Synthesis, radiolabeling and preliminary in vivo evaluation of [ 18 F]FE-PE2I, a new probe for the dopamine transporter Magnus Schou a, * , Carsten Steiger a , Andrea Varrone a,b , Denis Guilloteau c , Christer Halldin a,b a Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Stockholm, Sweden b Stockholm Brain Institute, Stockholm, Sweden c Inserm U619, Université François Rabelais de Tours, France article info Article history: Received 27 November 2008 Revised 8 June 2009 Accepted 10 June 2009 Available online 13 June 2009 Keywords: PET Radioligand Dopamine transporter PE2I Tropane abstract A new dopamine transporter (DAT) ligand, (E)-N-(3-iodoprop-2-enyl)-2b-carbofluoroethoxy-3b-(4 0 - methyl-phenyl) nortropane (FE-PE2I, 6), derived from PE2I (1), was prepared and found to be a potent inhibitor of rodent DAT in vitro. Compound 6 was radiolabelled with fluorine-18 (t 1/2 = 109.8 min) for PET studies in monkeys. In vivo PET measurements showed a regional distribution in brain that corre- sponds to the known distribution of DAT. This binding was specific, reversible and the kinetics of [ 18 F]6 binding in brain were faster than for its lead compound, [ 11 C]1. The possible presence of a hydroxy- methyl-radiometabolite formed by oxidation in the 3b-benzylic position of [ 18 F]6 warrants further detailed evaluation of the metabolism of [ 18 F]6.[ 18 F]6 is a potential radioligand for imaging DATs in the human brain with PET. Ó 2009 Elsevier Ltd. All rights reserved. The dopaminergic (DA) reuptake system has since long been of central interest in relation to the pathophysiology of several neuro- psychiatric and neurodegenerative disorders as well as being a tar- get for drugs of abuse. Since the first positron emission tomography (PET) imaging study of the DA transporter (DAT) was conducted with [ 11 C]nomifensine in a hemi-parkinsonian pa- tient in 1987, 1 there have been several studies demonstrating the utility of DAT imaging for diagnostic applications. In addition, by using PET and [ 11 C]cocaine, knowledge has been gained in the bio-distribution and pharmacokinetics of this drug inside the living human brain that would not have been obtained otherwise. 2 Given the high concentration of DAT in brain (B max  200 pmol/ g in human putamen), 3 and that the binding potential (BP) of a PET radioligand is proportional to the concentration of target sites (BP = B max /K d ), the DAT is a relatively straight-forward target for radioligand development. Consequently, there are several success- ful examples of radioligands that enable DAT imaging in vivo, most of which have been derived from cocaine. PE2I (1, Fig. 1), FECNT (2), FECT (3) and b-CIT (4) are examples of such radioligands. 4–7 Although radioligands exist that have been used in clinical settings already, none considered optimal for the accurate quantification of DATs is available today. Problems associated with current radioli- gands are slow kinetics, lack of selectivity and/or problems with blood brain barrier (BBB) permeable radiometabolites. 4,8,9 In view of our aim to develop an improved DAT radioligand that could overcome some of the abovementioned problems, we decided to use 1 as a lead compound. Compound 1 has excellent pharmacological properties, being a potent (K i = 17 nM) and selec- tive DAT inhibitor. 10 In addition, [ 11 C]1 has been used for PET imag- ing of DATs in both pre-clinical and clinical settings, thereby showing the potential for analogs of [ 11 C]1 to be useful as PET imaging agents. However, two clear disadvantages also exist for 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.06.032 * Corresponding author. Present address: AstraZeneca R&D Södertälje, Medicinal Chemistry, S-151 85 Södertälje, Sweden. E-mail address: magnus.schou@astrazeneca.com (M. Schou). Figure 1. Structures of cocaine and some DAT radioligands developed for PET. 4–7 Bioorganic & Medicinal Chemistry Letters 19 (2009) 4843–4845 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl