Synthesis and biological evaluation of 125I/123I‐labelled analogues of citalopram and escitalopram as potential radioligands for imaging of the serotonin transporter

Two novel radioligands for the serotonin transporter (SERT), [125I]{3-[5-iodo-1-[4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine ([125I]-2) and S-[125I]{3-[5-iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine ([125I]-(S)-2) were synthesized in a Br/125I exchange reaction. Binding experiments in rats yielded Kd values of 0.7 ± 0.06 and 0.52 ± 0.02 nM for [125I]-2 and [125I]-(S)-2, respectively. One hour after intravenous injection of [125I]-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 [125I]-(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-[123I]{3-[5-Iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine [123I]-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 [123I]ADAM. Copyright © 2010 John Wiley & Sons, Ltd.