Synthesis and biological evaluation of 125 I/ 123 I-labelled analogues of citalopram and escitalopram as potential radioligands for imaging of the serotonin transporter Jacob Madsen, aÃy Betina Elfving, by Vibe G. Frokjaer, b Birgitte R. Kornum, b Gerda Thomsen, b Lars Martiny, c and Gitte M. Knudsen b Two novel radioligands for the serotonin transporter (SERT), [ 125 I]{3-[5-iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran- 1-yl]-propyl}-dimethylamine ([ 125 I]-2) and S-[ 125 I]{3-[5-iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}- dimethylamine ([ 125 I]-(S)-2) were synthesized in a Br/ 125 I exchange reaction. Binding experiments in rats yielded K d values of 0.770.06 and 0.5270.02 nM for [ 125 I]-2 and [ 125 I]-(S)-2, respectively. One hour after intravenous injection of [ 125 I]-2, 0.34% of the injected dose had accumulated in the brain. The highest hypothalamus-to-cerebellum ratio was reached 2 h after injection of [ 125 I]-(S)-2 and amounted to 2.4. Pre-treatment experiments with paroxetine resulted in effective reduction of the target-to-cerebellum ratios. The corresponding iodine-123 labelled compound S-[ 123 I]{3-[5-Iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]- propyl}-dimethylamine [ 123 I]-S-2 was investigated in a pig single photon emission computed tomography (SPECT) study. Between 60 and 110 min after IV injection, the midbrain-to-cerebellum ratio was 1.2. However, the uptake did not differ between high-density and medium-density regions questioning the feasibility of the radioligand in imaging cortical SERT distribution in vivo. These data suggest that the iodine-labelled derivatives of citalopram and escitalopram are not superior to another SPECT tracer for the SERT, namely [ 123 I]ADAM. Keywords: serotonin transporter; escitalopram; SPECT; iodine labelling Introduction Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are non-invasive techniques, which can be applied for in vivo investigations of biological processes in humans using appropriate radioligands. 1 Radio- ligands are labelled with radionuclides such as 11 C (t 1/2 = 20.4 min) or 18 F(t 1/2 = 109 min) for PET and 99m Tc (t 1/2 = 6.0 h) or 123 I(t 1/2 = 13.1 h) for SPECT. The advantages of SPECT are first of all lower costs and the more facile handling of often longer lived SPECT radioligands, whereas PET is a quantitative method and the use of radioligands labelled with short-lived isotopes allow multiple investigations in the same subject on the same day. The serotonin transporter (SERT) is believed to play a central role in mental disorders arising from disturbances in the serotonin system. 2 There are now several PET-radioligands available for imaging of the SERT in the living human brain, especially the diarylsulfides [ 11 C]DASB, 3,4 [ 11 C]MADAM, 5,6 and more recently [ 11 C]HOMADAM. 7,8 For SPECT imaging, iodinated diarylsulfides such as [ 123 I]ODAM, [ 123 I]IDAM and [ 123 I]ADAM have all been suggested as candidates for visualization of the SERT in vivo. 9–11 Within this series of compounds, [ 123 I]ADAM is the most promising candidate as a SPECT radioligand and has been evaluated in humans. 12–14 So far, [ 123 I]ADAM remains the only available SPECT radioligand for human studies. However, robust quantification of cerebral SERT requires a 120-min data acquisition and another potential disadvantage with this radioligand is the presence of a lipophilic metabolite seen in some subjects. 14 In this paper, we report the radiolabelling and initial biological studies of iodinated derivatives of the selective serotonin reuptake inhibitors (SSRIs), citalopram and escitalopram. The novel radioligands [ 125 I]f3-[5-iodo-1-(4-fluorophenyl)-1,3-dihy- droisobenzofuran-1-yl]-propylg-dimethylamine ([ 125 I]-2) and 185 a PET and Cyclotron Unit 3982, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark b Neurobiology Research Unit 9201, Copenhagen University Hospital, Blegdams- vej 9, 2100 Copenhagen Ø, Denmark c Radiation Research Division, Risø DTU, Frederiksborgvej 399, 4000 Roskilde, Denmark *Correspondence to: Jacob Madsen, PET and Cyclotron Unit 3982, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. E-mail: jacob.madsen@rh.regionh.dk y B. E. and J. M. have contributed equally to this work. Research Article Received 8 December 2009, Revised 26 July 2010, Accepted 12 September 2010 Published online 30 November 2010 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jlcr.1841 J. Label Compd. Radiopharm 2011, 54 185–190 Copyright r 2010 John Wiley & Sons, Ltd.