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

Two novel radioligands for the serotonin transporter (SERT), [I-125]{3-[5-iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine ([I-125]-2) and S-[I-125]{3-[5-iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine ([I-125]-(S)-2) were synthesized in a Br/I-125 exchange reaction.

Binding experiments in rats yielded K-d values of 0.7 +/- 0.06 and 0.52 +/- 0.02nM for [I-125]-2 and [I-125]-(S)-2, respectively. One hour after intravenous injection of [I-125]-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 [I-125]-(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-[I-123]{3-[5-Iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl}- dimethylamine [I-123]-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 [I-123] ADAM.