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

摘要

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 0.7 +- 0.06 and 0.52 +-0.02 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-lodo-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 110min 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.