(11)C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain.

Abstract

The aim of this study was to explore the potential of a new selective dopamine transporter (DAT) compound as a radioligand for positron emission tomography (PET) examination of DAT in the human brain. The high affinity DAT compound N-(3-iodoprop-2 E-enyl)-2beta-carbomethoxy-3beta-(4-methylphenyl)nortropane (PE2I) was radiolabelled by the O-methylation approach and the binding was characterised by PET in cynomolgus monkeys and a healthy man. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography. O-methylation of the corresponding free acid precursor with [(11)C]methyl triflate gave high radiochemical yield (80%) and specific radioactivity (55 GBq/ microM). [(11)C]PE2I binding in cynomolgus monkeys was nine times higher in the striatum than in the cerebellum at peak equilibrium, which appeared 55-65 min after injection. Displacement and pretreatment measurements using unlabelled beta-CIT, GBR 12909, cocaine, citalopram and maprotiline confirmed that [(11)C]PE2I binds selectively to DAT. In a preliminary study in one human subject the radioactivity ratios of the striatum and substantia nigra to the cerebellum were 10 and 1.8, respectively, at peak equilibrium, which appeared at 40-50 min and 20 min, respectively, after injection. The fraction of the total radioactivity in monkey and human plasma representing unchanged [(11)C]PE2I was 15-20% at 40 min after injection. The present characterisation of binding in monkey and man suggests that [(11)C]PE2I is a suitable PET radioligand for quantitative regional examination of DAT in man.