitive - drug effects; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Citalopram - pharmacology; Cynomolgus; Dopamine Plasma Membrane Transport Proteins - metabolism; dopamine transporter (DAT); Dopamine Uptake Inhibitors - pharmacology; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; kinetics; Macaca fascicularis; Metabolic Clearance Rate; metabolism; midbrain; Nortropanes - chemistry; Nortropanes - metabolism; Piperazines - pharmacology; Positron-Emission Tomography - methods; Postmortem Changes; Protein Binding - drug effects; Protein Binding - physiology; Radiopharmaceuticals - metabolism; Serotonin Uptake Inhibitors - pharmacology; substantia nigra; Tissue Distribution
• ISSN: 0887-4476; 1098-2396; 1098-2396
• DOI: 10.1002/syn.20670

This study evaluated the in vitro and in vivo characteristics of a new dopamine transporter (DAT) radioligand, [18F]fluoroethyl(FE)PE2I, by autoradiography from postmortem human brain and by positron emission tomography (PET) in three cynomolgus monkeys. In the autoradiography experiments, high [18F]FE‐PE2I accumulation was observed in caudate and putamen that was selectively abolished by GBR12909 or β‐CIT but not by maprotiline. High doses of citalopram (>5 μM) also inhibited [18F]FE‐PE2I binding in the striatum. In vitro Ki of the radioligand was 12 nM at rodent dopamine transporter. [18F]FE‐PE2I brain uptake measured by PET was ∼4–5% of the injected dose, with highest uptake in striatum followed by midbrain and thalamus, lower uptake in neocortex, and lowest in cerebellum. Peak specific binding in striatum was reached ∼40 min and in midbrain 20–30 min postinjection. The ratio‐to‐cerebellum was 7–10 in striatum and 1.5–2.3 in midbrain. BPND measured with simplified reference tissue method using the cerebellum as reference region was 4.5 in striatum and 0.6 in midbrain. No displacement was shown after citalopram or maprotiline administration, while GBR12909 decreased the binding in striatum and midbrain to the level of cerebellum. [18F]FE‐PE2I showed relatively fast elimination and metabolism with the presence of two metabolite peaks with similar retention time as the labeled metabolites of [11C]PE2I. [18F]FE‐PE2I showed in vivo selectivity for the DAT and compared with [11C]PE2I, it showed faster kinetics and earlier peak equilibrium. The potential influence of the two radiometabolites on PET quantification requires further evaluation. Synapse 63:871–880, 2009. © 2009 Wiley‐Liss, Inc.